Patients, Families & General Public Ask the Mito DocSM


Information contained in Ask the Mito DocSM is for informational and educational purposes only. Such information is not intended to replace, and should not be interpreted or relied upon, as professional advice, whether medical or otherwise.

Keep in mind that we receive many questions and may not be able to answer them all. Please search here for responses to other questions to make sure your question has not already been answered.

Please note: As a rule, the doctors are not comfortable with diagnosing or treating a patient via this forum. They prefer questions that are more general in nature and could be applicable to a number of mito patients. We  also ask that you please limit your questions to three per year.

Submitting questions to Ask the Mito DocSM is a benefit of UMDF membership. If you are a member and would like to submit a question, please email your full name, your User ID and password to If you would like more information on becoming a member of UMDF, please email us at or join online by clicking here.


Q: Our  2 1/2 year old daughter has a suspected mitochondrial disease. ( we are just waiting for the final biopsy results.)   She has had hypotonia and laxity in the joints along with increased ammonia, an elevated lactate to pyuvate ratio, problems with her bowel, trouble recovering from any illness, migraines, etc.  
For the past two weeks, I have noticed as I try to pick her up, her upper back seems to "separate".  Can the back become "lax?”  And if so, what kind of test and therapies should we pursue?

A: Many children with hypotonia, or low muscle tone, will have associated hypermobility/loose joints.  When children have significant hypotonia, especially affecting the truncal muscles and muscles close to the body (proximal muscles such as shoulder and hip areas), they will have difficulty controlling posture and be unable to sit or sit in a forward hunched position.  Picking up a child under the arms will result in a "slip-through" when held up vertically.  The back can be a typical location to notice the hypotonia, and weakness can make the hypotonia more prominent.
I would schedule an appointment to have your child examined by her PCP and/or neurologist to see if any other testing needs to be done.  If the problem is due to hypotonia/weakness, then physical therapy can be aimed at core strengthening and there is additional supportive equipment that can be used to support truncal hypotonia.

Answered by: Amy C. Goldstein, MD

Q: I am a parent with mito disease and I have a child with it as well.  Are mitochondrial researchers looking into epigenetics; does this show promise in regard to treatment for Mitochondrial Cytopathies?

A: This is a complicated scientific question. Before we learned about mitochondrial diseases we used to think that inheritance was just about the DNA sequence of the genes in the nucleus of each cell, half of which we inherit from mom and half from dad. Understanding that many mitochondrial diseases were caused by changes in the sequence of genes located in the mitochondria was something of a shock to geneticists. Likewise the field of epigenetics has been another surprise and has received much attention in recent years. Epigenetics is basically about fine tuning the expression of genes by marking the DNA sequence directly or marking the histone protein coat that surrounds genes in the nucleus. These marks affect whether or not the gene can produce its regular product and in some cases the marking can be influenced by environmental factors. Mitochondrial DNA genes don't appear to be directly affected by epigenetic marks, because they lack the specific DNA sequences (known as "CpG islands") and the protein coat to which epigenetic marks are applied. However, most mitochondrial proteins are coded for by genes in the nucleus, including ones involved in maintenance and expression of mitochondrial DNA genes. So it is certainly possible, and indeed likely, that epigenetics will influence some aspects of mitochondrial function. I am not aware of any major findings from mitochondrial researchers working on epigenetics nor of any obvious applications of epigenetics in terms of treating mitochondrial diseases. However, these are rapidly moving fields and that may reflect my ignorance and limited imagination. I should mention that there are many researchers around the world working on a wide range of approaches to improving treatment of mitochondrial diseases. UMDF fundraising has been important in encouraging researchers to pursue innovative projects in this area, because they are often difficult to get funded by Government agencies, which tend to be conservative in making funding decisions.

Answered by: David Thorburn, PhD

Q: My daughter, age 6, was recently diagnosed with an OXPHOS defect 1 by muscle biopsy. My question is: she has severe constipation; nothing has helped including Miralax, Milk of Mag, etc. I frequently have to give her enemas. She had urinary reflux that has resolved, although she wets during the day as well as at night. In the past she was dry during the day.  She also frequently soils her pants. Her stools are usually soft to very soft.  Her urologist mentioned a MACE procedure. Is this appropriate? Is there anything else we can try? I am very concerned about this problem continuing when she enters regular school.
Dysmotility seems to run in our family. She has an aunt who had to have a large portion of her colon removed as an adult.  Also, all GI studies have been normal.


A: The MACE procedure is used to correct urinary and bladder incontinence in patients with a neurologic etiology. I don’t know of it having been used specifically in the context of mitochondrial disease but it certainly qualifies as a neurogenic cause and seems reasonable to consider. As always, the family should discuss this in detail with their metabolic and GI doctors before pursuing a surgical correction. I would proceed to surgery only when all medical options have been exhausted.

Answered by: Jerry Vockley, M.D., Ph.D.

Q: My daughter has blood work documenting low carnitine, low CoQ10, elevated lactate, elevated lactate:pyruvate level, normal fibroblast study, and muscle accumulation of c-2, c-15, c-16 and c-18 from muscle biposy.  She also has a significant mutation Collagen VI indicating Bethlehem's Myopathy.  Her clinical signs include a history of FTT, GI dysmotility-reflux, intermittent constipation, early satiety, muscle pain, muscle weakness, some muscle cramping, headaches, reactive airway disease, sleep maintenance insomnia, low ferritin levels, and delayed bone age.  She has frequent infections and difficulty getting over even minor illnesses although her immune function is fine. What is your take on this?  Is mito or FOD more likely?  Should we pursue more diagnostics?


A: We now know that many other diseases, medications and genetic conditions can secondarily impair mitochondrial function - and that biochemical testing such as blood/urine carnitine or lactate levels, and tissue enzyme analysis can be abnormal in these cases as well.
One of the challenges in the field is trying to exclude 'secondary' causes of mitochondrial symptoms.
In your daughter's case, if Bethlehem myopathy (BM) has been genetically diagnosed, her other symptoms may be due to secondary impairment of mitochondrial function; in mouse models, BM is known to affect mitochondrial structure and function.  There is also the possibility of her also having a 'mild' mutation affecting mitochondrial function that has not been identified - one that would not have caused problems if she did not have BM.
Treatment of mitochondrial symptoms, regardless of the cause, is unfortunately the same - and if these medications/supplements are helping her, it is worth continuing them.
If further evaluation is pursued, I would consider a focused genetic evaluation, especially of genes affecting mitochondrial fission/fusion, since this process may be stressed by BM  (though we have just started to learn about BM affecting mitochondrial function).

Answered by: Sumit Parikh, MD

Q: Our 12 yr old son son was diagnosed with CPEO (plus KSS) Syndrome last year when we were living in Houston, Texas. We have recently moved to the Richmond, Virginia area and have not had an appointment with a Dr. here yet. At our son's last Audiologist appointment, he had had a further loss in his hearing and his word repetition test. The audiologist said that he now could qualify for chochlear implants. My husband and I are starting to research this as an option. Our question: Is there any research/data involving the failure/success rate for Mito patients having coclear implants? And could you offer your opinion?


A: There are a handful of cases in the literature in which patients with mitochondrial disorders and sensorineural deafness successfully received cochlear implants, including patients with Kearns Sayre, with improvement in quality of life. Typically the successful cases are reported; I don't know about any adverse outcomes.  Because the numbers are small, it is difficult to generalize and perhaps a registry should be maintained.  In many patients with SNHL as part of a mitochondrial cytopathy, there is a cochlear abnormality, so in theory, a Cochlear implant appears a reasonable approach.  One should be aware, however, as to the special risks anesthesia may pose in patients with mitochondrial conditions, and this should be a major consideration in the decision to move forward. Information about anesthesia, induction medications and IV solutions as they pertain to patients with mitochondrial disorders undergoing surgical procedures may be found on the UMDF website.

Answered by: Andrea Gropman, MD

Q: I have a great neurologist who is seeking to diagnose me accurately.  He, with the help a neurogenecist, have done minimal genetic tests (6 DNA for MELAS and 5 for MERRF) with only 1438A>G showing up as an abnormality.  I have had a negative muscle biopsy for ragged red fibers but several abnormal blood tests for organic acids including pyruvic acid / lactic acid ratio and possible lactic acid which were questionable due to the blood draw.  My MRS showed increased lactic acid.  I have a brain lesion (maybe another couple vague plaques). I have the stroke-like seizures, spinal headache with nausea, balance issues / ataxia, dizziness, breathing difficulties, muscle pain and tachycardia and other symptoms without "normal" cause per my specialists, with memory issues for over 6 + years.  Because my symptoms are not meeting all criteria of a specific disorder, I am yet undiagnosed.  My insurance company does not cover a clinic which has more familiarity with mito dysfunction and we are close to bankrupt so further debt would be difficult.  I am 50 and fearful to go to one of our ER's when symptoms are either overly painful or "scary" because of misdiagnosis or given treatment which has been poorly thought out.  I'm not sure until I'm definitively diagnosed how to proceed when the stroke or stroke-like seizures occur or become too dizzy and nauseated to stand or even sit for days at a time.   I have Celiac's disease in remission for over 4 years now as well which doesn't make it any easier.  How is it best to determine whether going to an ER is necessary and how do I pick the best ER for my care?


A: I am sorry to hear about your symptoms and understand your dilemma.  Unfortunately, it may be difficult to find an ER with any expertise in managing an individual who may have an underlying mitochondrial disorder.  However, it seems you have an excellent neurologist who has the potential to serve as a sounding board regarding local ER care.  Your neurologist should also help guide you in determining when it would be appropriate to seek immediate medical attention or even hospitalization.  We have found it useful for our patients to carry emergency letters detailing a plan of care  in the event of an emergency.  It would be important that you discuss such a plan with your neurologist or neurogeneticist, who should be able to help you interact with a local ER and give them a "heads up" in case you need emergency care.  The doctors who have cared for you already know you best, so make use of their expertise.

Answered by: Gregory M. Enns, M.B., Ch.B. 

Q: I'm a 50 year old male with diagnosed MERRF #8344(8249 RFLP) and LHON #13708 through blood tests.  My questions are: Can Mitochondrial problems cause a deficiency in Immunoglobulin Igm (low level)? Can Mito cause Folliculitis?
Also, lately I have been extremely tired, total mental/physical fatigue with no energy, however, other times, I am full of energy and extremely hyper.  Usually these episodes happen every other day--from fatigue to hyperness--full of energy.  I noticed that if I'm on my feet for 8/10 hours one day, then, the following day is where extreme fatigue sets in.  Could this be a cause from Mito?  I have other problems not mentioned here, but this fatigue is the worst and most worrisome.  Please note:  I am aware that other than a Mito problem, there are other ailments that could be causing these symptoms, but am wondering in the absence of this, could Mito also be playing a role.


A: Mitochondria are present in all organs and therefore can potentially affect all organ systems.  Although not typically associated with mitochondrial disorders, a deficiency of immune function can be seen.  The immunodeficiency could then pre-dispose to infections, such as folliculitis.
Most patients with mitochondrial disorders experience episodic fatigue.  It is common for patients to become fatigued after activity and fatigue can set in many hours after the activity has occurred.  Many patients report improvement in their fatigue after beginning supplements such as CoEnzyme Q10 or Carnitine.

Answered By: Mary Kay Koenig, MD

Q: I have read the article on diet and supplements but is it general or specific to any mitochondrial diseases?  I have NARP and would like to know if there is a vitamin cocktail specifically for every form of mito disease(s). 


A: The article on diet and supplements (UMDF Mitochondrial News Vol. 9, Issue 1, Winter 2004) provides a broad overview of therapies for all mitochondrial diseases including NARP. Specific supplements are recommended for some mitochondrial diseases. For example, succinate is a substrate for enzyme complex II of the mitochondrial respiratory chain and therefore is theoretically most beneficial for patients with complex I deficiency because succinate will by-pass the enzymatic block. L-arginine produces vasodilatation, which may be beneficial in MELAS. Coenzyme Q10 and carnitine are generally recommended to all patients with mitochondrial disease, but are most beneficial for patients with specific deficiency of either compound. NARP is due to mitochondrial DNA mutations encoding a subunit of complex V. A recent publication (Baracca et al. Biochim Biophys Acta 2007;1767:913-919) noted that the most common NARP mutations  (m.8993T>G and m.8993T>C) cause overproduction of reactive oxygen species; therefore, anti-oxidant therapy may be particularly useful for this disease.

Answered By: Michio Hirano, MD

Q: Is there any reason why a person with Mitochondrial Disease or someone in the inherited line should not give blood at a Blood Drive?


A: I think the easy answer is that patients with a mitochondrial disease should not give blood products. However, I think there are situations where it might be okay. Let’s say that you know you have a mitochondrial DNA mutation. Red blood cells do not have mitochondria, so if there was an extreme blood shortage, then donating just red blood cells would be theoretically okay. However, let’s suppose that you were a carrier of some mitochondrial disease. It would depend on what type of carrier. Figuring that a carrier does not have the disease and the gene is nuclear and you are heterozygotic for the mutant allele (recessive disease), it should be fine to give blood.

Answered by: Russell P. Saneto, DO, PhD

Q: I am a 33-year old female that has, through muscle biopsy, been diagnosed with CPEO/KSS. In addition, through chest lymph node biopsy, I have been diagnosed with Sarcoidosis, Stage II (chest and lungs). I also have a herniated disc in L5-S1. I have been having increased back pain now for three years which I do not think is caused by the herniated disk. I used to be able to vacuum, etc but now I am very careful not to lift anything. The real problem began with pain in my lower back and hips and thighs at night while sleeping. It would seem like they were tight or locked up and would take me getting out of bed to make is stop. Sometimes the tightening feeling would last for days in these areas. After a year or so, I did get a new mattress, which helped with this pain, but then the pain went a new direction. In the last six months are so the pain has been mainly on my left side. There is also stomach pain associated with the back pain. I have had a gastric emptying test in which I received results linking to gastroparesis. The pain increases the longer I lay down and the exact location is determined by what position I am in. I do not have any pain that shoots down my legs and I have had a back MRI a year ago and recent back X-rays that were normal. It is frustrating to deal with this and not know why. I am concerning that I may be getting worse in some way as I know have pain in my arms/hands as well. It appeared that it was carpal tunnel but after trying the arm braces with no success, I am not sure. I also have some sporadic sharp pains in different areas of my body. Could this be mitochondrial-related?


A: Pain can certainly be mito related, especially in the form of neuropathic pain or a neuropathy.  Back pain can certainly be due to a herniated disc, but it also seems to be somewhat GI related.  Do you have slow motility elsewhere and if so, could some of the pain be related to constipation?  Are you on any medication for pain or for the gastroparesis?  Are you on any medication for the sarcoidosis (anti-inflammatory) and if so, has that made any difference?  I would attempt to look into any aggravating factors including other GI issues, and then try to see a doctor who will treat the pain with neuropathic pain medication.  This could be an orthopedist, a neurologist, or a neurosurgeon, or a pain specialist.  I would also look into physical therapy to help with the pain and also with the cramps/spasms that are causing the locking-up.  Sometimes a muscle relaxant is also helpful.

Answered by: Amy C. Goldstein, MD

Q: My son was diagnosed with Mito Complex III Deficiency in 1991.  He is an adult now & has developed seizures which cannot be controlled.  He has, on average, 1-2 grand mal seizures a week, each one more violent & lasting longer than the one before;  the last one was 45 minutes.  In addition, he seems to have some sort of problem with heat (temps over 65 degrees) and fluorescent lighting.  In these cases his body goes rigid, followed by shaking on the right side of his body.  So we do everything possible to avoid these situations.
I am more concerned with the grand mal seizures as they seem to be getting worse.  He is taking Dilantin 130 mg AM, 200 mg PM, Lamictal 300mg am & pm, Topomax 25mg am & pm and Valium 2mg am & pm.  We have also done the EEG monitoring both in hospital & ambulatory but these are the only times there have been no seizures.
I welcome any suggestions about what to do to stop the grand mal seizures.  Not being controlled puts him at risk not only at home but anytime we leave the house as they are so violent, keeping him from falling from his wheelchair is almost impossible.  We stay home except for medical appointments.


A: I am sorry to hear about your son. Treating seizures can be extremely difficult in patients with mitochondrial disease, but I don’t need to tell you what you already know. Treating seizures with medications is very much an art and dependent on the experience of the person ordering the medications. Those of us treating epilepsy have our own bias and therefore treatment varies from physician to physician. Suggestions on what seizure medication(s) to use will therefore vary between physicians. So, I will not make suggestions but indicate some principles that I use in treating seizures. First using enzyme-inducing medications (such as Dilantin) makes using many other medications more difficult as enzyme-inducing medications can alter the amount of other drugs in the blood. So, levels can wax and wane and keeping track of their levels can really be a problem. However, these enzyme-inducing medications have a long history and most of us know how to use them in relationship to other medications that we use. Strict serum levels are therefore needed to keep track of medication levels. With the exception of Clobazam (not available in the United States) I do not like to use chronic benzodiazepine dosing (valium, ativan, Klonopin, etc) and reserve them for aborting break-through seizures. What are you using to stop the longer seizures, those over 3-5 minutes? Most feel that having a rescue medication for longer seizures is critical and needed. Most of the literature suggests that the use of 3 or more medications is probably no better than 2 medications. After trying more than 2 – 3 medications, and seizures continue, then the likelihood of seizure freedom with medication is small, but not zero. Most of us try every medication and combination before we cry “uncle”, but you should be aware that complete seizure freedom is unlikely at that point.
So, working with your epileptologist, use the 2 most efficacious medications that have worked in the past or trial medications to try and find the two that stop the most seizures and are tolerated by your son. Use an abortive medication to stop the longer seizures, those greater than 3 – 5 minutes. If there is no single medication (such as Diastat) then figure out multiple dosing or emergency room plans when seizures are long, such as diastat to be given after 3 – 5 minutes of a seizure, then another dose after the next 10 minutes if seizures are not beginning to stop, calling 911 and when the EMS team gets there then another round of a benzodiazepine such as ativan or valium while transport to the ED.
A quick word on VNS (vagus nerve stimulator): We have implanted approximately 10 children with mitochondrial disease and seizures with the VNS and all have not responded (response is defined as > 50% reduction in seizures). We reported 5 of these children in an article. Due to small numbers, we could not tell if the duration of seizures was affected but clearly the frequency of seizures was not altered (at least myoclonic seizures). Whether the VNS works in patients with mitochondrial disease is not fully known, but from our data it doesn’t seem promising. I can not tell you not to consider implantation of VNS, but I would not expect a robust response.
There are also several small studies and case reports suggesting that the ketogenic diet may help in mitochondrial patients with intractable epilepsy. Once fatty oxidation disorders have been ruled out, this may be helpful. Tolerating the ketogenic diet is the main question, as many patients cannot tolerate the rigid adherence to high fats. This tact has to be fully discussed with your physician and a capable dietitian. Modification of the ketogenic diet such as the low glycemic and Atkins diet may be an alternative but data is lacking in the mitochondrial disease patient.

Answered by: Russell P. Saneto, DO, PhD  

Q: I have been taking 600 mg of Coenzyme Q10 for about 6 months, along with other commonly prescribed supplements (L-Carnitine, Alpha Lipoic Acid, D-Ribose, Creatine & other Vitamins) in smaller doses. So far I have seen, what I perceive to be, very little benefit, i.e., my muscle strength continues to deteriorate. In general, is it advisable to increase dosages of any of these supplements? (I know you probably need more information from me in order to properly respond to my question), but I thought I'd start off this way.


A: First, there is nothing harmful with the supplements that you are ingesting each day, including coenzyme Q10, L-carnitine, alpha-lipoic acid, D-ribose and creatine.  The only potentially harmful vitamins for adults include vitamin B6, vitamin A and vitamin D.  Having said this, any of these organic substances probably can have some side effect or induce complications in very high doses.  The most important question is whether they are, or can in higher doses, help your condition that involves muscle strength.  Unfortunately, it appears that not all patients with mitochondrial diseases will benefit from these supplements.  Some physicians believe that “vitamin megadosing” may only be helpful for a certain fraction of patients because of their underlying genetic or constitutional makeup.  The truth is we just don’t have the answers to these important questions because the proper prospective, well-controlled clinical studies have never been performed to satisfaction.  My suggestion to you, and to all patients with mitochondrial diseases, is to work carefully with your mitochondrial specialist who should be prescribing these vitamins and vitamin-like substances.  Together, you may agree that the doses of one or more of these medicinal agents may be increased or even one or more new ones added, but the physician needs to carefully guide you in the dosing, while at the same time keeping careful notes and records to document when a vitamin dosing change occurs and how it effects your clinical condition over a week, a month and longer.  Please remember that what is good for one person may not be good for another!

Answered by: Gerard Berry, MD

Q: My diagnosis has been lupus overlap, or undifferentiated connective tissue disease, but my doctors just call it lupus.  I have muscle weakness, ataxia, and difficulty with short term memory, talking (my tongue gets painful and weak) and walking which is worse when I'm fatigued.   I'm especially frustrated with not being able to think when I'm talking and I forget things that just happened.   I've had a TIA and couldn't speak, and have a condition called Chronic Thrombotic Angiopathy found in my kidneys. Can you explain the difference between Mitochondrial dysfunction and Mitochondrial Disease?  Also can a muscle biopsy diagnose mitochondrial dysfunction?  I have had a positive blood and urine with certain organic acids which can indicate mitochondrial disease and now my neurologist wants to do a muscle biopsy.  I also have had heart (pericarditis, lung, kidney, and small bowel obstructions, etc...) I'm a 41 year old female.


A: We think of mitochondrial disease as a process that produces abnormal signs and symptoms due to a primary mitochondrial abnormality. That means that it is the mitochondria themselves that are abnormal and dysfunction to cause the disease. An example would be the mtDNA mutation at position 8993, which can cause Leigh syndrome. Here the primary defect is within the mitochondria themselves and produce a variety of symptoms. Mitochondria can become dysfunctional as a secondary process in other diseases. For instance, in some patients with HIV, some of the drugs used to treat the disease can produce a secondary mitochondrial dysfunction and they can get muscle weakness, abnormal fat distribution and some kidney involvement. The problem is not that HIV is a primary mitochondrial disease, but that the treatment is affecting the way the mitochondria function.  Unfortunately, there is no one single test that fully defines whether a person has a primary mitochondrial disease. We usually combine abnormal laboratory tests, clinical symptoms, muscle biopsy (most of the time but not always), and Neuroimaging to make the diagnosis. Certainly, a primary mitochondrial disease can mimic another disease and visa versa. Sometimes it takes a great deal of information and medical acumen to tell the difference. So, a muscle biopsy by itself would not tell you if you have a primary mitochondrial disease. Your neurologist would have to weigh all the evidence to make a decision about what the proper diagnosis of you condition might be.

Answered by: Russ Saneto, DO, PhD 

Q: My 20 year old daughter is thought clinically to have a mitochondrial disorder due to a POLG gene mutation despite tests for the 3 most common autosomal recessive mutations returning negative (A467T, W748S, G848S). Her condition is presently stable further sequencing of her POLG gene is being carried out. Do abnormalities of this gene lead to too few mitochondria per cell, or a normal number of impaired mitochondria per cell, or both? And, can testing for their number  function be carried out to see if she's improving?


A: Complete sequencing of POLG is possible and that will give a definitive answer to your daughter's problems.  POLG is a gene which generates the mitochondrial polymerase - this enzyme is involved in replicating the mitochondrial DNA. Defects of the polymerase can cause either a low amount of mitochondrial DNA (this is particularly common in young children) or damaged mitochondria. This is more common in adults.
Testing after diagnosis is uncommon because the tests themselves can be quite variable and therefore would give unreliable results in terms of clinical situation.

Answered by: Douglass M. Turnbull, MD, PhD

Q: I have been diagnosed with Systemic Lupus and how been suffering from this for many years. Now at the age of 40 I am having more health problems with difficulty with balance, thinking, fatigue, and digestive problems. I have been positive for a urine and blood test which can indicate mitochondrial disease. Is it likely to have both lupus and mitochondrial disease? I have had joint pains, kidney problems, blood clots (thrombotic angiopathy in my kidneys), pericarditis, etc... these are some of my lupus problems. Can lupus cause mitochondrial disease?


A: I am sorry to hear about your Lupus (SLE). I am assuming that your SLE was properly diagnosed and the labs were convincing. It is possible that you might have a secondary mitochondrial dysfunction, but I would be very tentative and would not give you a diagnosis of also having a mitochondrial disease based on what you have told me. There are some disorders, especially those that have multisystem involvement that can mimic a mitochondrial disease by lab analysis but not be a primary mitochondrial disease. That is because the primary disorder, in your case SLE, may be secondarily altering mitochondrial function. Therefore the labs would look like a mitochondrial disease and some of your symptoms may look like a mitochondrial disease. However, I don't think anyone would give the diagnosis of SLE and mitochondrial disease. Most likely your worsening condition is the result of your SLE rather than a co-present mitochondrial disease.

Answered by: Russell Saneto, DO, PhD

Q: My adult daughter, 39 was diagnosed with Mito 2 years ago via a muscle biopsy following years of several misdiagnosis of symptoms starting in 1991, including MLD, bipolar, Atypical PPMS and dementia. She has an abnormal brain scan which indicates slowly increasing atrophy. I've read and seen a lot about homeopathic and alternative supplements to help with some symptoms. She is currently on 600 mg coq10, 660 mg of Lcarnitine and 15 mg of zyprexa, 50 mg clomipramine/Anafranil plus 500 mg calcium +D and a multi vitamin. She has severe urinary incontinence, tremors, mild slurred speech, impaired cognitive ability and dementia. My son was diagnosed 6 years ago with typical RRMS and is living a fairly full life with little disability as a husband and father of 3 active young boys ages 11 - 17. My son is 37 and injects beta-seron every other day. He's recently found some relief from symptoms by drinking his own generated "silver water." QUESTION: We are wondering if it would be harmful for my daughter to drink "silver water" or if it might provide her some relief from some of the symptoms she's experiencing. I'm thinking mostly of the tremors and incontinence or the muscle weakness. She also lists substantially to the left. It goes without saying, any information you can provide in addition to the question here would be greatly appreciated. We've not pursued trying to determine exactly what type of Mito we're dealing with but several of the complexes are affected. There is no evidence of Mito in the family history of which we are aware. Thank you for this opportunity to find answers.


A: In regards to your question about 'silver water', also known as "colloidal silver," we have little Western scientific evidence that it is effective for any disease/condition. Thus we do not know if it will help in cases of mitochondrial disease. While some alternative, non-Western medicine treatment approaches are worth a try, there have been a few that are harmful, including IV chelation, hyperbaric oxygen, and 'silver water.' Some of these treatments have led to deaths, and thus the FDA has attempted to stop their use.
Since this therapy involves giving a certain quantity of silver metal - complications have occurred including a condition called argyria - where silver deposits in various organs, and the eyes leading to problems with those body parts (liver dysfunction, cataracts). In fact, silver was used as a preservative in many products before the 1970's but was removed specifically due to this reason.
Medical studies of the products commercially available have shown:
1) bacterial contamination of most of the solutions sold (one of the benefits touted by makers of this therapy is silver's anti-bacterial effects).
2) varying amounts of too much or too little silver in the product - and not what is listed on the package
While many of our patients will attempt alternative medications, silver water is not one we can recommend.

Answered by: Sumit Parikh, MD

Q: I was diagnosed with Mitochondrial Myopathy in 1988. In September 2007 I developed a rash that baffled several doctors. After a punch biopsy in November, I was diagnosed with with Leukocytoclastic Vasculitis. I have an appointment with the Johns Hopkins Vascuylitis center in two weeks.Is there any known connection between Mitochondrial Myopathy and Leukocytolastic Vasculitis?


A: I have never heard of an association between Leukoclastic Vasculitis and "mitochondrial myopathy". In addition, and more in general, dermatological manifestations are rare in mitochondrial diseases. However, I note that the pathogenesis of Leukocytoclastic Vasculitis is still obscure in most cases, so a relationship with mitochondrial dysfunction in your case is conceivable (and interesting). In this respect, it would be important to have a more precise diagnosis than "mitochondrial myopathy": is the biochemical or molecular cause of your mitochondrial disease known? Is it a pure myopathy or a more generalized disease? Any way, the colleagues at Hopkins will undoubtedly look into this connection.

Answered by: Salvatore DiMauro, MD

Q: I am 60 years old and have recently been diagnosised with a Complex I deficiency Mitochondrial disease. My foot doctor put me on 250mg of Terbinafine tablets, (Lamsil), for toe nail fungus. I have to take one pill a day for 3 months. I was wondering if it was safe to take these pills since I have this Mitochondrial disease.


A: Terbinafine is an antifungal agent commonly used to treat nail infections. Rare cases of liver failure of unknown origin and decreased white blood cell counts have been reported, but most adverse reactions consist of common complaints or findings, such as headache, gastrointestinal disturbance, rashes and liver enzyme abnormalities (but not liver failure). There is a single report in the medical literature of terbinafine inducing mitochondrial dysfunction in a leukemia cell line, but to my knowledge no reports of using this medication in patients who have mitochondrial disease.  You should probably not take this medication if you have significant liver disease, kidney disease, immunodeficiency, or other serious disorder. In short, it may be safe to use, but given the reactions described above you should discuss the possibility of monitoring your complete blood count and liver function (or any other areas of concern depending on your medical history) with your physician.  In addition, your physician should also consider the possible effects on any other medications you are taking, because some drugs interact with terbinafine.

Answered by: Greg Enns, MB, ChB

Q: My 2 1/2 year old daughter was diagnosed about a year ago with mitochondrial disease, complex IV, COX deficiency. She has intractable seizures. She has been on most of the available medications and is currently on the ketogenic diet and has been for about 6 weeks. She had a very severe reaction to the intiation of the diet, including vomiting, diarrhea and extreme lethargy. She is on a 4:1:1 ratio. She had a complete amino acid and organic acid profile done previously that did not show any problems. She is eating again, but has not returned to normal cognitively and her seizures have not decreased. Her primary seizure type is tonic-clonic, but she appears to just sit and stare most of the day since the initiation of the diet. I do not think she is seizing during these times because eventually she will respond to her name, but very slowly. We have found that the more fluids she consumes the better she seems to feel and the less seizures she has. Everytime she is admitted to the hospital and put on IV fluids her seizures stop. If we give her a lot to drink during the day and her diapers are really wet her seizures are decreased later that day and the next. Her seizures stopped for an entire week when we went to visit family out of state. She went swimming 2-3 times a day everyday. While she was in the pool she was constantly drinking the pool water. Is there any type of relationship between fluid intake and reduced seizures in kids with mitochondrial disease?


A: I am sorry to hear about your daughter. The reaction your daughter had with diet initiation is not uncommon. This is why we like to introduce the diet while the patient is in the hospital. Is your daughter taking the ketocal formula or is the diet non-ketocal? We have found that depending on the patient and the beta hydroxybutyrate level achieved, various diet ratios are tolerated depending on the particular patient.
What I mean is that for one patient, a 3:1 diet works best, for another, a 3.5:1 diet works best and for others, a 4:1 ratio diet works best.
This needs to be considered, because we have found that one ratio does not fit all. The type of lipid used can also affect the toleration of the diet. Some of our patients cannot handle microlipid well. Toleration of the diet often depends on what seizure medications are used as well.
For instance, enzyme inducing drugs will often increase the triglyceride levels. We have also found that extremely high beta hydroxybutyrate levels can adversely affect cognition and awareness. The level of beta hydroxybutyrate inducing these changes varies between patients. We usually try to aim for beta hydroxybutyrate about 40-60. Some centers restrict fluids but we do not, as this does not seem to help. So, fluids are okay to give. I don't know what her beta level is when she gets IV fluids. My guess is that her beta is really high and you are reducing the concentration of them with added fluids or you are correcting a dehydrated state. We have seen this in some of our patients as well.
When the beta gets really high, patients can become irritable and some have increased vomiting and seizures. We do many labs during the initial part of the diet so we understand how a patient individual biochemistry is altered by the diet. I would think this might be helpful to your daughter.

Answered by: Russell Saneto, DO, PhD

Q: My daughter was diagnosed with MELAS in 2004. She had a severe migraine and a stroke. It took months to figure it out with the help of a genetics doctor. She has had several bouts with migraines that put her in the hospital for pain treatments. She also has muscle twitches which are little seizures. She is only 57 lbs. and is 18 years old. She does take a vitamin cocktail. I was wondering if there is a certin diet she should follow that might help her feel better and put on a few pounds. She does seem to like eating more carbs then protein. She is a very picky eater and doesn't like much. Basically she is anorexic. She has a great neurologist but she doesn't really know much about MELAS.


A: In regards to your daughter with MELAS, I am concerned by her poor growth and nutrition status. If you have not met with a gastroenterologist and nutritionist, I would see if this is possible. If she is not growing despite adequate 'age-appropriate' calories, she may need someone to determine her basal metabolic rate and see how many calories she actually needs. Many patients with mitochondrial disease have a higher metabolic rate and require more calories.
If she is not able to get enough calories into her, then ways to ameliorate that problem should be looked into, including, but not limited to night time G-tube feedings and calorie supplementation. If she is very picky and 'anorexic' as you imply in that she does not like to eat much - the G-tube mediated calorie supplementation is most likely needed.
In regards to diet - unless she has an identified problem in metabolizing fats or proteins (seen on amino/organic acid and acylcarnitine testing) OR if she does not get ill after ingesting a specific category of food (protein/carbohydrate/fat) - then there are no firm dietary changes that a MELAS patient needs. Some metabolic physicians do recommend a trial of small frequent well-balanced meals (5/day instead of typical 3) and a bedtime snack of corn starch to prevent prolonged fasting and secondary body catabolism.
Lastly, in regards to the cocktail - a trial of Arginine should be considered (see MELAS Arginine therapy, in Mitochondrion 2007, by Dr. Koga et al).

Answered by: Sumit Parikh, MD

Q: I have a 2 1/2 year old son with a Complex I mitochondrial disorder. A month after his second birthday he started experiencing episodes of vomiting. I do not think that it is cyclic vomiting syndrome, in that he only will vomit once. One day he will vomit without warning, it just pours out of his mouth with no gagging. Then for the next week he has a very poor appetite. He will start to regain his appetite and then he vomits again. When he vomits he becomes pale in color. We have had him to the doctor and they are unsure what it is. They did a blood test and nothing has showed up. Another thing that has been happening which may or may not be related is he gets a rash only on his face. It starts out as a red dot, raised into a white head and then disappears. He is not complaining of any itchiness and we are also unsure of the cause. Could the rash and vomiting be related to his diagnosis? Another question that I have is that my husband and I would like to have another child, they told us that there was a 25% chance of having another child with mitochondrial disorder. If I start taking the mito supplements prior to and during my pregnancy will it be beneficial in preventing another child with mitochondrial disorder or will it improve the childs outcome, so that they may also have a mild case as my son does?


A: I am sorry to hear about your son's episodes of vomiting. Yes, such episodes may occur in children affected by mitochondrial disease, even if a definite cyclic pattern is not present. Rashes may also occur, so it is possible that these symptoms are indeed related to his underlying diagnosis of complex I deficiency. Sometimes children who have mitochondrial disease experience a variety of symptoms related to the function of the autonomic nervous system (which functions to keep our bodies in equilibrium). Such symptoms include gastroesophageal reflux, a rapid heart rate, abnormal body temperature regulation, colonic dysmotility, migraine headaches, and blotchy rashes.  In my experience, sometimes treatment with an antihistamine (e.g. cyproheptadine) can help alleviate symptoms in some patients.
From what you say about the recurrence risk you were given, your doctor likely thinks that your son has inherited an autosomal recessive form of mitochondrial disease. In such cases, an affected child inherits an abnormal copy of a gene from each parent. The risk for having another affected child is 25% in autosomal recessive conditions, regardless of taking supplements or medications.  In general, siblings who are affected by an autosomal recessive condition are likely to have similar features, although numerous exceptions exist. I think it would be worthwhile to meet with a prenatal genetic counselor to discuss inheritance in more detail. I would not expect taking mitochondrial supplements prenatally to change the outcome, although it is important to take the usual recommended vitamins as prescribed by your obstetrician.

Answered by: Greg Enns, MB, ChB

Q: My son's seizures have increased dramatically. Does this indicate this is progressing or just maybe a different therapy approach? My son underwent muscle and skin biopsy in 2005 which were normal but clinical and other blood work up ( lacic acid elevated) indicated some kind of mitochondrial disorder, but undefined biochemically. His seizures increased dramatically and his breathing with breath-holding followed by shaking and extremities jerking have been progressively worse. Should we follow up with our mito doctor to see if we can do anything different to find the optimal therapy for it? I know there is no cure, but is it worth to see if we can change therapy?


A: I am really sorry that your son has seizures. What we know about epilepsy is that seizures are unpredictable; seizures have no time scale and can erupt at any time. You are very correct in thinking that the events your son is having need to be investigated. The first priority is to make sure they are actual seizures; that is, the events are driven by abnormal brain activity. This may even require to be admitted to a Video-EEG room in the hospital and undergo examination for a few days.
Hopefully, several events will be captured and then can be analyzed to see if they were actual seizure events. Then, working with an epileptologist, try to sort out which medications might be best to control these events. The medication part may take awhile to sort out but it is necessary to optimize seizure control and medication side effect profile. Unfortunately, this is usually a trial and error process. Each child is so individual that we need to see just what drugs and their dosing will achieve in a particular child. Since your son has some symptoms of having a mitochondrial disease, this should be mentioned to the epileptologist as well.
If these events are not correlated with the abnormality on EEG, then likely they are not cerebral seizures. Our seizure medications really do not work well for these non-cerebral events. But, it is critical to know if the events are or are not cerebral seizures.

Answered by: Russell Saneto, DO, PhD

Q: Our 3 year old daughter was diagnosed with Complex I and III defects in January. She has intractible seizures (since 9 months old) and developmental delay (she's seems to be doing very well despite her medical issues). The mito DNA sequencing showed no mutations, which means she has an autosomal recessive inheritance pattern from the nuclear DNA. We have an older daughter who is healthy, but are interested in having another child. I know there is a 1 in 4 chance for our next child to inherit the mutation. My question is, if our next child would inherit the mutation, would the symptoms and severity of the disease be the same as our daughter's or could there be other symptoms present with more or less severity? Would the actual nuclear DNA mutations also be the same (ie- same deletion, same insertion, base pair change)?


A: I am glad to hear your daughter is doing well. From what you mention, it sounds like your daughter almost certainly has an autosomal recessive condition. I say "almost certain" because I don't know the exact details and assume the enzyme studies and mtDNA sequencing were done on a muscle biopsy and the DNA was fully sequenced, rather than screened. Assuming that is correct, then siblings with the same autosomal recessive disease usually have similar symptoms and similar severity of disease. However, the disease gene is often not 100% responsible for determining the severity of a disease. Other genes can impact on this and so can the "environment", particularly things like infections, for example at what age and how severely a child may have flu or gastrointestinal disease, how well nourished they are, etc. Occasionally, affected siblings with autosomal recessive disease can show substantial differences, and we have seen that in some children with mtDNA depletion. However, as a general rule, the symptoms and severity are likely to be similar. If a second child was affected then we would expect them to have inherited exactly the same nuclear DNA mutations as the first child.

Answered by: David R. Thorburn, PhD

Q: My daughter has been suspected of having Mitochondrial Myopathy; we just had a second opinion from the local MDA and they said the same. Besides the normal blood work, or biopsy, is there a specific genetic test we can do to confirm this? This disorder seems so different with each child and all the research I do she fits in some cases and not in others. Is there a test we can do for an absolute yes or no? <br />


A: Unfortunately, there is no specific test for mitochondrial disease. Certain patients show a very specific clinical picture and this might be typical of a certain type of mitochondrial disease. Under these circumstances then a genetic test may be best. For many children however, a range of tests is necessary.

Answered by: Douglass M. Turnbull, MD, PhD

Q: Can a person with a mitochondrial disease be an organ donor?


A: There are no formal/studied guidelines. We would suspect if there is a mitochondrial DNA mutation that is known - that each organ's mitochondria harbor these mutations - thus the recipient would be receiving an organ with a certain % of unhealthy mitochondria. In this circumstance, our group advises against using the organs as donor tissue.
If there is a nuclear DNA mutation - the answer is not as straight forward.&nbsp; If there is a mutation causing mitochondrial depletion, then this organ has 'lived' its entire life without enough mitochondria and is likely functionally 'older' than the donor's chronological age.&nbsp; In this situation - using the tissue is not advisable.
Other situations would be determined on a case-by-case basis.

Answered by: Sumit Parikh, MD

Q: Is there any new research on Mito & the use of cord blood ? My daughter (age 29) is due to have a baby in Dec. 2007. She is looking into having the cord blood saved & stored. She asked if it could possibly help me with my mito situation. I have no idea if cord blood might be beneficial for mito patients. I read a previous cord blood Q&A posting on “ask the mito doc” but was told it was a couple of years old.


A: Two mito doc responders answered this question:
David Thorburn, PhD, Royal Children’s Hospital, Melbourne, Australia
Cord blood stem cells certainly remain an active area of research, including for potential treatment of neurological diseases. I am not aware of any specific research using them for mito diseases nor of any developments that make it likely there will be a breakthrough that would be useful for mito disease any time soon. In general I think it is a great idea to donate cord blood but not so sure about the practicalities of cord blood storage in the USA, e.g. costs, intention to store for directed use versus donation, etc.

Sumit Parikh, MD, Cleveland Clinic
I agree with Dr. Thorburn. While there are mitochondria in stem cells (including in cord blood cells) - we do not know how to utilize stem cells in general - and are not close to making use of them for mitochondrial disease (hopefully in 5 to 10 years).

Q: I have a two year old daughter with mitochondrial disease complex I.She is on the following drugs: Phenobarbital and Trileptal. She was still having break through seizures and was placed on Tennex last week to help calm her, I was told. Is this common? I was also told she was on the maximum dose and there was nothing else medication-wise.&nbsp;Are there other options? If not what does this mean for her life-wise? I have been told if they didn't get them under control she could 1) go into a coma and not come out&nbsp; 2) she could die 3) her organs would just stop working This is very scary; my husband and I have just been so upset. Could you please give us some insight on this matter? Is it normal for children with this diagnosis to respond this way? Also is there any truth to this information? We just need to know so we know what to expect. Thank You


A: I am sorry to hear about your daughter’s seizures. No, it doesn’t sound like you are at the limits of what could be done. Personally, I don’t like using Phenobarbital on someone who is 2 years old-too many side effects but that is my personal bias. The first question to answer is what does the EEG and her seizures look like? We use our seizure medications based on these two factors. For instance, if there are tonic spasms then clearly neither of the medications is proper as Phenobarbital nor Trileptal have efficacy in treating spasms. So, I would first find out what the EEG showed. Then talk to your epileptologist and find out how the seizures compare to the EEG. Based on that then formulate a plan of action. This can be time consuming as each child is different and respond to medications somewhat differently. I would start with a base medications, one may use what she is already on or change to another medication. Most will start with what they have the most experience with using. I usually start with Lamictal but that is just my choice. What we find is that when we have used two to three medications at their upper limit and seizures are not controlled, then likely we will not stop seizures completely using medications. Therefore, at this point we decide how many seizures are acceptable with respect to medication side effects. If the acyl carnitine profile is benign, then the ketogenic diet might be an option. We have had some good efficacy using this on children with electron transport chain defects. But, this is something you will have to talk over with your epileptologist. We have not found the VNS to be particularly effective in children with mitochondrial disease. For seizure lasting greater than 4 minutes; we usually use diastat (a benzodiazepine used rectally to abort seizures). I would highly recommend this medication as it may keep you out of the ED, which by now you have likely come to dislike.
The vast majority of patients with seizures never go into a coma. Even those with bad uncontrolled seizures do not. What we are trying to prevent is long seizures (10 minutes) that may produce neuronal damage. Thank goodness that greater than 85-90% of seizures are self limiting, lasting less than 2 minutes. No, her organs will not stop working. There are some side effects to our seizure medications that might reduce the performance of some of the organs, such as pancreatitis, low white blood count, low platelets, etc. But, these side effects are pretty well known and that is why we get labs to detect these side effects.
We find that having seizures in children with mitochondrial disease is common, especially with an electron transport chain defect. Seizures are often difficult to control. Working with an epileptologist is critical because each child is so different, that often there are many medication changes that occur.”

Answered by: Russell Saneto, DO, PhD

Q: Hello, My son has been diagnosed with mitochondrial myopathy with complex I and III defects. My question is that he seems to go through phases where he eats very little, has vomiting and when he does eat, his stomach becomes very bloated and hard. I was just curious if you had any recommendations on what to do when he goes through these spells. Thank you!


A: Episodes of vomiting in mitochondrial disease are not uncommon, and can have several different causes, which are briefly summarized here:
Cyclic vomiting - a migraine-like condition in which there are severe episodes of nausea, vomiting and lethargy (tiredness), with the absence of these symptoms between episodes. In a given patient, the episodes are similar to each other. Cyclic vomiting is treatable. For more information, visit
Gastrointestinal dysmotility refers to slow or abnormal movement of food, and can be at any level, from the top (GERD) to the bottom (constipation) of the GI tract. Unlike cyclic vomiting, the "episodes" are not as dramatic, and times of more and less symptoms tend to blur together. GERD (gastroesophageal reflux disease) is very common in mitochondrial disease. Delayed gastric emptying (DGE) is also common, and causes the early satiety (filling up fast) that you describe. Constipation, also common, can be so bad that food/feces builds up all the way to causing vomiting! Delayed gastric emptying and constipation can result in a hard bloated abdomen. Treatment depends on the level of the dysmotility and severity, but often consists of medications to make the gut move better (GERD, DGE), small frequent feeds (GERD, DGE) and polyethylene glycol (trade names: MiraLax, Glycolax, and others; constipation).
Many mito patients have more than one of the above conditions, sometimes all of them, at the same time. Finally, although much rarer, pancreatitis should be considered as well.

Answered by: Richard G. Boles, MD

Q: My daughter is 11 years old and has Complex I and IV mitochondrial disease. Her pediatrician was concerned with the curvature of her spine. We just completed an X-ray and found out she has a 24 degree curve. We will be visiting an orthopedic doctor soon. Should we consult our mitochonrial physician as well? What should we be aware of in regard to mitochondrial disease and scoliosis? What questions should we ask the orthopedic doctor as I am concerned they may not know as much about scoliosis and mitchondrial disease.


A: You are asking an excellent question. You do not mention whether your daughter has any neuromuscular problems. Neuromuscular problems (and especially if any hypotonia or hypertonia is assymetric) do lead to an increased risk of scoliosis. Since mitochondrial disorders can cause neuromuscular problems, there is therefore an increased risk of scoliosis in mitochondrial disease. I am not aware of any other reason that scoliosis would be increased in mitochondrial disease. Scoliosis is fairly common, and at age 11 your daughter may be in the growth spurt of puberty, and that is a common time for presentation of scoliosis - so the scoliosis may have nothing to do with the mitochondrial disorder. Regardless, it is a good idea to make certain that your mitochondrial physician is aware of what is going on. If your mitochondrial physician is also your neurologist, he or she can help to determine if there is an immediate neuromuscular cause or contribution of the scoliosis, and whether there might therefore be some specific treatment in addition to whatever the orthopedist has to recommend. And your mitochondrial physician can also help you to evaluate if any of the orthopedist's suggestions have any increased risk for an individual with mitochondrial disease. Most treatment for scoliosis is quite low risk, and I hope your daughter will never require any surgery, but if she does it will be your mitochondrial physician who will help the surgeons and anesthesiologists to know how best to help keep her safe.

Answered by: Carol Greene, MD

Q: My son was diagnosed with LHON. Now he has Lennox Gastaut syndrome. Can he safely go on a ketogenic diet?


A: I am sorry to hear that your son has Lennox-Gaustaut syndrome. In our center this epilepsy syndrome is extremely rare; in fact in 67 patients with electron transport disorders, we do not have a single patient with Lennox-Gaustaut. In the other 20 patients with either nuclear DNA mutations or mitochondrial DNA mutations (several with the LHON mutations), there is also no patient with Lennox-Gaustaut. However, this syndrome has been reported in children with mitochondrial disease in the literature. The reason a correct diagnosis is very important, is the treatment is based on having the epilepsy syndrome. So there should be mixed seizures: tonic, atypical absence and generalized tonic clonic.
Drop seizures are also extremely common. The ketogenic diet works best for the latter type of seizures as well as the atypical absence. The EEG should show slow spike and wave complexes, 1.5 - 2.5 Hertz as well as generalized paroxysmal fast. In children with electron transport chain disorders we usually begin the diet at a low ratio. This is because the ketone level often is high, out of proportion to the ratio (fats + protein/carbohydrate + protein). We have also found that side effects (mainly nausea and vomiting) are more pronounced in the electron transport chain children. Once we see that the child tolerates the diet well, we increase the ratio to efficacy and toleration. We monitor our kids on the diet very closely, for instance most all of them become selenium depleted and have to be supplemented.
So, your question of safety is generally yes it is safe. But, I always do an acyl carnitine profile before starting the diet just to make sure that fatty acids are being metabolized okay. If there is any problem with long chain fats, then the answer would be no. Depending on what other seizure medication is being used (usually not the ones used for Lennox-Gaustaut syndrome) there can be increased levels of triglycerides. We have found that the use of omega 3 can decrease triglycerides. Often removing the enzyme inducing seizure medication is the only way to reduce triglycerides. MCT oil supplementation does not seem to be tolerated well in our population. We have had fairly good luck with seizure control and the ketogenic diet in patients with electron transport chain defects.
In our regular Lennox-Gaustaut syndrome population (non-mitochondrial) the VNS stimulator works well. In one patient with a complex III disorder and drop seizures, we have found that the VNS stopped all his drop seizures, but unfortunately did not have any effect on his other seizures.

Answered by: Russell Saneto, DO, PhD

Q: If a person has MCAD, can she have kidney problems and migraines as a result of MCAD? The doctors have told her this is not possible. However, they also told her that it was impossible for her to have MCAD and Diabetes, and they were amazed when they found out that was her case. Could the MCAD be secondary to another mitochondrial abnormality, or be the primary cause of other mitochondrial dysfunction? Maybe she has more than one mitochondrial defect that is causing various unrelated issues? Any insight would help.


A: MCAD deficiency is easily diagnosable by a geneticist or metabolism specialist and shouldn't be confused with anything else. It does not cause kidney problems or migraine headaches. If a person has MCAD deficiency, they can still have a second disorder but it doesn't mean that MCAD caused it. For example, a person with MCAD deficiency can get the flu or a cold completely independent of the MCAD deficiency. Similarly, having MCAD deficiency doesn't preclude having mitochondrial disease but it would be rare and should be very well investigated before accepting it as true.

Answered by: Gerard Vockley, MD, PhD

Q: I'm going to have to have a root canal, fillings, etc. done at a dental general anesthetic, only injections to gums with usual lidocane or some type of medication given to numb the area. Are there any meds I need to avoid at the dental office as a mito patient?


A: I am so sorry you have to get dental work (without anesthesia, at that). However, there are no direct contraindications to local anesthetics. Some individuals with mitochondrial disease have noted that the effects of even the local anesthetic last longer than expected. However this is typically a transient issue.
The key concern is typically with general anesthesia, prolonged fasting or 'major' surgery. In case your dental work requires any of this, please use the UMDF's outlined anesthesia precautions.

Answered by: Sumit Parikh, MD

Q: I'm a 42 yo female, married with two children. I've reviewed the Mito Doc posts and there is much discussion on GI problems. I was diagnosed with Leukodystrophy in 2002, and have recently (2006) been confirmed to have Mitochondrial COX defect in complex IV, with others in I, II, III as well (confirmed by muscle biopsy) . . . it has been devastating to me and my family. I have been empirically on a mito cocktail since early 2003, and found benefits for general ADL's. I take CoQ10, Carnitor, Alpha Lipoic Acid, B complex, Gamma E, Ocuvites, Vit C, probiotics and recently Miralax . . . which caused some dehydration problems. I suffer a whole slew of symptoms, mainly severe fatigue and loss of strength and many autonomic problems including temperature regulation, difficulty swallowing and GI dysmotility. I have recently had severe 'loss of motility' and subsequent constipation . . . my GI, PCP have helped greatly resolve initial problems. My question is: Is there a way to rehab the GI tract and increase the GI muscular tone and general motility? Or is this problem completely related to the Autonomic Nervous System with no over-ride?


A: I am so sorry to hear of how devastating this disease has been for you and your family. Through testing, it seems that you have several signs symptoms and also several complex deficiencies. I was wondering if you have had any additional testing done, including MNGIE (thymidine phosphorlyase) because of the leukodystrophy and mtDNA mutations/deletions/duplications and/or the polymerase gamma 1 mutation.&nbsp; I would consult again with your PCP or GI doctor to see if any further additional tests could help you obtain a more specific diagnosis that is genetically based.>
Dysmotility issues are very common in patients with mitochondrial disorders. The symptoms can range from mild (gastro-esophageal reflux, irritable bowel syndrome) to severe (chronic intestinal pseudo-obstruction).&nbsp; When the problem is dysmotility, the symptoms can be fluctuating in nature.
Some patients do well on a modified diet alone, possibly with the use of supplements. I strongly suggest that anyone with GI symptoms work with a Nutritionist who is affiliated with a Metabolic Department or Gastroenterology Department of a University based hospital.; Any supplements need to be tried carefully and individually, as some of them can cause increased GI problems (such as Carnitine in particular but includes many others).
A specialist in the GI field of dysmotility is the best physician to help diagnose and manage symptoms. Other conditions may need to be ruled out; such as lactose intolerance, celiac disease, H. pylori infection, etc.&nbsp; In general, reflux and irritable bowel may be treated medically when needed, and there are several medications that may help ease these symptoms. Many of the neuropathic pain medications we use in migraine or depression can be helpful in treating irritable bowel symptoms, including the SSRIs (Prozac, Celexa, Zoloft, Lexapro, etc.), tricyclics (Elavil, Pamelor, Doxepin), anti-seizure medications (Neurontin, Lyrica), and Periactin (an antihistamine).
When motility is the problem, there are specialized tests (manometry) that can be done only in special motility centers in order to properly diagnose pseudo-obstruction and determine if the problem is in the nerves or muscles of the GI tract. There are a limited number of medications that can be tried (erythromycin, octroetide), and some of them are better to use when we know which part of the GI tract is more affected. Finally, there have been surgical techniques used to help ease pressure and many GI physicians work closely with surgeons whose expertise is in GI procedures.

Answered by: Amy C. Goldstein, MD

Q: After going to the symposium we had some more questions. We understood that mitochondrial disease is passed down 100% maternally, but after the symposium we heard it can be from 1 to 100%. I (the mom) have it and all of my children plus my mom and her mom. Three out of four of my siblings got tested and all have it. When I spoke to some moms and they didn't have it I was a bit confused because I thought they would have it. Maybe you could explain how this works. Thank you.


A: It is not surprising you were confused as there are lots of different types of mitochondrial disease, and they are complicated even for those who have studied genetics. The term "mitochondrial disease" can be a little ambiguous and I assume you are referring to mitochondrial diseases caused by mutations in mitochondrial DNA, which are the type passed on maternally. Other mitochondrial diseases are caused by mutations (changes in the DNA sequence) in some of the 25,000 or so nuclear genes. With those genes we get one copy from mom and one from dad, except for the genes on the X and Y sex chromosomes. Mutations in nuclear genes can cause "mitochondrial disease" but are not associated with maternal inheritance.
So if we focus on just the mitochondrial DNA, then you would have heard that our cells contain thousands of copies of mitochondrial DNA. In some mitochondrial diseases, for example most families with Leber's Hereditary Optic Neuropathy, every copy of the mitochondrial DNA contains the mutation that causes the disease. This is referred to as homoplasmy, and if the mother is homoplasmic then all her children will be homoplasmic, ie 100%. That doesn't mean they will all develop disease, since that may depend on other nuclear genes and the environment.
In other mitochondrial DNA diseases, only some of the mitochondrial DNAs contain the mutation, while others are healthy. That situation is called heteroplasmy, and in that case different family members can have different amounts of mutant and healthy mitochondrial DNA. The more mutant DNA, the more likely the individual is to suffer symptoms of mitochondrial disease. With heteroplasmy, if the mother has a high proportion of mutant mitochondrial DNA, then the chances are that all or most of her children will have inherited some mutant mitochondrial DNA. Some may have 100% mutant, some may have 50% mutant and 50% healthy, while others may have 10% mutant and 90% healthy. The fact it can vary so much between different children is due to the "bottleneck effect" which results in big differences in the amount of mutant and healthy mitochondrial DNA being present in a woman's oocytes. In fact, it is possible that the bottleneck can mean that some oocytes only end up with healthy mitochondrial DNA so they have 0% mutant DNA. The lower the amount of mutant mitochondrial DNA that the mom has, the greater the chance that some of her oocytes will have 0% mutant mitochondrial DNA.
That explains why we inherit all our mitochondrial DNA from our mom, but if our mom has a heteroplasmic mitochondrial DNA mutation then the amount of mutant mitochondrial DNA that we inherit can be anywhere from 0% to 100%. I should also mention that the amount of mutant mitochondrial DNA is not always the same in every part of our body. So finding 0% mutant mitochondrial DNA in blood doesn't always mean that there is 0% present in muscle, brain, etc. That is one explanation for why some moms don't have the mutation, at least in blood. However, it is also possible that they not have it elsewhere in their body. The bottleneck effect occasionally results in new mutations appearing in women who don't have the mutation anywhere else in their body, but may have one or more oocytes containing a mitochondrial DNA mutation. If that oocyte is fertilized, then that can be how a child with a mitochondrial DNA mutation suddenly appears in a family with no history of mitochondrial disease.

Answered by: David R. Thorburn, PhD

Q: I have Mitochondrial Myopathy with Fiber 2. Could you please explain to me the difference between Fiber1, Fiber2. Thank you.


A: I am sorry to say that this diagnosis does not make much sense. "Mitochondrial myopathy" is due to a mitochondrial dysfunction (the biochemical and molecular causes can be many) that affects predominantly or exclusively the musculature. Fiber 2 probably refers to one of the two major fibers composing muscle: type 1 fibers are richer in mitochondria and type 2 fibers contain less mitochondria and rely more on glycogen metabolism. In this sense, it is somewhat paradoxical that a mitochondrial dysfunction should affect more type 2 fibers: usually, we see the opposite. More than this I cannot say.

Answered by: Salvatore DiMauro, MD

Q: My son is 10 weeks old and was diagnosed with pyruvate dehydrogenase deficiency. He had the disease in-utero and was born with very high lactic acid levels and all the warning signs of the disease. He has received treatment and is on a cocktail of medications as well as the ketogenic diet. He is doing much better now, but I am wondering if there is more we can do to give him a better chance of survival. Can you provide me with a list of medications and treatments that have been used in the past to treat PDH so I can discuss our options with his doctors? I am also interested in dichloracetate and looking for facilities in our area that could provide us with the drug if needed. I have read quite a bit on the disease, and am also curious what the survival statistics are.


A: I was asked to reply to your questions regarding your son with pyruvate dehydrogenase deficiency. It appears, from your letter, that the treatment prescribed is appropriate. The outcome of PDH deficiency is really related to the severity of the metabolic block in metabolism. Some patients with mild disease can live long lives with only slight disabilities while those with severe deficiency may only survive for a few months. I have treated both types of patients and cannot predict you baby's outcome. The treatment of PDH deficiency is usually a ketogenic diet and use of vitamins such as thiamine and carnitine. I have used dichloroacetate on two neonatal severe patients and it did not improve outcome, both boys died by age 3 months. Peter Stackpoole, MD in Florida is the expert on DCA therapy and he is running the clinical trials.&nbsp;You have access to many metabolic centers in [your state] and should get "state of the art" treatment. Unfortunately, we do not have a cure for PDH deficiency and it is a severe disorder. I wish I had a crystal ball for you to look into the future and answer your questions. I know it is very difficult and scary to have a baby with such a life threatening disorder. My best advice is to hook up with a good metabolic center and follow their advice. There are many ways to treat the disorder and all seem to have a similar outcome. Best of luck to you and your little guy.

Answered by: Susan Winter, MD



Q: My son who is 9 years old has been diagnosed with a Complex II-III defect in the ETC by fresh muscle biopsy at the age of 10 months old. He was diagnosed with a severe seizure disorder at the age of 2 years old. He has been on 6 seizure medications over the last 7 years. He is currently taking Lamictal, Topamax, and Klonopin. Our local neurologist has brought up the idea of a Vagal Nerve Stimulator to help control the seizures he is still having. My concern regarding the surgery is that my son has had problems in the past with previous surgeries. He is g-tube fed, has a medi-port and had several other surgical procedures in the past. Can you please give me some information about how other Mito patients have done undergoing a Vagal Nerve Stimulator surgery? I am concerned about recovery and any complications that he might encounter due to his Mitochondrial Disorder. Thank you for your help and any information you can give.

A: I am sorry to hear about your son. Seizures can be particularly devastating (intractable to seizure medications) in patients with mitochondrial disease. The vagus nerve stimulator (VNS) is a device that has two parts. One part is a pacemaker (just like a heart pacemaker) that sends signals (electrical pulses) to an electrode connected to the vagus nerve in the neck. The electrical stimulation, for reasons that are not clear at the moment, seems to reduce seizures in about 50% of patients. We recently published our center's results on VNS efficacy in patients who were less than 12 years of age and found that about 50% of patients had a 50% reduction in seizure frequency. This finding was similar to patients who were older than 12 years of age. Our study included about 50 children, so it was a large study (largest to date in this age range). The trouble is that we do not know which 50% will respond and which will not. The VNS device usually does not reduce the number of medications a child is taking, nor does it usually produce seizure freedom (< 5%).

The interesting thing is that in this group were four patients who had electron transport chain deficiencies. We had another patient with a complex I deficiency and published another paper looking just at patients with mitochondrial disease due to electron transport chain deficiencies and less than 12 years of age. We did not have the room in the above paper to just describe the mitochondrial patients. We found that the VNS device did not alter seizure frequency in this population, especially with respect to myoclonic seizures in this second paper. All of these patients had multiple seizure types but the myoclonic seizures were the most frequent and the frequency was high, > 30 per day on average. So, at least in these five patients, the VNS did not help reduce myoclonic seizure frequency.

We have implanted several other children with mitochondrial disease having electron transport chain deficiencies who are older than 12 years of age. We did not include any of these patients in the paper due to their age. They tended to have less frequent seizures, but as the other five patients, the VNS did not seem to significantly decrease seizure frequency. Now, we have not tried to look at the various seizure types other than myoclonic seizures as the group is too small to arrive at meaningful data.

Surgery is another issue as sometimes anesthesia can have effects on mitochondria. We try to limit exposure to propofol, an anesthetic agent, in our mitochondrial population. Luckily, the time to place a VNS device (pacemaker and lead) is short and we have not had any trouble. This is an area that we are trying to address as a mitochondrial center and clearly is in flux and evolving on what is the best anesthetic agent to use. At our center, a child comes in during the morning and undergoes surgery and leaves that afternoon. The device is checked but not turned on until the wound has healed, about 2 weeks and the device is turned on and "ramped" up over the next couple of months.
Answered by: Russell Saneto, DO, PhD

Q: I am a 50 yr old woman with Mitochondrial Myopathy; Deficiency in Complex II and III. Recently I have been experiencing increase in muscle cramping in my arms, calves, and chest. I saw my cardiologist who did a work up due to the chest pain and tightness. I was told I have early repolarization and that may be causing the chest pain. I was wondering if cramping can occur in the chest area, without any heart involvement. I have also been recently diagnosed with Hashimoto's Disease and have a hyperfunctioning and hypervascular nodule, non cancerous, but my doctors have not been able to regulate the thyroid medication. To say the least the thyroid issue has complicated my Mito disorder - I'm so tired all the time and have increased muscle fatigue and cramping. I've gained about 18 lbs because of the thyroid; my thyroid is either hyperfunctioning or under functioning! Have you heard of individuals with Mito also having Hashimoto's? Do you have any suggestions so I can feel better. I would really appreciate any suggestions you might have for the course of treatment.

A: Hashimoto's thyroid disease is extremely common in the general population, and there has been no increased correlation with mitochondrial disease that I know of. Hashimoto's is usually very simple to treat. Since your course seems slightly more complicated, I would recommend that you find a good endocrinologist who follows your thyroid function carefully and makes sure that you are on proper therapy.

Answered by: Maria A. Yialamas, MD 


Q: I consider the most important testing I received was the respiratory enzyme. Is this possible without a muscle biopsy? I would like my relative to get it. If I have positive complex I deficiency, is it possible for this to be tested in my relatives?

A: Yes and no!

In some patients the respiratory deficiency is only picked up in muscle, but in other patients can be detected in cultured skin fibroblasts. It would only be worth testing your relative if your complex deficiency is also detected in fibroblasts.

Answered by: Douglass M. Turnbull, MD, PhD  


Q: I am 49 years of age and was diagnosed with MERRF as well as LHON. I started treatment for HEP C. To date, my liver enzymes are still rising instead of leveling out despite my viral load being undetectible. Before I went on treatment for HEP C virus, blood work showed elevated liver enzymes and since then they have been rising steadily. For this reason, I am told something else is causing the rise in liver enzymes other than my HEP C treatment and as such, my treating Physician is puzzled. My questions are as follows: In your opinion, could the rise in liver enzymes be caused by my Mitochondrial problems? Also, are there any other test that can be performed to ascertain the reason for the rise in liver enzymes and/or to rule out any other possible causes? What is the significance of RFLP in MERRF, and what are the clinical features associated with it? Had there ever been any studies done on Mito patients taking anti-viral drugs?

A: A chronic elevation in liver enzymes may be due to mitochondrial dysfunction (regardless of the mutation). I am glad the liver biopsy was okay. Did your physician evaluate you for other non-liver causes of elevated AST (muscle breakdown) and ALT levels (celiac disease)?

As to your second and third question, they may require quite a lengthy answer and more detailed review of the medical record. Visiting a clinical geneticist with an interest in mitochondrial medicine would be worthwhile.

Answered by: Sumit Parikh, MD


Q: About 12 years ago (before a confirmed Mito diagnosis) I began having episodes of severe diarrhea in which food would run through me undigested in about 6-8 hours. I was hospitalized for more than a week and the GI doc in town did an upper endoscopy and colonoscopy but all that was ever found was some inflammation that was not specific for any other disorders. For years the bouts of severe diarrhea would continue to occur periodically but because no one knew the cause, no one treated it. They are continuing with a greater intensity and now that I have been diagnosed with mito my GI doc gave me Levsin as needed. This has not been entirely effective but helpful at times. He has had to do more upper endoscopies for a few small ulcers. The ulcers are healed; however, they continue to see the gastritis and duodenitis. As far as the gastritis and duodenitis, is this connected to the mito?

A: Gastrointestinal dysmotility causing trouble swallowing, early satiety, diarrhea, or constipation is the most severe clinical feature of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), but is also being recognized in other mitochondrial diseases such as MELAS. I presume that malabsorption has been excluded. It is important for your gastroenterologist to screen your gastrointestinal system for dysmotility, which could be causing your diarrhea and might be contributing to your gastritis and duodenitis. Other factors that could contribute to the slow healing of your gastritis include intestinal inflammation, bacterial overgrowth (which is not uncommon in the setting of intestinal dysmotility), and microscropic colitis. Hormonal factors are rare (e.g. gastrin or thyroid hormone abnormalities), but may be considered in this setting.
Answered by: Michio Hirano, MD

Q: My daughter is affected with complex IV COX. She has many other problems also but they have only been able to diagnosis one mutation so far. Since she does not have an exact diagnosis, how do I know as her mother if I am affected and someday might become ill, or how likely is it if my next children will have it? All of her doctors I have asked can not answer this question. I live in a constant state of worry whenever I get any ache or pain. Is there a test for me to get done?

A: It is difficult to answer your question without more details. Based on your question, I assume your daughter has complex IV deficiency diagnosed by an enzyme assay on muscle. This is a specific diagnosis but can be caused by mutations in a number of nuclear genes or on the mitochondrial chromosome.

If the mutation you mention is on the mitochondrial chromosome, you could have sequencing done on DNA from several tissues to look for the same mutation. If you carry a mitochondrial mutation, all children will inherit it but in differing amounts. But there is always the possibility of a higher or lower number of mutations are present in the mitochondria of an egg cell that would in turn lead to a more or less affected baby.

If the mutation you mention is not on the mitochondrial chromosome, it is pretty good evidence that this is the gene causing the problem even though the mutation on the second copy of this gene is unknown. In this case your risk to have an affected child is 1/4 (25%). Prenatal diagnosis might be possible. In this case you would also not be at risk to show symptoms yourself. You should discuss these results with a medical geneticist or a genetic counselor familiar with mitochondrial disease to clarify these risks.

Answered by: Gerard Vockley, MD, PhD


Q: As the weather gets warmer, my five year mitochondrial myopathy son is having more muscle cramps, restless sleep and generalized pain - particularly after playing outside. What is the most affective method to relieve or prevent this pain?

A: Exercise intolerance, muscle cramps, and muscle pain are frequently encountered in children and adults who have mitochondrial disorders. Unfortunately, there is not a specific approach that works for everyone. This is understandable given the number of different genetic changes that have been found in those individuals experiencing such symptoms. As you certainly know, it is important to ensure that your son is well-hydrated during the summer season. Children with mitochondrial disorders may be more sensitive to glucose deprivation, so it is also important to ensure your son has adequate nutrition on board to keep on playing. Some patients have felt better eating frequent snacks or drinking fluids with dextrose during periods of exercise. I assume that your son is also taking some form of supplements and cofactors. There have not been many convincing studies performed to date, but some reports suggest that coenzyme Q10 treatment may improve exercise performance. Creatine supplementation may also help some individuals, but again, convincing evidence for efficacy is scant. In short, I wish I had a clear answer for you, but a common sense approach is probably best. Limit exercise if his symptoms are worsening, make sure he is taking adequate nutrition and fluids, and discuss supplements with your physician.
Answered by: Greg Enns, MB, ChB

Q: My son is 9 and was diagnosed with COX Deficiency 2 years ago. However, the enzyme testing was elevated and not suppressed. We were told that it still means he has mito and falls under Complex IV. Would this be accurate? In the last 7 months he has been losing more trunk control and holding his head up is more and more difficult. He lost his walking a few months ago too. We know he has poor nutrition and he will get the G-J tube soon. He already had the G-tube. If he does not regain strength and skills back after getting better nutrition would this indicate a progression of this disease? Thank you.

A: "I am very sorry to hear about your son. Without having the opportunity to view the actual enzyme activity of complex IV with control values, it is hard to make a judgment. I will assume that histological staining of the muscle revealed either lack of staining or patchy staining of COX or complex IV. I would also ask if there was evidence of morphological abnormalities of the mitochondria in the muscle sample. These findings would also lean toward the diagnosis of a complex IV deficiency. We try and combine what the evidence from testing tells us with the clinical state of our patient to make a diagnosis. Certainly there are times we are more reassured of our diagnosis than other times.

Nutrition is a very important part in the care of a mitochondrial disease. The foods that we eat are the resources for the mitochondria to make energy and function. When the nutritional status is impaired it can be very difficult to tease out which is the problem, nutritional induced mitochondria dysfunction versus worsening and progressive mitochondria dysfunction worsening the nutritional status. There are some circumstances when nutritional problems are not due to mitochondrial disease at all, such as when the tube is irritating the stomach or GI viral infection. I would say, optimize the nutritional status of your son. See how he responds to better nutrition and then see what his functional status reveals. It may take some time to recover optimal function (back to his baseline) once nutrition has been optimized.

Progression of mitochondrial disease is a difficult issue as it is not known how the poor nutritional status has been influencing and possibly inducing potential damage to mitochondrial function. But certainly, if nutrition has been optimized and your son continues to lose functioning, his disease is likely progressing."

Answered by: Russell Saneto, DO, PhD


Q:My daughter, 6, is diagnosed with mitochondrial cytopathy, complex I and lactic acidosis as well as autism and epilepsy. I have been told by other mito parents that air travel is contraindicated for mito patients and that if they have to fly supplemental oxygen is required. Is this true and who can my pediatrician contact for guidance as to the oxygen pressure, etc. for ordering the oxygen (we don't currently have a mito specialist)?

My daughter does poorly after air travel, but all of her specialists are out of state so we have to fly. She has a large number of seizures (typically petit mal) on the airplane, particularly during take off and landing. She typically has more seizures on the return trip which I'm assuming is due to flying a second time in a short period. She typically gets an infection or illness and/or is developmentally is 'off' for a weeks after flying.


A: Air travel as a whole is not contraindicated - unless a patient has had a poor experience in the past to air pressure changes bringing out symptoms. Oxygen would only be taken the first time around if it is needed for other conditions (after a seizure, for example)

If air travel has caused a deterioration in the past, but is unavoidable, I would recommend the following:

- Make sure the patient is well hydrated before, during and after the trip. Give fluids that have some sugar in it (gatorade/juice)

- Double up on the supplement doses starting a few days prior to travel - and return to normal doses a few days after travel ends.

- Do not travel if the child is ill or not at baseline.

- See if a preventative seizure medication can be used the day of travel if you already know that seizures may worsen (benzodiazepine) - and give a dose prior to starting the journey.

Answered by: Sumit Parikh, MD


Q: My 5 1/2 year old daughter diagnosed with a probable mitochondrial disease has to take (6) 330 mg. tablets of Carnitine per day and (4) 60 mg. tablets of CoEnzyme Q10 both of which can cause and does cause diarrhea and her dosages keep having to be increased. We have been having problems with it causing diarrhea for her which keeps getting worse and more often because she keeps having to get her dosage increased. It actually disrupts our lives because it can be so bad, it will go half way up her back or out through her diaper to her pant leg and get all over her clothes which is very difficult to deal with when we go places. Is there something we can give her to help with that? Maybe if we could give her an Immodium every day or something like that--anything???? I'm afraid it's going to get so bad, we won't even be able to go anywhere anymore. Please help!!!!

A: The loose stools associated with the use of these medications is a problem that can interfere with daily living activities. This is especially so for L-carnitine as only approximately 30% of the oral dose is absorbed. Therefore, the majority is malabsorbed and can then pass from the small intestine into the colon and induce water loss. The result is loose stools or even significant diarrhea. However, most patients with metabolic diseases who are receiving L-carnitine do not suffer from massive diarrhea.

Taken together, this suggests that in some patients with chronic significant loose stools another process such as a parasitic infection of the intestinal tract may be complicating the underlying tendency toward loose stools. I suggest that the child be seen by a physician who specializes in gastroenterology (GI) for evaluation of another possible cause of the chronic diarrhea.

Lastly, this referral may be valuable for another reason as, theoretically, dysmotility of the intestinal tract due to a mitochondrial disease could induce hypermotility, which in some individuals might manifest as diarrhea. The GI consultation would be the first step in the evaluation of this uncommon expression of a dysmotility syndrome. If the loose stools do prove to be due to L-carnitine alone and/or Coenyzme Q10, then a gradual increase in dosage of either medication alone over many weeks may help the body slowly develop a tolerance and in the absence of a gastrointestinal dysfunction .

Answered by: Gerard T. Berry, MD


Q: At 69 my wife died from seizures that, we then discovered, were attributable to MELAS. Symptoms have been identified in her grandmother, her mother, our two sons, and her sister’s son and daughter. They include deafness, diabetes, and muscle atrophy. Her niece has gestational diabetes, suffers from severe migraines, and has had, from the age of 23 (now 40) problems with both lower arms that have been variously diagnosed as RSI, tendonitis, bursitis, and others. The severity cycles from disabling to very mild. There have been three episodes of severe disability. Could this relate to the mitochondrial disorder, and if so how could it be managed?

A: All of the symptoms that you describe in your late wife's family correspond perfectly with the diagnosis of MELAS. The only unusual problem is the one that afflicts your wife's niece and the subject of your question. It would help me to know a bit more about the "problem in her lower arms": is it weakness, pain, or both? What is the duration of each exacerbation? Days, weeks, or months? While it is unusual in MELAS to see fluctuations in the degree of muscle weakness, diabetes may, of course, vary in severity and she may have a peripheral neuropathy partly due to the MELAS mutation and partly due to diabetes.

I think there is little doubt that - whatever the precise cause - this problem is also related to her underlying mitochondrial dysfunction. If this problem is related to diabetes, the best management is better management of the diabetes.

Answered by: Salvatore DiMauro, MD


Q: My son has Leigh Syndrome and he has been grunting when he urinates. He appears to have a strong stream when he urinates and he seems to empty his bladder. Has anyone dealt with this issue?

A: If kids are appearing to have difficulty or pain with urination, this needs to be evaluated first with PCP, then to consider Urology consultation. It is not necessarily related to mito unless there is neurogenic bladder.

Answered by: Amy C. Goldstein, MD


Q: My daughter is 20 months old and has recently been diagnosed with mitochondrial encephalomyapathy with a complex I defect. They are not sure if she also has a pyruvate dehydrogenase defect and are still trying to sort out if her complex I is primary or secondary. We are having difficulty getting weight on her even though she seems to have a good appetite. I know some disorders respond better to certain diets. Should she be on a high carb diet, high protein diet or a high fat diet? How about a ketogenic diet? Any suggestions you have would be great.

A: The dietary therapies in mitochondrial diseases need to be individualized. Some children respond better to high fat and others to high carb The only good rule is that if there is PDH deficiency a ketogenic diet does help with metabolic control. Ensuring adequate calories with all nutrients is the most important as well as feeding at regular intervals without too much time between feeds- even overnight. This should be with the help of a dietitian. Many children with mito diseases have a much increased caloric requirement than would be expected -even if they are less active, as their metabolic rate may be high. This can be assessed by doing indirect calorimetry testing. For complex I deficiency I have used higher fat diet in the range of 70% fat with good results regarding weight gain even if metabolic state is unchanged. I hope this helps.

Answered by: Annette Feigenbaum, M.D., FRCP


Q: I have a 4 year old son with Mitochondrial Encephalopathy, Complex I. He was diagnosed when he was 20 months old. Since then he was started on the Mitochondrial Cocktail and it has improved his life dramatically. He is now 46.5 pounds and at this point, his cocktail consists of CoQ10 (15 ml bid); Levocarnitine (3 ml bid); Riboflavin (5 ml a day); Vitamin C (2 1/2 ml tid); Vitamin E (15 ml-50 units/ml) Here is my concern: I just received my Science Annual 2006 (Heritage Family Library-Southwestern) and on page 248 it states "The dangers of vitamin E". Researchers at Johns Hopkins Medical Center in Baltimore reported in 11/2004 that people who routinely take high doses of vitamin E supplements may have an increased risk of dying from all causes. The researchers cautioned that most of the participants in the trials were over age 60 and had such pre-existing conditions as heart disease or cancer. Based on the study results, however, the team recommended that people avoid vitamin E supplements containing more than 400 IU's." I know that my son is a unique case in that he has Mitochondrial Disease, but I'm wondering if this is something we should be concerned about.

A: Simply put, we do not know all of the risks and benefits (if any) of anti-oxidant therapy in patient's with mitochondrial disease or in unaffected individuals. While we feel that most of the supplements are 'safe' there has been no hard scientific evidence to allow us to make this conclusion with medical certainty. Knowing that these medications are mostly safe, and not having other definitive treatments for mitochondrial disease, many physicians use the medications in the ' mito cocktail' with the hopes that they will mostly help. All of us who treat mitochondrial disease have seen remarkable gains in some patients on carnitine, coenzyme Q10 and the other cocktail drugs.

To answer your specific question, the study you are referring to was looking at a very different population and the results should not be extrapolated and applied to mitochondrial patients. That being said, large doses of vitamins, including Vitamin E, can have some neuro-toxic effects. The doses your son is on are not considered sufficiently large enough to be toxic, based on what we currently know. We do not have adequate medical evidence to determine if long-term use of these vitamins is potentially harmful.
Answered by: Sumit Parikh, MD

Q: Can selective breeding be ruled out as a cause of mitochondrial disease, i.e., hemophilia, paranoid schizophrenia or genetic anomalies?

A: I think by "selective breeding" you are referring to when the parents are related to each other eg as first cousins or perhaps distant relatives within a small village, ethnic group or cultural group. The quick answer is no it can't be ruled out. When two parents are related they will have an increased chance of having a child with a genetic disease, including mitochondrial disease. However, it is a somewhat complicated question, given the different types of inheritance associated with mitochondrial disease, so I need to explain a bit about inheritance to give a proper answer. For example, there is no reason to think that marrying a cousin would increase my chances of having a child with a mitochondrial DNA mutation. Those mutations are inherited from the mother, and effectively the father's genes don't count.

However, quite a lot of patients with mitochondrial disease don't have mitochondrial DNA mutations. The other major types of inheritance are called autosomal recessive, autosomal dominant, X-linked and multigenic inheritance. Apart from mitochondrial DNA mutations, autosomal recessive diseases are probably the most common form of mitochondrial disease and many other diseases. Autosomal recessive diseases are the ones that are relevant to your question.

Apart from our sex chromosomes (X and Y), we have two copies of all the other chromosomes, which are collectively referred to as autosomes. We therefore have two copies of each autosomal gene, so to some degree we can regard one as a backup copy. This is just as well, because we think that all of us carry faulty copies of perhaps 10 different genes. Altogether, we have at least 20,000 different genes, so my 10 faulty genes are probably different to the 10 faulty genes in most other people.

Autosomal recessive diseases occur when we can cope with one faulty copy of a gene but not two faulty copies. If the parents are both carriers of the same faulty gene, then their children are at risk of inheriting two faulty copies. The parents are almost always unaffected thanks to having one good copy. When they conceive a child, there is a 1 in 4 chance the child will inherit 2 healthy copies, a 1 in 4 chance they will inherit 2 faulty copies and a 2 in 4 chance they will get one of each.

We share about half our genes with our "1st degree" relatives (parents, siblings, children), a quarter of our genes with 2nd degree relatives (uncles/aunts, nephews/nieces, grandparents/grandchildren), one eighth of our genes with 3rd degree relatives (first cousins, great grandparents, great grandchildren) and so on. So if we get back to the 10 or so faulty genes that each of us carries, then so long as my partner's faulty genes are different to mine, we are not at risk of having an autosomal recessive disease. However, you can imagine that the chance of first cousins carrying the same faulty gene is much higher than for unrelated individuals. The more distant the relationship, the less likely we will carry the same faulty gene.

In practice, first cousin parents are probably about twice as likely to have a child with a genetic disease than unrelated parents. The risk would be higher except for the fact that autosomal recessive diseases are only one category of genetic disease, and we are all at a background risk of having a child with some type of genetic disease.

The other aspect of this issue you may have been wondering about is the risk in groups who share a geographic, ethnic or cultural origin. It is well known that some groups have a particularly high incidence of certain autosomal recessive diseases. For example, beta-thalassemia is more common in people from the Mediterranean, sickle cell disease is more common in African Americans, cystic fibrosis is more common in Caucasians and some metabolic diseases are more common in Ashkenazi Jews while others are more common in the Amish. Sometimes this is because being a carrier actually offers a survival advantage, meaning the "faulty" gene has become more common in that group. This applies to beta-thalassemia or sickle cell disease carriers, who have more resistance to malaria, and to cystic fibrosis carriers, who appear to be protected against cholera.

In some groups, like Ashkenazi Jews and the Amish, this may be because the current population is descended from a relatively small number of ancestors or "founders", often two or three centuries ago. Some faulty genes may be much more common in such groups because they were common in the small number of founding individuals. This is particularly the case when the group remains relatively isolated for geographic or cultural regions.

There are at least two examples where autosomal recessive mitochondrial diseases have been shown to be 10 to 20 times more common in a specific region or group than elsewhere. This occurs with Leigh disease in a particular region of Quebec, apparently because much of the current population is derived from a small number of French settlers, some of whom carried a particular Leigh disease gene. In Australia the frequency of mitochondrial disease is about ten times higher in the Lebanese community than in the general population. Like many other groups around the world, the Lebanese have a tradition of arranged marriages that favors marrying relatives. This is largely for cultural reasons and is common in both Christian and Muslim families. It has resulted in several different mitochondrial diseases being more common in this group. It is likely that other similar examples will be discovered in coming years.

Answered by: David R. Thorburn, PhD

Q: I don't know if this is normal or not, but here it is: my seven year old son constantly holds his breath. He does this several times a day. I don't know why he does this. He doesn't speak so he cannot tell me why. Is this something I should be concerned about? Could it have something to do with a mitochondrial disease?


Breath-holding spells are relatively common in young children and typically start between 6 to 12 months of age. Although these spells usually end by about age 3 years, children can have them up to 7 years. Such spells, especially if isolated, are not particularly concerning for mitochondrial disease. It is very important to evaluate children who have such spells, especially at a relatively late age, for other underlying problems, including seizures, central and obstructive apnea, or a heart condition.

Answered by: Greg Enns, MB, ChB


Q: Our son has Mitochondrial Encephalomyopathy Complex I and III. He had a Nissan and G-tube placement in November 2006. He has had three esophageal dilatations since for retching. He continues to retch with at least one feeding a day. He currently is only g-tube fed and receives 125 ml at 250ml/hr every three hours around the clock. We requested a swallow study and it showed that everything was "normal." However, he is still retching and when our speech therapist feeds him orally, after 5-10 mL of thickened food he gags and retches it back up. We have tried slowing down feeds and decreasing the volume which helps some. We also are venting him when his retching occurs. Is there any other suggestions? Could it still be the Nissan? He did not do this before the surgery. In fact he could safely drink about 4 ounces of formula orally the day before the surgery and has not been able to since. Thank you for your time.

A: This problem is likely due to a combination of the Nissen and dysmotility. Slowing the pump rate, or switching to continuous feedings, venting the G-tube after oral feeding, and using a pro-motility agent (Domperidone/Reglan) are worthwhile treatment considerations. Use of typical CVS medications such as Periactin and Zofran may help. In some instances, releasing the Nissen is necessary.

Answered by: Sumit Parikh, MD

Q: I am a 51 year old female with probable mitochondrial myopathy. I just had a gastroscopy & colonoscopy. Following the procedure my muscles are extremely tired making it difficult to walk - my legs are very wobbly. I was given midazalam & fentanyl for sedation during the procedure. They didn't give my propofol because they thought it may have contributed to a similar reaction on another occasion (5yrs ago - couldn't walk at all then). I had a colonoscopy 3 years ago using just these same 2 drugs and while a little tired my muscles didnt react to nearly the same extent. Can you offer any suggestions as to what might cause this muscle fatigue following the procedure?

A: I am sorry to hear about your muscle effects to the bowel procedures. I

hope that your tests were negative. Sometimes there is a direct

relationship both temporally (with a procedure or incident) and

theoretically (meaning we know that this procedure, medication,

stressor) with an event that exacerbates a mitochondrial disease

symptom. Sometimes there is not. The latter is difficult to completely

resolve and give a concrete answer to "why." My thought is that maybe your

energy reserves were slightly down compared to the last procedure. The

medications were used (hopefully the same dose and duration of

procedure-which could alter your response to the procedures) and the

same physician, so likely these variables were constant. That being

said, if your energy reserves were down (feeling fatigued, maybe diet

not as optimal as before, or alteration in sleep, etc), this could make

your response to the stress of the procedure more dramatic and affect

your muscle function. It is sort of like the "brownout" in New York

City, as the energy demand could not be met by the power available.

This is pure speculation without knowing what sort of mitochondrial

lesion you might have. You will be better able to judge the events as

you recover. I hope that your recovery is full and complete.

Answered by: Russell Saneto, DO, PhD


Q: I have a daughter who is 15 yrs. old and was diagnosed by fresh muscle biopsy with Complex I and IV and carnitine deficiency. She also has uncontrolled seizures. For the past year we have been having trouble with mild constipation. She has a bm approximately every 3-4 days. I am wondering if you can give me some specific suggestions for this. I know there are certain dietary things to try but I'm just not sure what. Also, I have read several articles lately about osteoporosis. Is this a common problem with mito patients? And what are the deciding factors when considering a bone density screening? Also, we had a doc suggest doing a sleep study because she is so drowsy sometimes and sleeps 10-12 hrs, most nights and also naps during the day. He thought she may have sleep apnea. But wouldn't her drowsiness and need for lots of sleep just as likely simply be from the mito disease? And if she did have apnea is there a good form of treatment for someone who moves a lot in bed and wouldn't understand to stay clear of the air lines? Thank you for any suggestions and help.

A: I am sorry your daughter is having difficulties. There are a number of questions embedded into this one question, so I will attempt to answer them separately. Because I have not had the opportunity to review your daughter’s records or examine, much of my response will be somewhat generic in character.

First of all to address the constipation, there are a number of factors that lead to its development—neurological tone in the bowel, not enough fiber or fluids, and immobility. It is not infrequent in patients who are not ambulatory or mobile (i.e. not walking) to develop constipation. Additionally, some patients with mitochondrial disorders can have low muscle tone in the GI tract, as well as poor motility. For some patients it is not uncommon to not have a daily bowel movement. Constipation depends upon the interval between stools, but also the consistency (i.e. hard) or quality (pellets) of the stool as well. For many patients a daily laxative such as milk of magnesia may help and does not lead to dependency. Ensuring adequate fluid intake and fiber in the diet will help (prunes and pears might help). If this is not working, and the stools are hard, a stool softener can be added to the regimen or mineral oil. Beyond this an irritant to the colon such as enemas or even lactulose may be required in recalcitrant cases. Is your daughter taking carnitine?? In some individuals carnitine causes some loose stools, which may help the problem in this case. Keep in mind that the antiepileptics may be affecting GI transit time as well.

People who are immobile or on certain anticonvulsants are at risk of osteoporosis. An X ray can detect radiographic features of this such as hyper lucent bones, and the decision to pursue a bone scan can be made, however this is a nuclear medicine test. Calcium can be added to the diet, the caveat being that it can enhance constipation (see response above).

Lastly, you have questions about sleepiness and sleep disorders. Drowsiness in the day can be a symptom of mito disorders, and also of a sleep disorder as well. Patients with sleep apnea appear to be sleeping at night, but because of multiple respiratory issues such as decreased oxygenation and apneic spells, have very inefficient and nonrestorative sleep. As a result they fall asleep often in the day and appear overly sleepy. Narcolepsy can present with need to sleep and falling asleep quickly in the day and may have a genetic component. Medications such as antiepileptics can cause sleepiness or disruption in sleep as can many neurological disorders which interfere with circadian rhythm of sleep. The best way to determine if there is a medical sleep problem is an overnight sleep study and daytime multiple sleep latency testing. Other signs of sleep apnea may include snoring, gasping in sleep, cessation of respiration, and restless legs. The treatment depends upon the underlying cause and may include tonsillectomy, CPAP machines at night, or activating medications.

Answered by: Andrea Gropman, MD, FAAP


Q: My question is related to hyperbarics and Mitochondrial Disease. What are the risks of undergoing hyperbaric treatment with Mitochondrial Disease? There are stories of mito families online who have benefited from hyperbarics and published animal studies with mito that have shown positive results! So why are no human clinical trials being started?

A: This is a recurrent question from patients. No human studies have been done because experts in mitochondrial diseases are not convinced of the benefits and are very concerned about possible side effects. I agree that a thorough review of normal animal studies (unfortunately, there are no good animal models of mitochondrial diseases) should be conducted and a consensus should be reached about the risks versus benefits of this techniques in patients. I know that this avoids the question but it is the best I can offer.

Answered by: Salvatore DiMauro, MD


Q: I am a newly diagnosed adult with mitochondrial myopathy primarily affecting my respiratory function and fatigue. My neurologist suggested taking CoQ10 200mg per day and L-Carnitine 1000 mg per day. I am having a terrible time tolerating the side effects of carnitine, primarily nausea and headaches. I have tried hard caps, gel caps, emptying powder from gel cap but stopped each after 3-4 days. Any suggtions? I couldn't even tolerate 250mg at a time.

A: L-carnitine often causes gastrointestinal symptoms including nausea, vomiting, and diarrhea. In addition, patients sometimes develop a fishy body odor. The side-effects are often worse with high doses of L-carnitine; therefore, I suggest you start taking the lowest tolerated dose. The dose can be increased gradually. In addition to pills and gel-cap preparation of L-carnitine, there is a liquid form, which is preferred by some patients.
Answered by: Michio Hirano, MD

Q: Do you have a biochemistry reference as to difference in chemical structure or activity of the different formulations of coq10? I just received some bottles of it as a donation from my aunt, and it is a big savings, but it says on label: coenzyme q10 200 mg caps AS UBIDICARENONE instead of the ubiquinone that the others have. If no reference, do you have clinical experience with this formulation of the coq10 product?

A: As far as I know, Ubidecarenone is the brand name of CoQ10 used in Italy and - as far as I know - it is a perfectly adequate formulation. I know several Italian patients with CoQ10 deficiency or other mitochondrial diseases who responded very well to Ubidecarenone administration. So, take it without hesitation: it is CoQ10 and I hope it will prove beneficial!

Answered by: Salvatore DiMauro, MD


Q: I have a 17 year old daughter who has been diagnosed with Leigh's based on her clinical presentation at age 15 months. She has seizures (clonic-tonic, I believe partial) fairly well managed with Keppra but she also takes Neurontin and Klonopin for pain. Previously she was using these for the seizures but they were too sedating or not effective. Her EEGs over the years have never demonstrated seizure activity. For years, she has had "episodes" where she spaces out. Over the last 6 - 9 months, they have increased in frequency and duration. A 24 hour EEG demonstrated no seizure activity, and a 6 hour video EEG showed no seizure activity during the "episodes." The events last up to 2 minutes; sometimes she will respond to verbal or tactile stimuli then go back to the staring, and other times you can touch her lids with no response. Given the events are apparently not seizures, is there any explanation for then from a mitochondrial perspective? Could there be a transient severe energy deficit?

A: I am very sorry to hear about your daughter's mitochondrial disease.

Sometimes it can be very difficult to discern between an unprovoked seizure event and a behavior. Staring spells or episodes of unresponsiveness are difficult to make the diagnosis, seizure or behavior. One clue we often ask about is whether light tactile touching can "bring a patient out of an event." If so, then this is not a seizure. Mitochondrial patients are more problematic, as sometimes even tactile stimulation will not alter their staring but other symptoms tell us that the events are not seizures, such as having the eyes closed or rocking back and forth, or having the event only during particular times and never while doing an enjoyable task. The best test is what you had, a Video-EEG where we can look at the event at the same time as the EEG.

If the EEG does not show an electrical seizure during the event in question, then it is not a cerebral seizure. That is good news.

The next question you ask is what this event might be. In some patients we think it is a "brown out" or period of energy deprivation. Some times it is just "tuning out" that we all have. In children with cognitive dysfunction, the latter is more of a possibility. Certainly the two can occur either separately or at the same time. I have also seen in some patients who have "air hunger" in which they develop shallow breathing for a period of time and then have a "staring" event and can occasionally have some shaking of the body or extremities. This is likely due to a brief lack of oxygen.

Answered by: Russell Saneto, DO, PhD


Q: I have concerns about further immunizations for my son who is age 5 and a Mito patient. I’ve heard that some Mito children do not tolerate immunizations well and he seems to be one of them. Unlike a previous question, our son has a history of severe reactions. Specifically after his MMR shot at 12 months of age - Large purple splotches (within minutes of the injection w/hyperactivity), followed by complete loss of verbal skills and increased "autistic tendencies”. After almost two full years of intense speech therapy and early intervention programs, he began functioning at all age appropriate levels and above. He has continued to thrive in preschool and daycare up to this point (current treatment is only a modified diet, with a daily multi vitamin and vitamin C). We also suspect reactions to his DTaP and/or IPV shots which were always given at the same time (diminished use of his right side). Physical therapy was performed and issues seemed to resolve after 30 days. We had many unexplained issues to deal with in that first year and I am sure not all were injection related as this was prior to his diagnosis and we were clueless as to what we were dealing with at that point. Now, the huge dilemma. It’s time for more immunizations. With the severity of the reactions do we immunize or not? Are live virus injections more risky with Mito kids? Is it better to avoid the “combo” injections? We live in a small rural community and our PCP has stated the risk contracting some of these contagious diseased is much lower here however, there is still that risk. She definitely has concerns with the MMR shot. Our Mito doctor is completely undecided on this one and has suggested I “Ask the Mito Doc”. We are trying to make the best educated decision possible for the well being of our son and ask for your help in this matter.

A: To our understanding - it is not the immunizations themselves that are harmful in mitochondrial disease - but rather the potential for associated fever after the injection, since a fever might precipitate a "metabolic crisis."

In regards to immunizations and autism, medical authorities on the matter world-wide feel that there is nothing about the vaccines or the mercury in them that cause autism. There may potentially be a subset of children inherently at risk of autism that have their symptoms become more noticeable after any illness - including the fever brought on by immunizations. However, there is no good medical evidence to support such a theory either.

Your son seems to have had both, an allergic reaction (splotches) and regression (autistic behavior) correlating with the time he received the MMR vaccine.

If you have a concern that he will have another allergic reaction to the immunizations, I recommend that your pediatrician consult an allergist, to ensure that such a reaction is avoided. The allergic reaction might have been enough of a 'catabolic' reaction to bring out metabolic symptoms in him. For the vast majority of children and adults, the benefits of the vaccines do outweigh their risks - but in case your child is one of a few individuals who is more sensitive to the body's changes that occur after an immunization - I agree with approaching this matter with caution. In such a case, holding off on a 'booster' vaccine until he is older or more developmentally stable, is a reasonable decision.

There are no other specific guidelines or precautions that I can provide - except that any post-vaccine fever should be treated, and that he should be kept well-hydrated afterwards.

Answered by: Sumit Parikh, MD

Q: My 9 yr old son has lactic asidocis and Complex III deficiency. I have never been fully tested for the disease through biopsies and am wondering if it would be useful. I experience muscle weakness especially under stress, chronic fatigue, thyroid dysfunction and severe constipation. I also have a heart murmer. My mother also experiences similar symptoms and most prominently, severe vertigo. I am wondering about the possible genetic link and courses of treatment.

A: Mitochondrial disorders, including complex III deficiency, can be transmitted from mother to child in the mitochondrial DNA (mtDNA). mtDNA is inherited intact (without recombination) only from the mother. Thus, in the absence of a new mutation, a child has exactly the same mtDNA sequence (good, bad or in-between) as his/her mother and siblings (brothers and sisters), as well as his/her mother's mother and siblings.

Despite having the same mtDNA sequence, it is quite common for family members of a more severely affected child to be mildly affected themselves. In fact, you listed some of the most common conditions in family members of a patient with mtDNA disease: muscle weakness, bowel disorders (including constipation), chronic fatigue and thyroid disease. Some other common manifestations are migraine, other chronic pain, depression, and rapid heart beat (tachycardia). Vertigo is not common, but not that rare, in mtDNA disease in my experience.

Certainly, many of the above-listed symptoms are common and have many potential non-mitochondrial related-causes. It is when many of these conditions are seen much more frequently among family members that carry the same mtDNA sequence, than among other relatives, that maternal inheritance of a mtDNA mutation should be considered.

When energy demand is high, this creates even more problems in mitochondrial disorders, in which energy supply is lowered. Stress increases energy demand (as do viral and other illnesses, and many other things), and thus symptoms that occur with stress are often seen in mitochondrial disorders.

In my opinion, I would advice against a muscle biopsy, but others might advise differently. Most often, muscle biopsy results in mildly affected relatives are borderline or normal in my experience. But, I would advise speaking with your physicians regarding biopsy as well as the following potential options:

1) Sequencing the cytochrome b gene, which is the only complex III gene in the mtDNA. However, if other muscle respiratory chain enzymes are slightly low, then it is likely that the mutation is elsewhere in the mtDNA. Complete mtDNA sequencing is available from a couple of laboratories. I recommend starting with cytochrome b, then proceeding with sequencing the whole mtDNA. However, an obvious mutation is often not found in cases like that of your family. However, if one is found, you have a diagnosis in your child and you can be personally tested for the mutation (in which case you almost certainly would have it).

2) Obtain quantitative urine organic acids from yourself during a period of physiological stress, such as during a non-trivial viral infection, especially if associated with fever or vomiting. In patients with mild mitochondrial dysfunction, urine organic acids are often normal when well, but show characteristic abnormalities while ill.

3) Discuss with your physicians a trial of mitochondrial supplements. These are often as or more effective in patients with milder manifestations of mitochondrial disease than in those with more severe disease. A discussion of the options, dosages and recommendations for the supplements are beyond the scope of this response. However, co-enzyme Q10 makes particular sense in a complex III deficiency.

Answered by: Richard G. Boles, MD


Q: I was recently diagnosed with a possible mitochondrial disease. The skin biopsy showed damaged mitochondria and several other tests pointed in this direction. My doctor has me on the supplements: carnitine, CoQ10 and B2. I was talking with another adult who has a mitochondrial disease and she brought up some questions to me that I am also wondering - how would I find out if I have a fatty oxidation problem? Is this useful information to know? How would I be tested for it? Are there any treatments? Is there a certain diet I can go on now to see if my condition improves and if it does with diet does it mean that I did have a fatty oxidation problem? I do not know what type of mitochondrial disease I have. If we were able to find out, is this useful information and why? Will it change my course of treatment? Can you please tell me the pros and cons of the muscle biopsy? Can it determine the fatty oxidation issues or the type of mito disease I have?

A: In regards to your questions - let me try and answer each one separately - though the questions you ask suggest the need to meet with a mitochondrial medicine doctor.

1) Based on what you have said - I agree that you could possibly have mitochondrial disease - but more testing is needed (on the skin fibroblasts at the very least).

2) Fatty acid oxidation (FAO) problems can be tested for in blood acylcarnitines and fatty acid oxidation studies in skin fibroblasts.

3) The treatment for disorders of FAO depend on which one it is. Some individuals with unhealthy mitochondria can have a problem with FAO just due to the "back-up" in the system, and has nothing to do with a primary FAO disorder.

4) Dietary changes are not recommended unless a specific FAO disorder is being treated. The only dietary change that is worthwhile is what all docs recommend - "a low fat, low calorie intake that is age appropriate, with plenty of fiber, fruits and vegetables." This type of a diet has been shown to help a person gain healthy mitochondria (as has routine exercise).

5) Knowing the type of mitochondrial disease (Complex, acronym subtype or genetic type) rarely allows us to give accurate prognosis or adjust treatment. It is more important to exclude other diseases that can lead to secondary mitochondrial dysfunction since some of these diseases are treated differently.

6) The value of a muscle biopsy is to allow for your mitochondria to be studied more accurately, and better confirm that you have unhealthy mitochondria. FAO can also be studied in muscle (though if skin fibroblasts are available, these should be tested first). Having muscle and muscle testing might allow for more focused genetic testing (but not always). The results do not change prognosis or treatment.

Answered by: Sumit Parikh, MD



I was diagnosed over 13 years ago with adult NARP (8993-TG). Has anything changed, or more learned, regarding its DNA maternal inheritance and nutritional supplements with dose ranges?


A: There has been no major recent progress in our understanding of NARP. It is clearly maternally inherited and the severity of the presentation varies with the degree of heteroplasmy (i.e. the percentage of mutated mtDNAs in various tissues). We, among others, are experimenting with different conditions in vitro (using cultured cells containing the NARP mutation) in an attempt to identify pharmacological compounds or dietary regimens that would "shift down" the percentage of mutated mtDNAs. Unfortunately, all I can say is "stay tuned"! My colleague Michio Hirano has already answered the second part of your question.

The recommendations for nutritional supplements for mitochondrial patients have not changed significantly over the last few years. Our recommendations are as follows: Coenzyme Q10 (CoQ10) 50-200 mg three times daily (although some patients with primary CoQ10 deficiency have taken up to 1000 mg three times daily) levo-carnitine (L-carnitine) 300-1000 mg three times daily (many patients develop gastrointestinal side-effects at high doses) Thiamine (vitamin B1) 50-200 mg daily Riboflavin (vitamin B2) 50-600 mg daily Vitamin C 100-400 mg daily (usually divided into 2-3 daily doses) Vitamin E 200-1200 IU daily Vitamin K3 5-80 mg daily Folate 1-10mg daily Alpha-lipoic acid up to 400mg three times daily Creatine monohydrate 5-10 grams daily Idebenone 45-360 mg three times daily (Sometimes used instead of coenzyme Q10) Michio Hirano, MD

Answered by: Salvatore DiMauro, MD


Q: I am getting near the perimenopausal age, and even though I have regular periods, I suspect they aren't always ovulatory anymore. This would be consistent with the fact that the lifetime of symptoms I had would always occur immediately before menses onset of each cycle, and since the pain disorder, I noticed that the pain itself would increase at that time as well. Is there any documentation of the effect of female hormonal cycles on mitochondrial function in healthy people as well as those with mito disease?

A: Hormones in females can exacerbate many neurologic symptoms, including pain. Perhaps this is due to edema (fluid retention) around the nerves; most notable are menstrual migraines or catamenial epilepsy (seizures right before a period). I do not know how much has been studied in the mito population, but there is ovulatory dysfunction described in the mito population that can cause missed periods, early menopause, or infertility.

Answered by: Amy C. Goldstein, MD

Q: Can you comment on the new form of prescription coenzyme q10 product that is on the market called coquinone, I believe, that is touted to be more available for production of ATP and less likely to cause oxidative damage because of the combination with alpha lipoic acid? Is it proven as effective in mito diseases? Side effects? Availability?

A: Thank you for your question. CoQuinone is a combination of lipoic acid and coenzyme Q10. Unfortunately, it is not a prescription formulation.

In fact, there is no formulation of coenzyme Q10 that is a prescription medication. The company claims that their product is more bioavailable (meaning that what you take gets to your blood stream) than forms of coenzyme Q10 found in dry tablet/capsule formulations. The added lipoic acid is included to keep coenzyme Q10 in its active or pro-oxidant form.

The use of any product should be talked over with your physician before using and benefits are not universal.

Answered by: Russell Saneto, DO, PhD


Q: I am having trouble again with my breathing. However, the lung doctor who put me on oxygen said that my problems were not his place to treat because my lungs were fine it was only the muscles around my lungs so my muscular dystrophy doctor would have to take care of me. Therefore I don't know whether to try a new lung doctor are just wait until my next appointment with my Mito Doc for help. Also I sleep with a cpap machine with a warmer because my muscles want to collapse while I sleep. I read in one of the Mito news letters where a writer said that a C-Pap machine could be fatal in Mitochondria Patients, and they should only use a V-Pap machine. Therefore, I am very concerned about this. I just need to know if this information is true or not. If it is I will contact my sleep doctor and discuss the matter with him.


Your symptoms sound quite severe. I think it is most important for you to have a full evaluation by a pulmonologist as soon as possible. Because of your neuromuscular disease, I agree that CPAP will not be helpful. You need help with ventilation or "moving air", and CPAP does not do this, while BiPAP will. A pulmonologist can help evaluate your breathing difficulties by performing pulmonary function tests, including a sleep study, and prescribing appropriate medications, if needed. Importantly, a pulmonologist can correctly set up BiPAP, which has the potential to help with your symptoms.

Answered by: Greg Enns, MB, ChB


Q: My daughter, age 4, has Mitochondrial Disease Complex 1 and 3. We are currently awaiting test results from her specialist, who is analyzing her DNA to see if it is maternally based or recessive. My son is 7 years old and has severe food allergies. He has also started sleep-walking and woke up one morning with a gash over his eye that required stitches. He does not remember it. Are there any links with Mito and food allergies and/or sleep walking.


There have been no reported associations with food allergies or sleep walking with respiratory chain deficiencies. Food allergies and sleep walking are of course common in this age group, so are most likely coincidental to the respiratory chain deficiency.

Answered by: Gerard Vockley, MD, PhD


Q: I am 50 yrs old and have a diagnosis of Mitochondrail Myopathy. I have recently been diagnosed also with myasthenia gravis. Have you seen this in others with MITO and how will this affect the mito symptoms, if any?


The diagnosis of mitochondrial disease and myasthenia gravis are often very similar - I have not heard of patients with both diagnoses, but often heard of patients in whom one diagnosis has been made but subsequently are shown to have the other. My question would be, how much evidence is there that you have mitochondrial disease and how much that you have myasthenia?

Answered by: Douglass M. Turnbull, MD, PhD


Q: I am 51 years old and have been diagnosed with MELAS. I had a positive muscle biopsy in Feb 05. My question is I have parkinson's symptoms but my neurologist in Houston says it is a result of the disease. My local neurologist has me on parkinson's meds but they have caused some side effects such as more confusion than normal and myoclonic jerking, so we reduced the dose. My symptoms have leveled out but I am confused on whether these drugs are helpful or have I just had a plateau of symptoms. I have cardiac problems along with this mito disease so I am on lots of medicine. Thanks for any information. I realize you are not here to diagnose; I'm just confused!


As the name implies, mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS), is a mitochondrial disease characterized by unusual stroke-like episodes in young people (generally under age 40) and elevated lactic acid in blood. Parkinsonism (symptoms or signs resembling Parkinson disease) is not typical of MELAS, but has been reported in at least one young boy with MELAS (Ann Neurol 1999;45:130-3). In addition, mutations of the mitochondrial DNA polymerase gamma (POLG) sometimes cause Parkinsonism. Therefore, it is possible that your Parkinsonism is due to your mitochondrial disease.

Because you do not have Parkinson disease (PD), your response to medications will be different from typical patients with PD. It is difficult to know whether the leveling out of your symptoms are due to the medications, plateau of the disease, or both. Since your Parkinsonism has not improved with medications, you should talk to your neurologist about continuing or changing therapy.

Answered by: Michio Hirano, MD


Q: I am a 49 year old male with LHON AND MERRF. I am scheduled for a colonoscopy on 1/29/07 and thought I've read that those with a Mitochondrial problem should watch out for fasting, and special measures should be taken. Could you please tell me if fasting for 24 hours should be avoided and what kind of precautions should be put in place during the procedure?


Wow, sorry to hear that you have two problems, LHON and MERRF. Do you have both the most common mutations, 8344 (MERRF) and 11778 (LHON)? The reason for the fasting is so the colon can be as clean as possible to view. You should be allowed to have fluids, water, soda, jello, chicken broth before 6 pm the night before the procedure. If you schedule the procedure early in the am, then you will not be without nutrition for too long. The procedure is short so likely there will not be the need for prolonged anesthesia. If possible I would see if you can use the FLEETS treatment. It is better than the Go-Lytely and you can drink it with some root beer (source of carbohydrate). I hope that the procedure does not yield any polyps and you can have another 10 years before the next one.

Answered by: Russell Saneto, DO, PhD


Q: My son has been diagnosed with Complex I. The diagnosis was confirmed after a muscle biopsy was performed. Is it possible that he has another disease instead that interferes with how the mitochondria work and this is what caused the test results. In other words, could he have something else which causes a "mis-diagnosis" of mito disease?

A: You are asking a very sensible question but one for which it is difficult to give an absolute yes or no answer. You are correct in thinking that some conditions can interfere with how mitochondria work and lead to a change in the amount of Complex I and other mitochondrial enzymes. For example, children and adults with many problems leading to muscle disuse or weak muscles may have fewer mitochondria and less Complex I in their muscles than a healthy person. Conversely, an elite athlete may have lots more mitochondria and hence more Complex I in their muscle than a person of average fitness. So a low amount of Complex I per gram of muscle doesn't necessarily mean that someone has a primary genetic cause of Complex I deficiency.

All experienced mitochondrial diagnostic centers therefore have to look at not just Complex I, but Complex II and Complex IV and other mitochondrial "marker" enzymes as well such as citrate synthase. The pattern and ratios of enzyme activities are more important than the absolute amounts. For example, if we found less than 20% (one fifth) of the normal amount of Complex I in a muscle biopsy and the other enzymes were all 100% of normal or higher, we would regard it as strongly indicative of Complex I deficiency. But if other enzymes such as citrate synthase were also low, then we would think the low Complex I activity may be secondary to some other condition rather than a primary Complex I deficiency.

I would expect that any experienced diagnostic center performing measurement of mitochondrial enzyme activities should have studied muscle samples from individuals who have muscle disease that is caused by something other than a mitochondrial problem. That type of experience helps the lab to distinguish primary genetic problems from secondary ones. However, we and many others take the attitude that for a definite diagnosis of mitochondrial disease, we cannot rely on measuring enzymes alone but need to consider the complete picture.

For a definite diagnosis we want to see support from other independent sources, such as the specific symptoms, imaging studies, metabolic studies, mutation analysis or other studies such as muscle histology. That is a relatively conservative approach which means that we only give a definite diagnosis to patients with strong evidence from two or more sources. For those patients we are essentially certain that they have a primary mitochondrial problem. The downside of that approach is that some patients end up with the unsatisfactory label of a probable or possible diagnosis. Since you are clearly concerned about whether the diagnosis is certain or not, I suggest you ask your physician to confirm whether they regard the enzyme results and other investigations as sufficiently strong to warrant a definite diagnosis.
Answered by: David R. Thorburn, PhD

Q: Is it likely to have a healthy baby after having a late miscarriage of twins four years ago, then having a one year old mito-affected baby, and then another miscarriage a few months ago, in a mito-affected mother who also has cancer?

A: Unfortunately, it is virtually impossible to answer your question. From what you say, I assume that the mitochondrial disorder affecting both you and your child is due to a mutation in the mitochondrial DNA (mtDNA) because it appears to be maternally inherited. This is the aspect that worries me more than the cancer for what concerns the health of a new baby. Most mtDNA mutations are transmitted from the mother to the fetus, but for most of them it is impossible to predict how they will distribute in different tissues of the baby. Do you know the nature of the mutation? This may be very important.

Answered by: Salvatore DiMauro, MD


Q: I have a specific question regarding lactate levels in blood with children with mito diseases or who are being tested for mito diseases. My son who is almost four is being tested for a mito disease. In spring 2006 he had blood tests done and his lactate levels were in between 5 and 6. Prior to this first test my son was very sick. He had colds, flu, and had vomiting and diarrhea issues. He missed half of his days at preschool due to sickness. In fall 2006 he had another blood test to check his lactate levels. They were between 1 and 2. My question is this: In the summer, July and August, he was not sick and actually during this time he was very healthy, finally progressing, and made huge strides in his development. Does the swing in lactate acid levels happen in people without mito diseases? Or do lactate acid levels reach that high normally with sickness? Is this an indication of the disease? A muscle biopsy was done and found no red ragged fibers. I am not sure if I should mention this to the doc testing my son. We met with him and I am not sure that he knows how sick my son was for the first test versus the second test?

A: I would need more details of your son to answer specifically. In general, however, lactate levels are very variable; even in definite cases of mitochondrial disease we have seen repeated normal values. As we know, levels are definitely affected by illness even in non-mito kids. Fever, dehydration, viral infections, etc. can all raise the levels and usually when children are sick, they may cry more, which also affects levels. Even IV glucose can raise levels. So in a nutshell, yes, the levels described do not confirm or exclude the diagnosis of a mito disease; neither does the absence of ragged red fibers. One would need to review all the features and results to have a good pciture and even then it is difficult.

I have statistics to illustrate this for children even proven to be Complex I deficient, as an example. Many other mito kids can be similar. The only real situation I have found that the lactate is persistently elevated (other than children wo are severely ill) are those with Pyruvate carboxylase deficiency and some but not all children with the MELAS 3243 mutation. When lactate is elevated, it is helpful with diagnosis; when it is not, it isn't helpful. I think there are other mito doc Q&As along these lines in the archives, too.

Answered by: Annette Feigenbaum, M.D., FRCP


Q: Is it rare for a child to not show any signs of having a mitochondrial disorder except protein wasting in the urine? Could the skin biopsy be a false positive? My son has a Complex I mitochondrial disorder. He shows no outward signs of a disease; he is strong and the only problem that he had was that he had protein wasting in the urine and was slow to grow (10th percentile for height and weight), but that could be attributed to his parents' height and weight also. When could I expect to see some outward signs of the disease?

A: I am sorry that your son has kidney problems. Yes, there are patients

who do not express "outward" signs and still have a mitochondrial

disorder. This can be especially true in children who have a mutation in

a mitochondrial gene and only develop their disease when they become

young adults or later. Single organ involvement may also be seen in

patients who have mutations in structural nuclear genes of one of the

electron transport chain complexes.

There has been some debate on how reliable the fibroblast assay for

complex I is in various labs around the world. I know that the Netherlands

group has done a lot of nice work with complex I assays and skin

fibroblasts. There are other labs whose work is excellent as well. That

being said, yes, mitochondrial disease can be limited to a particular

system such as the kidney. It is difficult to give you an exact answer

as "protein wasting" is a broad term. Some mitochondrial diseases can

give a tubulopathy where there are electrolyte abnormalities and others

can give episodic times where there is elevated protein in the urine,

often associated with muscle cramps and maybe some weakness that will

resolve. The latter is particularly true in coenzyme Q10 deficiency,

which may give lower values in complex I, I/III and II/III, as well as

normal values on analysis. A complex III disorder has been shown that is

expressed as myopathy with myoglobinuria (protein in the urine).

So, I can't tell you if your son has a primary mitochondrial disease or

not. However, he does have a complex I dysfunction in his skin

fibroblast. He is short (albeit may relate to family height genes and

not a mitochondrial-influenced reason). He also does have "protein

wasting" evidence in his urine. There is no crystal ball to give us

information concerning when "symptoms and signs" of mitochondrial

disease may occur, although stressors such as illness and growth spurts

often are triggers. Let's hope that his only problem will be periodic

"protein wasting."

Answered by: Russell Saneto, DO, PhD


Q: My son is almost 4 years old and he has Mito, Complex I. He recently had a Nissen Redo. and Pyloraplasty, due to his reflux. He has been having pain after medications and feedings ever since this surgery. We recently found out he has dumping syndrome. We are going to put him on Levsin to help with the GI issues. Do you know of any problems with using this drug on a child with Mito? I read an article about the drug and it stated that it could cause him to not sweat which could lead to heatstroke. He does have autonomic dysfunction and has trouble controlling his temperature, but we were told our only other alternative would be to hook him up to a pump to feed him. He is rolling all over and we believe doing this would limit him.

A: I am sorry to hear your son is sick. Although I am a Child Neurologist, I have followed children with Mitochondrial Cytopathy that includes GI involvement. Reflux and GI motility issues are very common in children with mitochondrial disease. There are many medications that can help control GI symptoms, and Levsin is a common medication used for cramps. Your son may not experience any of the listed side effects, so if his doctor thinks it will help his GI symptoms, then you should try it and observe for side effects. I have not heard of children with mito in particular not being able to take this medication, and several of my patients are on it and doing well. There are several other medications that can be used to help treat the symptoms. It does not sound like he is having pseudo-obstruction or slowed motility/delayed gastric emptying, but rather motility that is too quick. Amitriptyline, Neurontin, Periactin, and the SSRIs (like Prozac) can all help the GI tract motility and can be used for irritable bowel syndrome. Speak to your doctor about the possibility of using these as well. Finally, even if you need to feed him via pump (he has a G-tube?), he may be able to have "bolus" feeds instead of being on a continuous pump, which would allow him to be mobile in between his feedings and your doctor can work out a feeding schedule for him.
Answered by: Amy C. Goldstein, MD


Two questions regarding dental issues:

We have a 5 yr old daughter with complex 1 deficiency.She has developed dental caries and gum inflammation, probably due to difficulty obtaining optimal dental hygiene, due to neural and GI impairment. Do you have recommendations regarding prevention and optimal dental hygiene? Secondly, she requires general anaesthesia to allow theraputic dental surgery.What are the precautions or recommendations regarding anaesthesia, and general peri-operative care?

mito disease affect dental health? I am a 51 year old woman diagnosed 2 years ago with MELAS. So far this year I’ve needed 3 root canal treatments. Now I have 2 more teeth that are presenting as problems, with electrical shooting sensations through them. I have had similar pains in my feet and hands. Could mito somehow cause injury or death to the nerve of the tooth? I don’t look forward to an additional 2 root canals or the cost of the subsequent crowns on these teeth.

A: Although as clinicians, we recognize that mitochondrial dysfunction can cause multiorgan system disease, we know very little about the possible impact on dental health. Some studies have suggested that patients with significant periodontal disease have low levels of endogenous Coenzyme Q10, pointing to mitochondrial dysfunction. Additionally the generation of reactive oxygen species by the mitochondria may contribute to apoptosis and gingival inflammation. Dietary effects of mitochondrial disorders may impact the ability of the enamel and gums to remain healthy and recover from minor traumas. Future research is likely to reveal more information on this subject.

In children with neurological impairment, dental hygiene may become a difficult issue to address. Additionally, certain medications given to control seizures, spasticity, etc. may cause gum hypertrophy or bleeding. The impacts of poor oral motor tone, mouth breathing, and residual food in the mouth may increase risk of dental caries and poor hygiene. The control of saliva and secretions can lead to either improved care or alternatively increased caries as saliva contains important antioxidant protective effects. Often there is no choice but to perform an examination, or perform dental care under anesthesia. The potential risks of anesthesia in a patient with mitochondrial disease may not be trivial. This topic is covered in much detail by an article authored by Drs. Bruce Cohen and John Shoffner that appears on the UMDF web site, and I refer you to this for more detail.

Answered by: Andrea Gropman, MD, FAAP



Are there known documented reasons why mito patients should NOT have a stress test on a treadmill? I had a stress test on a treadmill two and a half years ago and it nearly killed me. My cardiologist wants to update my cardiac status by doing another stress test in three weeks. I am physically dreading it. My stamina and endurance are not great now so why expend my energy on a treadmill?

A: The main contraindication to a stress test in mitochondrial patients is if the amount of exertion needed for the study would lead to a regression or decline in baseline functioning. If a patient or guardian does not feel that this test would be safely tolerated, it should be pursued with caution and a limitation on the amount of activity performed during the study.

Answered by: Sumit Parikh, MD

Q: We have a 5 year old son with muscle biopsy confirmed diagnosis of Mitochondrial Disease, Complex I & Complex III. In the last 9 months he has had 6 pneumonias, has lost tone in his face; his tongue seems to hang out a lot of the time; he no longer has reflexes in his hands, arms, ankles and knees, and has been diagnosised with paralysis of his left vocal cord. He just had an MRI of his brain and CT scans of his lungs as well as chest to base of skull - in which none of these tests showed anything. Are all the above issues expected with children with mitochondrial disease, or are these things that will return within time? Does this mean that his disease is progressing and if so what should we expect next and what should we do?

A: What you describe seems to point towards a mitochondrial disease affecting predominantly - if not exclusively - the musculature: brain MRI is described as normal and I assume that your son does not have seizures or cognitive problems: is this correct? The difficulty in giving advice and, especially, prognosis (that is, predicting the future) is that, even when one considers only the myopathies, there are so many different causes. A combined defect of complex I + III does not give me sufficient data to venture a precise diagnosis or a prediction on his future course. I would need to know family history, detailed clinical picture, histochemistry, detailed biochemistry, and whatever molecular studies have been done. I am sorry, but these diseases are like a tangle of string; you need to consider every loop before you can straighten the situation.
Answered by: Salvatore DiMauro, MD

Q: My doctor tells me I have had c difficile syndromes many times, even though only toxin positive twice. An immunologist suggested I get a carnitine level in June when I was complaining of leg weakness and he knew I had protracted c diff illness. When the levels were low, I began on supplements and during taper off my vancomycin at the end of June, I began getting what my doctors call air hunger, and I call shallow breathing followed by gasping. I was told to inquire about mitochondrial disease, but when I do, I am received by doctors in humiliating and disrespectful or outright non-communicative manners, and I am told this disease is only one of children, even though my reading tells me otherwise. Is c diff known to be an acquired cause of mitochondrial disease? How can I suggest this possibility to doctors who are ready to disclaim the idea of adult mito disease, and are not as aware as my own internist is that when someone gets a distended swollen belly and smells of stool all over, and feels very sick, that in the setting of antibiotic use, it is possible to have c diff because some of the treatments neutralize the toxin, I am told, or the toxin may not be secreted all the time. Please suggest how I go about broaching this without ridicule if there really has been an association in the literature.

A: I am sorry to hear about the difficulties you have had with your health and during your attempts to communicate with certain physicians. You are correct in asserting that mitochondrial disorders are not restricted to children. In fact, they can affect anyone at any age. Because mitochondrial disorders are associated with a variety of symptoms (virtually any organ system can be affected), these conditions are often considered when an individual has a confusing set of problems affecting different parts of the body. Although some individuals with mitochondrial disease have impaired immune function and an increased susceptibility to infection, I am not aware of Clostridium difficile infections actually causing mitochondrial disease. There have been reports in the medical literature describing how a toxin made by C. difficile likely affects mitochondrial function. This is not surprising because many different types of bacterial toxins harm mitochondria. However, this is different than having a toxin exposure cause permanent mitochondrial disease. If you are still experiencing weakness and breathing difficulties, your internist should be made aware of these symptoms, because a referral to other specialists, may be helpful. You can always refer a health care provider to a good source of information on mitochondrial disease, such as the UMDF website, but it might be best for your internist to contact directly the other doctors with whom you have had a difficult time discussing the possibility of mitochondrial disease.

Greg Enns, MB, Ch.B

Answered by: Other Doctor (Noted in Answer)


Q: Our daughter who is almost 11 is basically good all week and then on Fridays after school she goes into crisis. This has happened 3/7 weeks of school and also almost 100% when it has been a full week of school. They take her stats at school and they are "normal" for her (she has sinus tachycardia) and seems fine in school. They want to know what they can do in school to prevent this from happening. She is in a small self contained special ed classroom so they can do whatever we want specialized to our daughter. Seems that she uses all of her energy to get thru the week and then bottoms out come Friday night and it takes until Sunday for her to recover. Do you see this in other children and what can we do for it?

A: You described the chronic fatigue that is all-too-common in individuals with mitochondrial disease. It is well appreciated that patients with mitochondrial disease tire easily and show decreased stamina in physical and other activities. However, this is rarely studied or discussed in detail, perhaps because it is so intuitively obvious that an energy deficiency could result in fatigue. What is not often appreciated in the literature (but "lived" in so many families), is that this fatigue can be so severe and incapacitating as to be THE major concern of the patient and family. In fact, in an unofficial survey of our patients, the fatigue frequently is severe enough to meet the international diagnostic criteria for chronic fatigue syndrome. Among the families that demonstrate maternal inheritance, this is the case even more so in their mothers. For your information, a simplified version of the international criteria for chronic fatigue syndrome is:

1. Chronic fatigue for more than 6 months
2. Suffering from at least 4 of the 8 following symptoms:
a. Muscle pain
b. Joint pain
c. Headache
d. Sore throat
e. Tender lymph nodes
f. Still feeling fatigued after sleeping
g. Feeling "worn out" for more than 24 hours after strenuous activities
h. Substantial impairment in short-term memory or concentration

Although not on the above list, tachycardia (rapid heart rate) is a dysautonomia-related sign that is common in patients with mitochondrial disease, especially during fatigue.

Unfortunately, the fatigue that is so common in people with mitochondrial disease is very difficult to treat. Some children derive benefit from frequent snacks (especially with a high starch content, not a lot of simple sugars, and with some protein). Many children cannot tolerate the full school week and go onto half-day or otherwise reduced school schedules. I do not recommend this unless necessary as the children benefit from the activities, socialization and activities in school, and reduced schedules can delay dealing with the problem until later in life (college, job, family, etc.), when a higher productivity is more mandatory and people are less forgiving.

Some physicians recommend uncooked cornstarch and/or energy drinks/bars prior to exercise, as well as the supplement creatine (about 140 mg/kg/day or 5 grams maximum). Sometimes, caffeine can help with alertness, and with associated pain. These measures have not been well studied, but some families claim that they help a little.

In my experience, the best therapy for chronic fatigue in patients with mitochondrial disease is exercise. Exercise is also helpful in people in general with chronic fatigue syndrome. Whether you are a gold-medal athlete, a patient with severe mitochondrial disease, or somewhere in between, exercise will increase the number of mitochondria and the ability of each mitochondrion to make energy. Regardless how poorly the mitochondria may be functioning, more of them is better than less of them in this regard.

But some of you might be asking yourselves: "Doesn't exercise increase energy demand and thus cause symptoms?" Well, "yes" and "no". Many of our children with mitochondrial disease (and in many families, the mother and other maternal relatives as well) have had experiences in which a lot of physical activity resulted in severe fatigue, nausea and other symptoms, which then lasted for days. Exercise in mito patients can be a "double-edged sword". While precautions against excessive exercise should be taken, keeping active and participating in as many normal activities as possible is very important for patients with mitochondrial disease, both medically and socially. If walking one block makes your child tired and walking two blocks results in a day of fatigue, then walk one block - a few times every day! Frequent rest breaks, snacks and an increased fluid intake can often help. Exercise should be cut back or postponed when other causes of high-energy demands are present, such as hot weather, a viral illness (a "cold", etc.), allergies, etc. If your child experiences fatigue, headaches, nausea, or muscle pain as a result of excessive exercise, your child should be allowed to discontinue the exercise regimen or rest until the symptoms subside. If possible, discontinue exercise prior to the onset of these symptoms. It is imperative that the patient be listened to in regards to the symptoms listed above, as he/she is the only person who can dictate how much is too much exertion. A physician-written letter to the school/PE coach explaining this can often avoid problems and promote a more active and healthier lifestyle.

Answered by: Richard G. Boles, MD



What are the mechanisms behind the elevated ammonia levels and Reye-like syndromes that are referred to in Dr. Parikh's sample mito letter in patients with mito disease? How often are elevated ammonias seen in isolation from routine liver function test abnormalities? Given the mchanisms you cite, what are the tests recommended - i.e., is liver biopsy useful? And what are the treatments, other than oral lactulose and ruling out infections?

A: Reye-syndrome refers to a rapid onset, often progressive form of liver failure that has been anecdotally linked to aspirin use in children. We now know that some of these cases are due to disturbed fat metabolism (fatty acid oxidation disorders) - and the disorder presents as acute liver failure at the time of a metabolic crisis. Some individuals with mitochondrial cytopathies can have a secondary disorder of fat metabolism that can also lead to these symptoms.

The etiology of liver failure in those with a primary or secondary disorder of fat metabolism is still being studied - but it is often a physiologic stressor (illness, surgery, anesthesia, medications) that leads to the onset of symptoms and worsening liver function. In these situations, ammonia may become elevated since the liver helps the body remove excess ammonia.

Ammonia, in itself, can be elevated in mitochondrial cytopathies as well as other metabolic diseases, without concomitant liver disease. Ammonia is processed in the liver by a set of chemical reactions known as the "urea cycle." These reactions and the enzymes that are a part of it can become inhibited by some of the toxic species that build up in certain metabolic diseases. Marked elevations can be due to primary disorders of the urea cycle itself.

If ammonia levels are substantially elevated or leading to symptoms (sleepiness, vomiting, headache), they should be treated while the underlying cause of the elevated ammonia level is being investigated. While traditional medications such as lactulose can help, "metabolic medications" such as dextrose-containing solution, arginine, sodium benzoate, and sodium phenylacetate might be needed. If there is a concern of elevated intracranial pressure, mannitol can be used. Oral and IV protein restriction is helpful. In cases of very high ammonia elevations due to metabolic disease (such as in disorders of the urea cycle), sodium phenylbutyrate (brand name Buphenyl) is now prescribed.

Answered by: Sumit Parikh, MD


Can an adult with possible mito disease and is on supplements get a flu shot this season? My PMD was afraid to give it to me because of the possible neurologic complications. But I am getting home care and the aides change so often I believe I am at high risk of exposure to the flu. Whenever I get the slightest infection, I don't seem to breathe very consistently. I get air hunger until an antibiotic is started, so I am afraid I won't survive a viral disease. Is the flu shot now a live vaccine? What is the general recommenation regarding flu shots for people with mito disease?


A: I am sorry to hear about your condition. Yes, the flu vaccination uses a live virus, but one that has been engineered to be less harmful but yet give you protection against what is thought to be the strain(s) of the possible virus inducing infections for the flu season. My recommendation to my patients is to receive the flu vaccination. It is always possible to have a reaction from the flu shot as well as have a very mild version of the flu, although these are not common. The protection from coming down with the flu is worth the small possibility of having side effects from the shot. This would be especially true for someone with a fragile medical condition.
Answered by: Russell Saneto, DO, PhD

Q: If someone gets a muscle biopsy but is already on high doses of coenzyme q10, carnitine, supplemental phosphate, and namenda, and is unable to tolerate a taper because of respiratory and hepatic consequences, what is the likelihood that normal electron transport chain complex assays will miss a partial deficit or impaired function of some of the mitochondrial proteins?

A: This is impossible to really know but it is unlikely to be high. These supplements don't usually restore activity to normal so even partial deficiencies are unlikely to be completely masked. Certainly if there are observed clinical changes with discontinuation of the medications, they should remain and interpretation of results can be modified appropriately.

Parenthetically, the assay of cultured skin cells (fibroblasts) will not be affected by supplements and may offer another diagnostic option if any confusion remains over the diagnosis. Remember, however, that no test is 100% accurate in these disorders.

Answered by: Gerard Vockley, MD, PhD


Q: My 12 year old son has mito, complex I (by fresh muscle biopsy). Every few weeks he develops hives all over his body, which coincides with increased seizure activity (takes Lamictal and Keppra) and increased sleeping. Might the hives be related to an increase in specific levels related to mito? Your help is appreciated.

A: I am sorry to hear that your son has complex I disease as well as seizures that sound somewhat difficult to control. Seizures can influence the autonomic nervous system and induce changes in heart rate, blood pressure, decreased gastric mobility, etc. One of the changes can be pilomotor erection (hair on the body standing up). This might look like hives in some respects (feeling the skin with piloerection of hair and the change of skin color due to increased sympathetic nervous system output) but certainly it is not hives. Hives are a type of rash that moves in location and can be triggered by the release of histamine by chemicals, drugs, foods, and even physical touch. They can vary from pea size to large circinate patterns with red borders and white centers.

Since your son doesn't usually get hives from his medications (only seen during seizure events), and is related to his seizure activity, it is not clear to me the cause. Hives is not something that I have seen induced by seizures in children with epilepsy or having both epilepsy and mitochondrial disease.

A seizure is electrical chaos within the brain. Many, if not most children will be tired or sleepy after a seizure. Sleepiness or the postictal state is associated with seizures. If you are talking about continual sleepiness, that can be due to a variety of things. Those of us who take care of a lot of patients with epilepsy, worry about ongoing seizures that we can't see that may look like sleepiness.

Sometimes the extra medication used to stop seizures, such as diastat, may make a child sleepy. Talking with the physician who takes care of your son may help clarify his sleepiness.

Answered by: Russell Saneto, DO, PhD


Q: I have a Mitochondrial Diagnosis with deficiency in Complex III. I am a 49 yr old woman. A few months ago I had severe chest pain, as if someone was squeezing my chest. They did an EKG and said it was abnormal, so I went to see a cardiologist who after doing a stress test and Echo said I had an "early repolarization." The doctor felt what I experienced was more due to my Mitochondrial Disease. Is this something that is common in Mito Patients with a Deficiency in Complex III?

A: Mitochondrial disease can affect the heart in a number of ways. It weakens the muscle directly (a cardiomyopathy). It can also cause abnormalities in the ability of the heart to conduct electrical current. One consequence of this is rhythm disturbances (arrhythmias). Another is a disruption of the ability of the heart to reset itself after a beat (a repolarization defect).

Finally, it can lead to death of muscle tissue (a heart attack). A stress test is the best way to identify and differentiate these and to decide on the need for treatment.

Answered by: Gerard Vockley, MD, PhD


Q: I have metabolic myopathy and the doctor prescribed niaspan for my cholesterol. I can't take the other cholesterol pills because of the muscle disease. Now I am getting the same weakness with the niaspan. Do you know of any other cholesterol pill that can be taken? I am taking 900 mg. of CQ10 a day and that was helping me. When I took the other cholesterol pills (Lipitor, Zocor, Pravachol, etc.) they all gave me muscle weakness. Thank you for your help.

A: Cholesterol drugs that can lead to myopathy or muscle weakness include the family of "statin" drugs.

These medications inhibit cholesterol formation from a chemical mevalonic acid. This chemical is also the precursor to Coenzyme Q10 which is utilized by the mitochondria as electron transport shuttle. Thus statins impair CoQ10 production and lead to a secondary CoQ10 deficiency.

These drugs also inhibit 'heme' production. 'Heme' molecules are essentially iron cages or iron infra-structures used by various parts of the cell to build upon (including our red blood cells). 'Heme' molecules are an essential part of certain mitochondrial "buildings" - including Complex 4.

Thus statin drugs affect mitochondria by impairing CoQ10 and Complex 4 to varying degrees. Whether or not these drugs interfere with mitochondrial functioning in any other way is not known.

Some individuals who have symptoms on a certain statin drug, may be symptom-free on another statin drug. Some individuals with myopathy due to statins have the symptoms resolve with CoQ10 or Magnesium Orotate supplementation. Others need to avoid this category of drugs completely.

The non-statin family of cholesterol drugs include triglyceride lowering drugs (fenofibrate), drugs that limit bile acid or cholesterol recycling by the intestines (cholestyramine/ colestipol/ colesevelam/ ezetimibe), drugs that impair fat & cholesterol recycling in the body (gemfibrozil/niacin), and drugs whose action is not completely understood but variably effective in cholesterol lowering (Omega-3-fatty acids).

These drugs do not impair heme production or CoQ10 production - and typically do not lead to symptoms of myopathy.

If statin drugs have not been effective, I would speak to your PCP or cardiologist about whether one of these other medications are potential alternatives for you.

Answered by: Sumit Parikh, MD

Q: I am 26 and have a primary diagnosis of autonomic neuropathy that has become increasingly progressive over the past several years. In affects my blood pressure, heart rate, & temperature regulation, digestion (I have severe gastroparesis & am dependent on TPN & saline), and bladder function (I self-cath). I use a wheelchair for all but very short distances and can only sit up for several hours at a time on a "good day" and also have sleep apnea and disabling fatigue not relieved by rest/sleep. At times I have cognitive difficulties which seemed to improve about a month after CoQ10 and Carnitor supplementation (after bloodwork showed deficiencies.) This spring was the first time the possibility of a Mitochondrial Disease was broached and we are now debating the usefulness of proceeding with a muscle biopsy. My understanding is that a biopsy can confirm but does not necessarily rule out mitochondrial involvement. Some of my doctors feel that because treatment would not really change the biopsy is not necessary. I understand the hesitation as my history suggests that any procedure can lead to complications and I certainly do not want to embark on useless testing, but am curious to what any advantages might be to proceeding with a biopsy. How definitive could it be and what are the chances - if any - that it will provide any useful information toward disease management? Thank you so much for your time.

A: Autonomic dysfunction can occur with mitochondrial diseases but is not common, at least as a predominant clinical feature. I understand the hesitation in proceeding with a muscle biopsy. Before coming to that, however, some simpler tests are in order (if they have not been done already), including blood levels of lactate and pyruvate (lactate is often elevated in mitochondrial diseases). It would be interesting also to know the level of lactate in your cerebrospinal fluid (CSF): short of a spinal tap, this can be checked non-invasively (but more expensively) by nuclear magnetic resonance spectroscopy (MRS), which shows lactate as a "peak" in the brain ventricles (i.e. the CSF) and in the brain tissue itself.

You mention "gastroparesis": do you also have intestinal pseudo-obstruction? Chronic diarrhea? Have you lost a lot of weight? If the answer to all these questions is yes, then we should look for the levels of thymidine in your blood and for the activity of an enzyme, thymidine phosphorylase, in white blood cells. These tests would rule in (or, more likely, out) a mitochondrial disease called MNGIE (mitochondrial neurogastrointestinal encephalomyopathy - quite a mouthful, don't you think?). Finally, is there any family history of similar problems?

Answered by: Salvatore DiMauro, MD


Q: Although Duchenne’s muscular dystrophy is not a mito disease, are there other muscular dystrophies that could be mitochondrial disorders? In other words, could there actually be a direct connection between some types of muscular dystrophy and mito disorders? The definition of “dystrophy” in one medical dictionary seems to be general enough that it could include mito disorders (i.e. “a disorder caused by defective nutrition or metabolism”). Since we occasionally see articles stating that mito disorders are a rare form of muscular dystrophy, any further clarification would be helpful.

A: "Classic" muscular dystrophy refers to genetic disease that affects the formation of the muscle proteins themselves. "Classic" muscular dystrophy refers to Duchenne and Becker muscular dystrophy - diseases that specifically affect the dystrophin protein.

Since then, other muscular dystrophies have been identified, all of which involve some alteration in a key building block of muscle. These alterations lead to the muscle not being built properly and functioning poorly. This process would be similar to a house not being constructed well and needing repairs much sooner. In the case of muscle, we can not provide such repairs, thus most individuals with muscular dystrophy have a steady decline in muscle functioning.

The Muscular Dystrophy Association has become a support group for individuals with myopathy (muscle disease) of many causes - even if the disease is not a typical "dystrophy." Mitochondrial disease is such a condition in that it can sometimes lead to muscle disease. Mitochondrial disease is not a typical "dystrophy" however - since it does not affect the ultra-structural formation of muscle components and is instead a problem in making energy for the muscle to work.
Answered by: Sumit Parikh, MD

Q: My daughter has NARP 8993 T-C mutation. Since 1996 she has been unable to walk, talk and eats only soft meals. She was constipated for one year and afterwards had stool incontinence for several years until 6 months ago. Now she has constipation again, in spite of eating many fibers in cereals and fruits. Not even mineral oil helps. Fleet enema helps sometimes.She has been on two unticonvulsants (phenobarbital and lamotrigine) for several years. Any suggestion ?

A: I am sorry that your daughter is having severe constipation. Unfortunately, this seems to be a common problem in children and adolescents with epilepsy as well as mitochondrial disease. In my patient population, those with both disorders seem to be more difficult to control. For the most part, most of us do not think that it is the seizure medications themselves, but the central nervous system and likely the enteric (GI tract) nervous system and it's control of the muscles of the GI tract. The usual controls that interplay between the GI tract and the brain are disrupted in epilepsy. The movement of the GI tract is compromised and there is likely a slowing of the constant pulsating GI tract and constipation. Likewise, when the muscles of the GI tract are affected with abnormal mitochondria (deficient energy) they become dysfunctional and add to the poor efficiency of GI movement. Together, all this adds up to a lot of stool in the bowel and constipation.

Treatment can be very challenging. We usually try a stepwise plan. Initially we try high fiber and fruits (especially pears). The next step is mild laxatives and if no effect the use of stronger laxatives. Intermixed with this is the use of glycerin suppositories. When the problem is severe, we sometimes have to resort to enemas. Many of my patients are on chronic laxative dosing with intermittent enemas.

Answered by: Russell Saneto, DO, PhD


Q: We have a mito child with an unknown gene defect (mildly affected) and an unaffected child. Testing shows it is probably autosomal recessive. If a future pregnancy yields another mito child, will that child present symptoms similar to the affected sibling .... or could they be much sicker?

A: I am afraid it is difficult to give a definitive response to your question. The quick answer is that siblings with autosomal recessive conditions are more likely to have a similar severity than children with mitochondrial DNA disease. However, the disease gene is usually not 100% responsible for determining the severity of a disease. Other genes can impact on this and so can the "environment", particularly things like infections, for example at what age and how severely a child may have flu or gastrointestinal disease, how well nourished they are, etc.

I am not sure what type of testing indicates that "it is probably autosomal recessive" so it is also difficult to know how confident that conclusion really is. If it is firm, then the best answer I can give is that if your child has mild disease, then a future affected child is probably unlikely to have a much more severe disease. However, there are no guarantees with such predictions and it would really be better to discuss this face to face with a physician who has expertise in mito disease and has access to the tests done on your child. If you don't have such an expert locally, it may be worth travelling to an expert in another city or to attend a "Doctor is in" session at next year's UMDF meeting.

Answered by: David R. Thorburn, PhD

Q: My son's gallbladder will be removed sometime in the next several days. His neurologists wanted to do more muscle biopsies and we've resisted at this time. As the gallbladder is technically a muscle, could this tissue be considered for Mito-testing/Muscle-Biopsy?

A: If the gall bladder is being removed via an open operation - then abdominal rectus muscle can be obtained for mitochondrial evaluation. If the gall bladder operation is a laparoscopic procedure then this can not be done (most cholecystectomies are now performed laparoscopically). The gall bladder itself can not be used for mitochondrial testing.

Answered by: Sumit Parikh, MD

Q: Our 13 year old son is in his 3rd year of evaluation for both lyme and mito. His lyme titers are always positive, western blot is not (not lyme by CDC standards). His EMG shows mild/moderate muscle and nerve. Sural (leg calf area) nerve and muscle biopsies show extensive damage but are inconclusive. He has peripheral neuropathy/stocking glove, tinitus w/ U/L hearing loss, severe POTS (postural orthostatic tachycardia syndrome), and recent gallbladder disease. He has no noticeable muscle limits - but atrophies very quickly and has cramping/pain with exercise. He has had various symptoms for years but is otherwise thriving. Does this present as any specific Mito diagnosis you can name?

A: To my knowledge, this is not a "classic" mitochondrial syndrome (implying a mitochondrial disease due to a mutation in the mitochondrial DNA). However, his constellation of symptoms: POTS, neuropathy, exercise intolerance and muscle cramping could be due to a mitochondrial cytopathy. If he had developed weight loss and has dysmotility, his symptoms could fit the spectrum of MNGIE syndrome. It is reassuring that he is thriving. Essentially all patients with MNGIE have had severe weight loss/cachexia as part of their symptoms. His symptoms do sound similar to many patients I have seen. I am sure he has received an extensive and expert evaluation. I would want to know the answers to the following questions: - Has he had metabolic testing after an overnight fast and after a high carbohydrate meal (sepcific tests of interest include plasma amino acids, urine organic acids and plasma acylcarnitines) - If a muscle biopsy was done was it done on a fresh specimen? - Has he seen a physician specializing in dysautonomia? - Has he tried DDAVP and/or midodrine for his POTS? - Has he tried mitochondrial medications for 6 months to see if there is any improvement? - Has he tried creatine for his muscle cramps and muscle fatigue? All of these are not automatic recommendations, but should be considered as part of his evaluation.
Answered by: Sumit Parikh, MD

Q: Is there some place that would be beneficial for me to move to where my mito daughter would feel better: weather, humidity, doctors, hospitals, relief of symptoms and pain?

A: Your question is difficult to answer as there is not very much information concerning your daughter. I have taken care of a few patients who have moved to help their symptoms (but this is probably true with many medical conditions, not just mitochondrial disease). One patient who did not do well in the heat and humidity of the southern gulf coast decided to move to the Northwest where it is cooler and less humid. He thought that this helped him feel better. Although subjectively he felt better and could be more active, objectively it was not possible to quantify whether this helped his disease. I have taken care of another family that did the opposite and moved from the Northwest to the Southwest to be where it is warmer.

All things being considered, moving to where there is a person who understands mitochondrial disease would be a plus. But often, you might find a person who is willing to work with a mitochondrial expert. This might allow you to move and only cause maybe a couple of trips to the mitochondrial expert at a distant city each year.

Answered by: Russell Saneto, DO, PhD


Q: Is it safe for a pregnant (approx. 6 weeks) MELAS patient to take the mito cocktail? Is it safe for the fetus? If okay to take, at what dose? Are there any words of advice or warning on getting through a pregnancy if you are a MELAS patient?

A: We only have some evidence-based data on the use of the mitochondrial medications during pregnancy. However - that being said - most of the medications and supplements are naturally occurring dietary components for all of us - just not in the high doses prescribed for metabolic disease.

Carnitine is considered pregnancy category B (Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women). It has been used in pregnant women at high doses and there are no case reports to date of problems associated with high dose carnitine use in pregnancy.

Arginine is another supplement that is pregnancy category B.

Riboflavin (B2), thiamine (B1) and other "vitamins" on the other hand are pregnancy category C at high doses (Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.) These medications are not used routinely during pregnancy at the doses prescribed for mitochondrial disease - but have been used when deemed necessary by a physician.

Supplements such as alpha lipoic acid, creatine and coenzyme Q10 have no data available to make educated recommendations.

In regards to pregnancy and metabolic disease - the pregnancy is a physiologic stressor for the body. It can worsen fatigue and any metabolic symptoms. In some cases pregnancy can lead to a metabolic crisis. In someone with metabolic disease, preventative care needs to be taken during pregnancy - the same preventative care that is taken when not pregnant. This care includes avoiding prolonged fasting states, maintaining a healthy diet and exercise routine (as tolerated) and continuing carnitine supplementation if needed. If a person is excessively fatigued or symptomatic - IV Carnitine has been used by some practitioners with modest success.

Answered by: Sumit Parikh, MD

Q: Our 8 year old daughter has been diagnosed with Oxphos Defect in Complex 1 and 3. She has been also diagnosed with Cyclic Vomiting syndrome. She has had periods of vomiting that will last up to 12 days and then has a rapid recovery. We are now in day 45 of uncontrollable vomiting with no end in sight. She had a partial fundoplication when she was 2. They did an endoscopy and found only a hiatal hernia. Other than the vomiting episodes that are few and far between, she is a normal functioning child. Our question is: can Complex 1 and 3 develop into more severe complications or has she been misdiagnosed? We are searching for any ideas or answers. We are so frustrated and are unable to get any answers.

A: Regarding the complex 1 and 3 deficiency, I doubt that there has been a misdiagnosis. Cyclic vomiting syndrome refers to multiple episodes of nausea, vomiting and lethargy, with the essential absence of these symptoms between episodes. Many patients do have other conditions/symptoms consistent with dysautonomia (migraine, irritable bowel, muscle cramps, rapid heart rate, chronic fatigue, etc.) and/or other neurological conditions (developmental delay, seizures, hypotonia/floppy muscles, depression, anxiety, etc.). However, many patients only have vomiting episodes and are otherwise healthy. In most of those patients both with and without other conditions, mitochondrial dysfunction/disease is present. The mitochondrial dysfunction is often, but not always, maternally inherited, with some of the above listed dysautonomic and/or other neurological symptoms being present in the mother and her other relatives that have the same mitochondrial DNA.

In those children with cyclic vomiting in which a muscle biopsy is performed, complex 1 deficiency is common, and I have seen cases with complex 3 deficiency as well.

In cyclic vomiting syndrome, vomiting episodes usually last from a few hours to several days. Episodes that last for 12 days can occur, but are uncommon.

In some cases, an episode can last much longer, but it is also possible that there is now an additional problem in your daughter that is contributing to the very prolonged episode of vomiting. There are far more possibilities than can be covered her, but malrotation of the gut and pancreatitis deserve mention.

In mitochondrial disease, additional problems can occur with time. However, in children with normal to near-normal intelligence in which cyclic vomiting is the only major problem, the vast majority do well and the episodes can be brought under good control. Mitochondrial-directed therapies such as frequent feedings/fasting avoidance, L-carnitine and co-enzyme Q10 are often helpful in my experience. An excellent resource is the Cyclic Vomiting Syndrome Association at, which can be helpful in terms of other conditions that might be present, how to prevent and treat vomiting episodes, and in finding a physician who is an expert in the field.

Answered by: Richard G. Boles, MD


Q: My daughter is 24 yrs old and was diagnosed with CPEO & KSS 11 years ago. The tremors are her biggest problem currently, especially in her hands. Are there any medications to help this? All her EKGs have been normal thus far, no heart block detected.

A: It is difficult to answer your question without more information about your daughter's tremor. There are many causes and types of tremors. Since your daughter has KSS, it is likely that she has cerebellar ataxia and therefore, she may have a cerebellar tremor. Other causes of tremor include medications, enhanced physiological tremor, Parkinson disease, and essential tremor. Your daughter should be evaluated by a neurologist with expertise in movement disorders to define her tremor before initiating potential treatments. Medications used to treat tremors include propanolol (e.g. Inderal) and pyrimidone.

Answered by: Michio Hirano, MD

Q: Our daughter (Complexes I, III, possibly II and PDH Deficiencies) is almost two years old and she seems to be in a pattern of behavior in which every other day she acts as if she is run by a motor. She is not unhappy during these fact, things are often hysterically funny to her. Her arms and legs move around constantly all day and her breathing rate is in the 60s. She does not want to nap,and if she does, it is short-lived. She has difficulty falling asleep at night and spends the majority of the night flipping around uncontrollably like a fish out of water. These "manic" days are usually followed by a bad day in which she is miserable, has low energy, drools a lot, and has poorer than normal tone. She sticks her tongue out and grinds her jaw as well. I am trying to figure out what these behaviors mean for her and what can be done about them. What is happening in her brain when she has these behaviors? Her neurologist has just prescribed chlonidine to help her sleep at night. She also takes 160 mEq of Sodium Bicarbonate over the course of the day to keep her bicarbonate level in the close-to-normal range. Her lactic acid levels are usually between 5 and 7. Thanks for your help!

A: Behavior issues around age two are going to occur, with or without any underlying medical condition. Kids with metabolic issues can have more behavior problems. In your daughter's case, I would check with your neurologist to make sure it is in fact a behavior issue. For instance, hyperkinetic movements can be due to a movement disorder, common in some of the complex deficiencies or PDH especially if it is causing a Leigh's syndrome (Lesions of the basal ganglia in the brain). Inappropriate laughter can also be a rare symptom of seizures. If her behaviors can not be explained neurologically in those ways, I would continue to see if there are any other things that may trigger her to act differently. For instance, some children need a strict routine, and will behave differently if you take a different road to school, if the food for lunch wasn't what they were expecting, etc. It does not sound like this is due to a medication she is taking, but for others, medications can be the problem. Clonidine is a good medicine for hyperactivity and for sleep, and many neurologists and psychiatrists use it for behavior issues. Hopefully it will help her pace herself, so she is not crashing the next day. Continue to work with your neurologist, and perhaps consult with a child psychiatrist, especially one who specializes in special needs children, if this continues to be problematic.
Answered by: Amy C. Goldstein, MD

Q: My 9 year old daughter was diagnosed with Leigh syndrome at the age of two. Now her local neurologist thinks she has NARP because she is doing so well. We just want to know what she has, Leigh syndrome or NARP? She has the 8993 t-c mitochondrial DNA mutation with 87% mutant mitochondria tested in blood. When she was diagnosed with Leigh syndrome, basal ganglia damage was seen on MRI's and CT scans. Now she is a typical 9 year old with some fine and gross motor delays. I would greatly appreciate your thoughts on this. Thank you

A: This depends on who is using the words. The reality is that she has the T8993C mutation. This can sometimes but not always cause Leigh disease if there is a high percentage mutant DNA in brain, and NARP ( neurogenic ataxia and RP) if lower- to no symptoms if even lower, so it really is just a matter of semantics and which tissues are more affected. Leigh disease is often the label given if there is neurological disease affecting the basal ganglia and brainstem due to a mitochondrial condition but clearly not all children with this follow the clinical picture one reads about with chronic progression/deterioration. I am pleased to hear how well your daughter is. Some people regard the T-C mutation the same as T to G at 8993 but clearly it is milder and has a better outcome even at 87% mutation. There is a case report of a similar child due out soon in the literature.
Answered by: Annette Feigenbaum, M.D., FRCP

Q: Can a person diagnosed with mitochondrial disease also have multiple sclerosis?

A: Yes, patients with Leber's Hereditary Optic Neuropathy (LHON) can have a disease clinically indistinguishable from multiple sclerosis. Individuals with confirmed mutation in 11778 of the mitochondrial DNA, especially females, can have symptoms and signs of demyelinating disease combined with nonremitting visual loss typical of LHON. Cerebrospinal fluid and MR Neuroimaging findings are characteristic of multiple sclerosis.

Does this mean that patients with LHON have an increased chance of developing multiple sclerosis? The answer is probably no. When closely evaluated, the mutations associated with LHON are not overrepresented among multiple sclerosis patients. However, among those with early presentation of optic neuritis of multiple sclerosis, the primary LHON mutations are more frequently found. What is thought is that an underlying LHON mutation may worsen the prognosis of optic neuritis in patients with multiple sclerosis.

Answered by: Russell Saneto, DO, PhD


Q: What is the difference between the brand name Carnitor and its generic name? The pharmacist said there is no difference. But if you have kids with Carnitine Deficiency plus a Mitochondrial Disorder, you don’t want to play with your children's lives.

A: Brand name Carnitor is licensed by a company called Sigma-Tau. However, both the brand name Carnitor and generic versions of L-carnitine are manufactured by a company called Hi Tech Phamacal and are identical, the same product. Over-the-counter non-prescription carnitine supplements are not made by Hi Tech and we have no reliable data on their pharmacokinetic/dynamic properties.
Answered by: Sumit Parikh, MD

Q: test

A: test
Answered by: Douglass M. Turnbull, MD, PhD

Q: Our 13 yr. old son, presumed mito, has had significant cognitive trouble over the past few years, and tested recently in the mild MR parameters. This has been a progressive difficulty, and frightens us that if we don't turn it around, we don't know how far the cognitive dysfunction will progress. He uses O2, and also bi-pap to blow off CO2 retention. We want to aggresively seek out the problem and solutions. Our questions are: what suggestions do you have as far as testing that should be done, and is it just inevitable to see progressive cognitive impairment in mito kids? Would it help to aggressively seek out a specific type of mito disorder?

A: Thank you for your question. I am sorry to hear that your son is having cognitive issues.

Cognitive decline can be a feature of mitochondrial disorders as well as result from a variety of other causes. Because I don't know your son's history, nor do I know which testing was done and whether it was performed during optimal conditions and/or whether you believe it was a true representation of your son's abilities, I cannot answer except in a general manner.

Cognitive decline in neurologic disorders may be static (unchanging) or progressive (getting worse with time) or waxing and waning (gets worse with an episode of illness or event and improves during recovery either to baseline or below baseline). In terms of reversibility, it is important to rule out conditions which may cause or look like cognitive decline, but may be potentially treatable. This would include, for example epilepsy or seizure disorders, medication effects, or the presence of other illnesses.

Either clinically evident or subclinical seizures may present with apparent cognitive decline and may be improved with medications in some cases. Therefore, if there is concern that your son could be having seizures (changes in behavior, staring, shaking spells, etc. ) an EEG can be requested.

You mentioned that your son is on CPAP and has a tendency for CO2 retention. Hypoxia (low oxygen and high CO2) can cause cognitive slowing, therefore it would be important for your son's pulmonologist to ensure that his oxygen status is adequate.

Medications can have cognitive side effects. If your son is taking any medications, you should review the list with your son's physician to determine if medication side effects may be an issue.

Chronic diseases (other than mito) may lead to secondary cognitive decline due to toxins such as liver or kidney disease. Endocrine disorders can also potentially cause cognitive problems (thyroid, diabetes, etc.)

MRI imaging can give a picture of the degree of anatomic injury to the brain and whether it appears fixed or potentially reversible; however, a completely normal scan does not necessarily denote normal brain function.

Lastly, the choice of cognitive test can be important in giving a clear picture of his true abilities. For example in a nonverbal child, use of a test that is heavily language based (as are most IQ tests) would underestimate abilities and IQ and may not be appropriate.

Answered by: Andrea Gropman, MD, FAAP


Q: If I understand correctly, DNA mutations exist in heteroplasmy and usually are at 50% abnormal in a tissue before you can see any clinical effects. My 3 yr. old displays no symptoms, but my second son (17 mo) has mito (poor GI, myopathy, delayed motor). Does this mean that my other son should be tested? Could he be at 20% abnormal while my other is obviously over 50%? I've seen where kids start displaying symptoms at 11, so I'm assuming this could happen to my "well" child. Please correct me if I'm wrong. Another question of mine concerns the DNA's repair ability. I read that we should be careful when it comes to physiological stressors. My little one wants to play outside every second of the day, but he sweats like crazy after 5 minutes. Could episodes like this permanently damage his cells? How careful should I be, and would a cooling vest help?

A: Mutations in the DNA chromosome are most often heteroplasmic and the percentage of abnormal chromosomes usually varies from tissue to tissue and can change with time. This also varies significantly among family members. The exact percentage of abnormal chromosomes needed to cause tissue malfunction (the threshold level) is difficult to determine, but is probably closer to 75-90%. Remember that since heteroplasmy varies in different tissues, a 50% mutation rate determined in blood or skin (the most frequent tissues tested) doesn’t necessarily reflect muscle or brain levels. Remember that we inherit all of our mitochondria from our mothers, and the presence of a mitochondrial chromosome mutation in one child makes the presence of the same mutation in the mother and other children likely. If both are asymptomatic, the heteroplasmy may be low and thus difficult to demonstrate. In rare cases, a truly new mitochondrial chromosome mutation is found that is not present in other family members. Also remember that only 5-10% of respiratory chain defects are due to mitochondrial mutations. The rest are caused by mutations in the nuclear chromosomes and these are not subject to heteroplasmy. You should review the precise genetic mutation identified in your family with your geneticist and decide on testing for additional family members based on that information.

Sweating in your child who has a mito disease is not dangerous per se and won’t damage his cells. The major concern is for dehydration if he has significant water loss due to his sweating, and salt imbalances in his blood if his fluids aren’t correctly replaced. To avoid this, keep him well hydrated while playing using a sports drink containing minerals such as Gatorade. Pedialyte would also be acceptable. A cooling vest might be helpful if he is too uncomfortable to play or can’t regulate his body temperature when he does play but these can be cumbersome.

Answered by: Gerard Vockley, MD, PhD


Q: My son was suspected of having a mito disease and now I am wondering if my mom has been showing "soft signs" of a mito disease. She has suffered from depression and anxiety for many years and it seems to be getting worse as she gets older. She has been on over 10 different anti-depressants and they seem to work for a brief while and then the symptoms come back. Is it possible for CoQ10 to help with depression/anxiety? Also, if she takes the CoQ10 and it helps, is that indicative that she may indeed have a mito disease?

A: If you suspect your mother has mitochondrial disease it is important that she is investigated properly. Treatment with CoQ may just be effective as a placebo - so does not really help.
Answered by: Douglass M. Turnbull, MD, PhD

Q: I have been diagnosed with Mitochondrial Myopathy (adult onset), possible metabolic involvement. I am still waiting for results of my 2nd biopsy for a more definitive diagnosis. I do know that my Citrate synthase activity is low, 45, and my Carnitine Palmitory transferase Tissue was low, 34.4. I was sent to a memory clinic because my short term memory has diminished. I have trouble with word recognition, ie. inserting the wrong word while speaking and just plain forgetting a word. I may for example say mentor and mean to say medium. Sometimes the 1st letter is correct and sometimes the words are completely way off. I was sent to a memory clinic and given a battery of tests. My MRI and lumbar puncture were both negative, so why am I losing my memory? Is it from fatigue from the disease or is this just part of the progression of the disease. A doctor prescribed ARICEPT, thinking it could possibly help. Have you prescribed this before and if so has it been beneficial for your patients? I am nearly 45 years old, but feel I have the memory of a 90 year old. Any suggestions or information would be greatly appreciated.

A: I am sorry to hear of your problems. I guess the first question to ask: is what were the results of your neuropsychological testing? It would also be nice to verify what type of mitochondrial disease you might have. Since this remains unknown at present, I will assume that there has been a confirmed diagnosis of mitochondrial disease. Abnormal mitochondrial function has been implicated in some patients with Alzheimer disease. However, the direct causality of mitochondrial disease and Alzheimer disease is only implied and has not been firmly proven. Our unpublished work with children and a few adults has indicated a non-verbal language and memory problem in a wide variety of patients and types of mitochondrial diseases. We have not found a rapidly progressive memory loss in any of our patients, but again they are mostly children.

Your problem sounds like (am I correct?) has been one of memory regression? How long has this been going on? There are a variety of disorders that can affect memory. Alzheimer disease is only one. The finding of normal MRI scan and CSF results is reassuring that major causes of memory loss such as tumors, hydrocephalus, cerebrovascular disease, or subdural hemorrhage are not occurring. Your age is a little early for Alzheimer disease unless you have the presenilin 1 gene on chromosome 14. Neurologists will use Aricept to delay the memory loss in Alzheimer disease. Studies have shown that it does help delay entry into assisted living. Whether it also helps memory in other etiologies of memory loss is not clear. This would be especially true in mitochondrial disease induced memory loss (which has not been firmly proven). I am sorry that I am not able to give you a better answer.

Answered by: Russell Saneto, DO, PhD


Q: My son has been diagnosed with Kearn-Sayre disease. He is 21 years old and is legally blind, has diabetes and CPEO. In February this year he had a kidney biopsy because of increased protein in his urine. He also had a Urethroplasty done several years ago due to a urethral stricture and kidney infection. On Thursday evening of this week he had a very sudden headache and it happened again on Friday evening immediately after urinating. The headaches come on VERY suddenly and are excruciating. Friday evening I took him to the ER where they did a CT scan of his head and some blood work. The CT scan appeared normal - I don't have the results of the blood work yet. He has had 3 more episodes of these headaches since Friday evening and always immediately after urinating. When he got the ER on Friday his blood pressure was 187/122. I have been monitoring his BP since then about every 4 hours during the day. Each time he has these headaches his blood pressure has been 162/104, 181/101, 191/124 respectively. HIs pressure when he was not having the headaches was 137/72 and 141/81. It appears that urinating is causing his BP to rise VERY quickly and I'm guessing that in turn is causing the headaches. The ER doctor suggested giving him 600-800 mg of Ibuprofen if this happens again. I've been doing that but of course he doesn't take the Ibuprofen unless he has one of these headaches. What is strange is that if he stands to urinate - he doesn't appear to have the problem. Most often though, because of his vision loss he sits to urinate and that appears to be when the problem occurs. After typing all this out I am guessing that this problem may very well have to do with his previous urethral stricture problems (maybe a recurrence) but I would sure appreciate your advice. Thank you!

A: Your son's problem - hypertension when voiding - is a form of "reflex" hypertension. This is a problem that can occur due to dysautonomia or an abnormal baro-recepter reflex from either primary mitochondrial disease or long-standing diabetes. The headache is likely due to the sudden hypertension.

If it is okay with his treating physicians, he needs to see a cardiologist and potentially obtain a tilt table test. His hypertension may need medication - even though it is periodic in nature. Until then I would continue to monitor his blood pressure whenever he has a similar headache - and document the circumstances around the event - as you have already been doing.

Answered by: Sumit Parikh, MD

Q: I had a muscle biopsy that showed a profound deficiency of Succinate-cytochrome C reductase. I had a normal succinate dehydrogenase. I have read several articles that say that succinate-cytochrome C reductase is a defect of complex II and others that say it is a defect of complex III. Which is correct and does the normal sucinate dehydrogenase influence this? My specific complex III was not tested.

A: That question sounds like it should be straight forward, but is a little tricky to answer. The Succinate-cytochrome C reductase assay is intended to be a way to measure the activity of both complex II and complex III at the same time. It is therefore also known as Complex II+III and its deficiency can be caused in four ways:
(1) Deficient succinate dehydrogenase (Complex II), (2) deficient Ubiquinol cytochrome c oxidoreductase (Complex III), (3) deficient coenzyme Q (ubiquinone or ubiquinol), or (4) artefactual loss due to problems with processing or storage of the muscle biopsy.

The first explanation is very unlikely if the lab has found normal succinate dehydrogenase. In making that conclusion I am assuming this was measured in a similar way using a spectrophotometer, rather than relying on just "SDH staining" of muscle biopsy sections.

Complex III deficiency is a possible explanation but the succinate-cytochrome C reductase activity is much more dependent on Complex II activity and less sensitive to Complex III. It would need to be a very marked Complex III defect to cause profound deficiency of succinate-cytochrome C reductase. Personally I think it is necessary to demonstrate deficient Complex III activity directly to be sure that it is truly deficient.

Coenzyme Q deficiency is a possibility since the succinate-cytochrome C reductase relies on the coenzyme Q already present in the muscle biopsy to link Complex II and Complex III. If any of the muscle biopsy is left over and has been stored appropriately, then it should be possible for this to be measured directly.

The final possible explanation is one I am always wary about. My experience is that the Complex II+III assay is not as robust as the assays for individual complexes, at least in frozen samples. If the lab is confident that the sample processing and storage (if done on a frozen rather than fresh biopsy) were optimal, then this shouldn't be a problem. Unless this is absolutely clear I am always a little concerned about the certainty of a diagnosis of succinate-cytochrome C reductase deficiency.

So if possible, I would suggest you see whether Complex III and coenzyme Q can be measured in the original muscle biopsy. That may help to clarify the diagnosis.

Answered by: David R. Thorburn, PhD

Q: Have you ever heard of severe secretory diarrhea that comes on when an illness strikes (even something like a bad cold) as being part of a mitochondrial disease? I've heard that acidophilus can help with regular diarrhea. Has there been anyone with secretory diarrhea that's ever benefitted from it?

A: Gastrointestinal problems are common in patients with mitochondrial disease. In my patient population, constipation is a more common finding than diarrhea. In the patients with diarrhea, most have episodic diarrhea that we haven’t found the etiology other than their mitochondria disease. We usually try increasing the frequency and altering the content of meals, as well as good hydration. The diarrhea is self-limiting in most cases. I have not seen diarrhea limited to only illness in my patient population. Many of my patients have used acidophilus, some it has helped and others it has not. So, it is difficult to say if acidophilus should be used or not for every mitochondrial patient. I am sorry that I could not be more definitive.
Answered by: Russell Saneto, DO, PhD

Q: My son is 18 and recently diagnosed with mito disease complex 3 deficiency. It affects his muscle [parkinsonism] and brain [encephelopathy]. He has had just in the last weeks several behavior outbursts where he can't be controlled. It comes on suddenly; he gets agitated and hits, mostly in the car. Police and ambulance can calm him down, but it is getting out of hand. He looks to me, as if he loses it. It has to go through his brain and then he breaks down and cries. He will apologize, but looks like he can't recall the incident. He is totally normal afterwards, clear speech, pleasant and very hungry. Any help? The CLE clinic just started him, besides vitamins on Seroquel 25 mg. Any help is appreciated, I can't live on the edge any more.

A: I have heard many mothers of mito patients tell me similar stories during clinic visits in which there are sudden and severe outbursts of anger. There does not appear to be a single cause or solution.

Anger management is a difficult feat in many youths that do not suffer from any disease, and the presence of cognitive deficits can complicate growing up even further because of difficulty in understanding situations, communicating one's wants, and dealing with the burden of illness. If the outburst appear as a result of frustration (not getting ones way, etc.) then behavioral approaches are generally indicated.

In my experience in some mito patients with complicated migraine-related disease, pain (perhaps not well understood or articulated) and possibly migraine-related decreased blood flow to certain brain regions, can trigger behavioral outbursts. In these cases, the behavior is sudden, unexpected, and not readily attributed to frustration. I have seen cases in which the behaviors resolved on treatment with an anti-migraine medication (amitriptyline in particular), returned when the drug was held, and resolved again when re-instated.

Although rare, seizures might also be considered if the behavior is sudden and unexpected, and a video-EEG might be indicated.

Answered by: Richard G. Boles, MD


Q: I am trying to gather any information I can to help my PCP and Mito Doctor help me with a OBGYN question. I am a mito adult, 52 yrs old. I have been perimenopausal 5 + years and now at the point where I am having hot flashes every day and all night long. This condition has caused me to be 75% more ill. I know my body can not regulate temperature anyway so this condition is really making me ill. In 2002 I had a fresh muscle biopsy that showed I have complex 1 and 4 and partial 2. I am also post stroke 6 yrs. I was told I had Mito and that is what caused the stroke. I can not take hormone replacement because my mother is a breast cancer survivor. I am not able to sleep; I do not eat solid food as I can not pass it. I drink 6 cans of Ensure+Protein a day. I have no energy at all. I also have autonomic nerve insufficiency. Do you have any ideas to help my doctors help me?

A: In general, postmenopausal women with hot flushes should first have their thyroid function tested to make sure that hyperthyroidism is not present since hyperthyroidism can cause "hot flush"-like symptoms or worsen underlying hot flushes. If your thyroid function is normal and you cannot take estrogen, medications such as Effexor and serotonin reuptake inhibitors have been shown to significantly improve symptoms (hot flushes and night sweats) in many postmenopausal women. Before beginning any of these medications, I would definitely check with your mitochondrial specialist and/or PCP to make sure that you have no contraindications to taking these in your individual case and that there are no significant reported reactions with other medications which you are currently taking.

Yialamas, Maria A.,M.D.

Answered by:


Q: Can obesity sometimes be associated with certain mitochondrial diseases? The general assumption is that mito patients will be average or under-weight. But that doesn't always seem to be the case. What mito-related factors might cause obesity?

A: Most patients with mito disease tend to be underweight rather than obese. Indeed, one of the most common symptoms in children diagnosed with mito disease is "failure to thrive" when the child is not putting on weight at the expected rate. It is easy to imagine that if our cells can't generate enough energy then we will struggle to grow at the normal rate. Inefficient mitochondria can also "waste" energy as heat rather than converting it into the ATP used by all our cells. It may sound counter-intuitive but an inefficient metabolism that wastes energy in this way promotes weight loss rather than weight gain. Mito diseases and regulation of body weight are both very complex topics, and it is certainly possible for patients with mito disease to become obese. One often hears that body weight is determined by energy balance, which is basically how many calories we consume (energy intake) and how many we burn (energy expenditure). Energy expenditure is not just about how much we exercise, but is influenced by a range of factors. The basal metabolic rate varies between individuals and even healthy people appear to differ in how efficiently their mitochondria burn fuels such as fats, sugars and proteins. Mito disease can impact directly on this efficiency of fuel conversion and can also act indirectly, by affecting the regions in our brains controlling appetite and by influencing hormone levels, such as insulin secretion, and responses to hormones, such as insulin resistance. Many patients with mito disease have trouble doing much exercise. Some patients, for example with complex I deficiency, are put on high-fat diets. So whether a mito patient will be skinny, average weight or obese depends on the specific type of mito disease they have plus their energy intake and expenditure. Ideally, any concerns about obesity in a patient with mito disease are best discussed with a physician who has expertise in both mito disease and metabolism or endocrinology.
Answered by: David Thorburn, PhD

There is a theoretical metabolic link between tendency to obesity and mito diseases and indeed yes, some children are obese and /or tall as well rather than the classic description of short with failure to thrive. This is different to the risks of obesity per se causing mitochondrial dysfunction as well described by Dr. Douglas Wallace in his publications the last few years. Calorimetry has been done on a number of mito kids and the results are very variable- some have low BMR ( basal metabolic rate ) and some high. This needs to be correlated to energy expenditure( exercise heart rate, respiratory renal status) and caloric intake and could be assessed in detail by a qualified dietitian. Once hormonal issues e.g thyroid have been excluded, it needs to be done on a case by case basis.

Answered by: Annette Feigenbaum, M.D., FRCP


Q: My oldest daughter(7) was diagnosed last year with a Complex I and III defect. I also have two younger daughters (5 and 4). Both of them appear healthy and have shown no signs. Do you have any precautions I should take or recommendations of supplements or vitamins I should give them just in case they might have the same disorder in a lesser form? I did start them on a small dosage of CoQ10.

A: It is good to hear that your other children are doing well. At present, we do not have any evidence that shows a benefit in either testing or treating asymptomatic individuals. The only caution I would recommend is that in case any of them develop "metabolic," neurological or developmental issues, then I would see a neurologist or geneticist sooner rather than later.

"Metabolic" symptoms include declining with illness or fasting, developing an odd odor to their body or urine, tiring too easily, and avoidance of certain food categories (proteins/carbohydrate/fats). Neurological and developmental symptoms are more self-explanatory.

Answered by: Sumit Parikh, MD

Q: Does Mito hinder the healing process once an injury occurs? My daughter was in an auto accident 2 years ago and still has not fully recovered from a wrist injury. Has research been done on trauma and mito, and if so, where can I get more info?

A: I would say yes. I have begun to do bone mineralization dexascans on some of my patients. What I am finding is that bone age is delayed. We think that this is from hypothalamic problems as when given growth hormone, the bone age begins to normalize. (Proper testing shows a growth hormone deficiency) In addition, I have several patients who started into puberty early, and I reversed it by giving a GnRH analog. So, long story short, bone problems may be affected by abnormal hypothalamic output and bone mineralization problems. I don't know if this affects other healing processes, such as blood clotting. I am not aware of any processes in the clotting cascade directly related to mitochondrial defects. Although poor lipid metabolism can alter platelet function and certainly certain mitochondrial diseases elevate lipids.
Answered by: Russell Saneto, DO, PhD

Q: Our son was diagnosed with pyruvate dehydrogenase complex deficiency. He was born with a high level of lactic acid (12). His diagnosis came from a skin biopsy. Since the diagnosis, we have changed his diet to include a formula called Ketocal mixed with his neutramogin, 50 mg of B1, B50, and coq10 (1 teaspoon of 50mg)/day. His lactic acid is now 2.9 and he does seem to be more alert, less tired. How many kids truly survive past the age of 5? All research seems to state most kids die by then. Of the children that live, are they all mentally and physically handicapped? We can tell his vision is not the greatest. He had eye muscle surgery. Both eyes went out and they moved each muscle 5 mm. They seem to be together more, however, still not comfortable that he sees all too well. Are most kids blind with this, or just have vision troubles? We are so thankful for every day we have him, but we are just anxious to hear what more we can expect and if there is a chance we can have him around longer than research states.

A: Not all children with PDH deficiency are blind. The variation in the disorder is quite large and so it is difficult to provide much guidance regarding any one child without specific details. The same is true of suggesting additional therapies. If you don't feel that you have received adequate counseling regarding your child's condition, you should see a metabolism specialist with experience in this disorder (or spend more time talking with your current one).
Answered by: Gerard Vockley, MD, PhD

Q: Can a mitochondrial disease go into complete remission and then return? Can you tell me about mitochondrial disease and remission?

A: In regards to your question about mitochondrial disease and remission/regression - as is our answer about many mitochondrial disease related questions - we are not completely sure. Let me clarify. We suspect that certain stressors (illness, fevers, surgery, anesthesia, fasting, dehydration) can worsen symptoms. However this worsening does not always occur. We hope and have some evidence that the medications we use help decrease the severity and frequency of symptom worsening. But most remissions and regressions in mitochondrial disease occur for no clear reason we can provide - or specific stressor we can identify. And most individuals with mitochondrial disease do have cycles of fluctuating symptom severity - and even transient resolution of symptoms (some or all).
Answered by: Sumit Parikh, MD

Q: My 7 year old son became sick about 5 months ago. Prior to that he was a healthy active boy. It all began with drooping eyelids and then fatigue, a gait. They did spinal taps, IVIG, blood and urine work, MRI and nothing showed. They then did a muscle and nerve biopsy and he has not walked since. The nerve biopsy showed the myelin sheath of the nerve was being attack by his immune system, and that was it. A few weeks later he began tremors in his arms with eventual partial paralysis. We returned to the hospital with all the tests done again. Still nothing shows. They have thought it was so many things but now sent blood to be tested for a mito disease. His mind is great, remembers everything, still reads. We sought a second opinion which is still pending but he said that a red flag was raised with mito because his intellectual ability was so good. What could have he meant from this? Anyhow, other docs said he was dying about 3 weeks ago and he looked as though he was going to; it got really bad. Now we see every day a little change in him; his legs are stronger, arms are moving better, tremors almost stopped. This is with no meds! Could this possibly still be mito?

A: With this history it is not clear as to what your son has. Common causes of sudden/rapid onset motor weakness include Guillane-Barre syndrome (Acute Inflammatory Demyelinating Polyneuropathy or GBS) and myasthenia gravis. GBS is an immune system misdirected attack of the myelin sheaths (as the nerve biopsy may have shown) While Guillane Barre can and does get better on its own, recovery can be sped up by giving IVIG. Recovery is usually over months. Patients can become sick enough to need ICU care. The MRI can be normal. The spinal fluid may show abnormalities (elevated protein). Recovery is prolonged and in atypical forms (AMSAN and Miller-Fischer variants) can be over many months, and at times incomplete. There are special antibody tests that sometimes help sort out which type of GBS is affecting the patient though they are not always diagnostic. The EMG test is also helpful. Some infections can mimic GBS, including Lyme disease, West Nile disease, HIV, as can heavy metal poisoning. Myasthenia Gravis is an immune system misdirected attack of the muscle's neurotransmitters functioning. It usually does not improve without medication. The EMG is diagnostic. A pediatric (or adult) neuromuscular specialist is often the individual who can help sort this out. While metabolic and mitochondrial disease can present with an "acute" decompensation of functioning - including muscle functioning - it is usually not because of an immune system attacking the nerve sheaths (myelin). In addition, muscle disuse (from weakness or bedrest) can artifactually affect the appearance and function of mitochondria on muscle biopsy testing. I would want to know if there were other signs in blood/urine/spinal fluid of metabolic disease (this includes mitochondrial disease). With mitochondrial disease we have learned to "never say never," since almost any symptom can be the presenting one.
That being said, your son's presentation is far from typical for mitochondrial disease, and I would want to "rule-out" the 1st 2 conditions completely and review the specifics of how and why the diagnosis of mitochondrial disease is being made.
Answered by: Sumit Parikh, MD

Q: My son is 3 1/2 years old and has Mitochondrial Encephalopathy, Complex I. We are having trouble figuring out what is a seizure and what is not. His EEG is chaotic (that's what the neurologists have called it) and it's really hard to know what's a seizure. He has staring spells that we think might just be resting spells, but more recently we've had what I call lethargic spells, his eyes roll in the back of his head and he is just not with us. Our neurologist told us to use tylenol and see if that helps, and believe it or not, it did. She was thinking that it might be pain related, but we do not know the cause of his pain because he cannot tell us. Most recently, he got angry for the first time in his life. He is always happy, and he just turned red and grunted and threw his arms up in the air, which again we are not sure if it is a seizure. We have never had to deal with him being in pain before now and I'm wondering if this could be a progression of the disease and we may not be able to ever find the cause of the pain. His hips are out of socket by 50% on one side and 25% on the other, but the Orthopaedic doctor said it's not enough to cause him pain.

A: I am sorry to hear about your son. Sometimes defining what is a seizure versus what is a behavioral event can be very difficult. Many times staring episodes or periods of unresponsiveness can be a seizure(either generalized or focal), but sometimes staring can just be a behavior. One can see other types of behaviors that can look like seizures as well. One of the things about seizures is that for a particular patient, they are stereotypic meaning that they occur over and over in the same way. There are some tricks that we sometime use to figure if staring events can be seizures. One would be to gently stimulate him with your hand and see if he responds. If he responds then likely staring or loss of responsiveness is not a seizure but a behavior. Similarly, eyes rolling up and becoming lethargic may or may not be a seizure. When we get tired and begin to fall asleep, our eyes roll up (called the Bell's reflex) and we become lethargic-looking. If we are gently stimulated by a touch we arouse and may even jerk awake. When events cannot be accurately determined clinically, we have to use Video-EEG to determine. Although expensive and time consuming, when we need to know it often gives us definitive answers. The Video-EEG is a EEG study with a video camera running in a special unit in the hospital. This allows us to view the seizures by video with the EEG running. There is a correlation with EEG changes suggestive of a seizure event and the Video change in behavior. This way we can tell if the event is actually a cerebral seizure, not just a behavioral event. Pain is difficult to determine as well as frustration in a child that has difficulty in telling you what is going on. Body language can often help as well as the circumstance. These types of behavior usually have some circumstance that can be linked to the event (at least with frustration). As the events become more frequent, you will become more adept at defining what type of event. Remember, seizures reoccur in the same fashion over and over again, while pain and frustration would vary in their presentation. Just as an aside. You might want to think twice about using Tylenol for pain. Tylenol can deplete some of the glutathione in cells. Glutathione is one of the major antioxidants used by our bodies to combat oxidative stress. Since oxidative oxygen radicals (oxidative stress) is increased in complex I disease, you might want to preserve all the glutathione possible.
Answered by: Russell Saneto, DO, PhD

Q: I am a 34-year-old female who was diagnosed with CPEO. I showed the first symptoms when I was about 16, with a left eyelid ptosis, significantly worse than the right. I had reconstructive surgery to raise the eyelid when I was about 22, since it seemed to be getting worse and last year went ahead with a muscle biopsy for genetic counseling to determine for sure that this was in fact CPEO. My first question is about my eyes/face in general: What is the outcome of this disease? Will my eyes, lids, and my face eventually become completely paralyzed? Will my eyelids both continue to droop until I have no ability at all to raise them? I feel as though they are getting worse with each year and that I am constantly straining to keep them open. As a result of the reconstructive surgery in my left eye, I now have severe dryness of the eye as well as a benign corneal growth, which doctors have said is nothing to worry about (it’s the cornea protecting itself from the dryness) but there is a visible white film over a part of the cornea. My left eye more often than not feels as though there is sandpaper rubbing against it and it’s also frequently bloodshot. I use drops almost every day and have tried sleeping with an eye mask, but most days, it’s just really irritated. Both eyes are extremely sensitive to light and my eyelids are always swollen when I wake up – it decreases throughout the day. I’m wondering: as my eyelids continue to droop with each year, is it possible for me to keep having these reconstructive eyelid surgeries to keep them open? Will it be harmful to my eyes? Will the muscles eventually become useless, rendering the surgery ineffective anyway? Oddly enough, I still have 20/20 vision in both eyes... The other part of my question has to deal with my overall fatigue. I am 5’4” and weigh about 108 lbs, and I have no energy at all – ever. I have been taking COQ10, 400mgs/day for about a year now and really don’t notice any difference, (though I wonder if I’d feel worse if I wasn’t taking it.) Is there an additional supplement I’m supposed to be taking along with the COQ10? I would like to begin an exercise plan/routine as I’ve read that exercising might give me more energy, but am a little hesitant to begin on my own because of the cardiac complications that might arise. I had one EKG done about 2 years ago and it was fine, but I notice sometimes (maybe once every 4 or 5 months) that when I exert energy into doing something quickly like running, or riding my bike, I do get palpitations, sometimes so severe that I feel my heart pounding strongly against my ribcage. They go away after a few minutes, but it’s enough to keep me concerned. I noticed this starting to happen when I was quite young, perhaps around 12 or 13, though it was much less frequent at that time. Since it happens so infrequently, how would a yearly EKG pick up any abnormality unless I was having palpitations during the exam? Is there anything that you can suggest to me in the form of a daily exercise routine? I feel as though every time I go to a physician such as a GP or even my GYN, they have no idea what I’m talking about when I discuss this disease. I imagine the same thing would happen if I went to a personal trainer as well. If you could provide me with any additional insight on CPEO, it’s prognosis, and it’s treatment, I would be most appreciative.

A: I read your inquiry with great interest. I presume that your muscle biopsy showed mitochondrial alterations. It would be useful to know whether you have a single deletion or multiple deletions of mitochondrial DNA. I presume that you have a single deletion since you do not mention any family history of PEO or other mitochondrial disease. Single deletions of mitochondrial DNA (mtDNA) typically manifest in three different disorders: CPEO, Kearns-Sayre syndrome and Pearson syndrome. Pearson syndrome causes severe anemia and pancreatic dysfunction in infants. Kearns-Sayre syndrome (KSS) is a multisystemic disease defined by the triad of: 1) onset before age 20, 2) PEO typically with ptosis, and 3) pigmentary retinopathy. In addition, KSS patients have at least one of the following: ataxia, elevated protein in cerebrospinal fluid (CSF), or cardiac conduction block. Patients with CPEO have a pure muscle disease affecting extraocular muscle, but often other muscles are affected such as facial, oropharyngeal, and limb muscles, therefore, patients often have difficulty closing their eyes, trouble swallowing, nasal speech, and weakness of arm and leg muscles. Generally, CPEO is a slowly progressive disease. Often patients have only weakness of extraocular muscles which is cosmetically bothersome. Sometimes CPEO causes double vision or such severe drooping of the eyelids that vision is impaired. In cases of severe ptosis, we recommend placement of eyelid slings to attach the upper eyelid to the forehead (frontalis) muscle. Blepharoplasty (shortening of the eyelids) is a more risky procedure because if the eyelids are shortened too much, then they will not close properly leading to exposed and dry eyes. In fact, chronically exposed eyes can develop corneal scarring (exposure keratitis) that will impair vision. I think that you should consult an ophthalmologist about your dry eyes. You may need to use saline eyedrops during the day. If your eyes do not close at night, you may need to apply special ointment to your eyes and tape them shut. In some patients, weakness of limb and swallowing muscles can become bothersome or even disabling. Your chronic fatigue may be due to muscle weakness. Patients with CPEO and other mitochondrial diseases are often short and thin. The thinness is often due to lack of muscle. Regarding nutritional supplements, we typically recommend a cocktail which is listed below. In my experience, CoQ10 and creatine often improve (but do not cure) fatigue in mitochondrial patients. Coenzyme Q10 (CoQ10) 50-200 mg three times daily (although some patients with primary CoQ10 deficiency have taken up to 1000 mg three times daily), levo-carnitine (L-carnitine) 300-1000 mg three times daily (many patients develop gastrointestinal side-effects at high doses), Thiamine (vitamin B1) 50-200 mg daily, Riboflavin (vitamin B2) 50-600 mg daily, Vitamin C 100-400 mg daily (usually divided into 2-3 daily doses), Vitamin E 200-1200 IU daily, Vitamin K3 5-80 mg daily, Folate 1-10mg daily, Alpha-lipoic acid up to 400 mg three times daily, Creatine monohydrate 5-10 grams daily, Idebenone 45-360 mg three times daily (Sometimes used instead of coenzyme Q10). I am concerned about your heart pounding. As I mentioned, KSS patients often develop cardiac conduction blocks that can produce life-threatening arrhythmias. I strongly urge you to see your physician and get an electrocardiogram which may show a conduction block even when you are not having palpitations. Cardiac conduction blocks can be effectively treated with pacemakers. Regarding exercise, Drs. Taivassalo and Haller have clearly demonstrated that moderate aerobic exercise can reverse deconditioning in mitochondrial patients. About 30 minutes of aerobic exercise (e.g. riding a stationary bike) at least three times a week is reasonable. It is uncertain whether exercise increases the amount of mutant mitochondrial DNA in patients with CPEO or other conditions.
Answered by: Michio Hirano, MD

Q: Is it okay for Mito kids to be on Felbamate or Felbatol to control seizures? If it is one of the seizure drugs that they shouldn't be on, why not?

A: Felbatol is one of the newer medications and when it came on the market a decade or so ago, it was almost the "silver bullet" in the field of epilepsy when it came out. In a severe epilepsy syndrome, Lennox-Gaustaut syndrome, it was heaven sent. It was very effective against the drop seizures that caused so many problems with these patients. In addition, many other patients who had intractable seizures had their seizure frequency reduced or stopped. It is a good medication for generalized as well as partial or focal seizures. The bad news occurred when it began to be widely used. What was found, in older children (age > 10-12) and adults it could cause aplastic anemia (the bone marrow stops making red blood cells). Although this was never seen in younger children, because of this condition the FDA gave the medication a "black box" warning. It has also been found that Felbatol can cause liver failure (approximately 1:5000). It is a good seizure medication. I have used it with some success, but clearly like any medication, it does not work for all children with epilepsy. It is my feeling that it works well for drop seizures, atypical absence and generalized (or secondarily generalized) tonic clonic seizures. It seems to work rather well in combination with Valproic acid. My experience with my mitochondrial patients with seizures is only so-so. The side effects of weight loss, difficulty in sleeping, and very frequent laboratory testing did not out weigh its use. But that being said, as long as it is monitored well it might be a good alternative if all the other alternatives have been utilized.
Answered by: Russell Saneto, DO, PhD

Q: Whaat are the most recent (2006) recommendations for nutritional supplements and their dose range for adults with MELAS?

A: The recommendations for nutritional supplements for mitochondrial patients have not changed significantly over the last few years. Our recommendations are as follows: Coenzyme Q10 (CoQ10) 50-200 mg three times daily (although some patients with primary CoQ10 deficiency have taken up to 1000 mg three times daily) levo-carnitine (L-carnitine) 300-1000 mg three times daily (many patients develop gastrointestinal side-effects at high doses) Thiamine (vitamin B1) 50-200 mg daily Riboflavin (vitamin B2) 50-600 mg daily Vitamin C 100-400 mg daily (usually divided into 2-3 daily doses) Vitamin E 200-1200 IU daily Vitamin K3 5-80 mg daily Folate 1-10mg daily Alpha-lipoic acid up to 400mg three times daily Creatine monohydrate 5-10 grams daily Idebenone 45-360 mg three times daily (Sometimes used instead of coenzyme Q10)
Answered by: Michio Hirano, MD

Q: I am 34 and have CPEO. My eyes have limited movement. My left eye is turning out and it has been suggested that surgery to move the eye in would be needed. My regular ophthamologist is worried that it may affect my long distance vision but does not have experience with the disease, especially in adults. He wants me to try to excercise my eyes to see if I can get movement and control back. Is there any research that would suggest that this might work? I am currently taking a supplement cocktail that includes CoQ10 also.

A: Chronic progressive external ophthalmoplegia (CPEO) is a common manifestation of mitochondrial diseases. Asymmetric eye muscle weakness can cause double vision and may be cosmetically unpalatable. Elegant research by Drs. Taivassalo and Haller has clearly demonstrated that patients with mitochondrial myopathies can improve limb muscle functions with aerobic training, but I am not aware of any similar studies of exercise therapy for eye muscles. Because eye muscles are constantly exercising, it is unlikely that exercise will improve eye muscle functions. Nevertheless, I think it is perfectly reasonable to try benign eye muscle exercise before invasive surgery. Presumably the patient does not have double vision because he/she is currently suppressing vision from one eye. I share the ophthalmologist's concern that surgery may leave the patient's eyes aligned imperfectly causing blurred or double binocular vision.
Answered by: Michio Hirano, MD

Q: Can chronic upper back(shoulder) and neck pain and tightness go along with MELAS? I also seem to have a lot of "muscle knots." I have a definite diagnosis of MELAS with an accumulating amount of other symptoms. Sometimes the pain is bad enough to keep me from functioning normally.

A: As the name implies, MELAS (mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes) affects brain(encephalo) and muscle (myopathy). Usually, the myopathy manifests as weakness of proximal limbs. Sometimes MELAS patients have weakness of extraocular muscles causing drooping of eyelids and impaired eye movements. Most MELAS patients report exercise intolerance due to muscle involvement. Occasionally they have muscle pain. In one study of 50 MELAS patients (Brain 2005;128:1861-9), half had myopathy and 3 had myalgia. Thus, muscle pain and tightness may be due to MELAS.
Answered by: Michio Hirano, MD

Q: If a child has a diagnosis of mitochondrial disease, does his/her mother, who begins to have adult onset, similar symptoms, have the same type as the child or can the mother have a different form of mitochondrial disease?

A: This question sounds straightforward but the answer isn't always clear. Many symptoms associated with mitochondrial disease can be found in the general adult population. Examples include diabetes, stroke, hearing and visual problems, lethargy, exercise intolerance and neurological problems. If these symptoms occur in a maternal relative of a child with mitochondrial disease then one may tend to automatically assume there is a connection. However, some of these symptoms are relatively common and quite often it can be a coincidence. The general answer is that the individual should seek medical advice from a specialist, and should of course mention the family history of mitochondrial disease. The same applies even if the child's symptoms have been shown to be caused by a mitochondrial DNA mutation. If the mother has also been shown to carry the same mutation and her symptoms are very suggestive of mitochondrial disease then it is likely that they are caused by the mutation, but it still needs proper investigations to confirm this. If that is the case then it doesn't mean that the mother will develop the same range or severity of symptoms as the child. In most cases, the mother will have more healthy mitochondrial DNA and less with the mutation. So she may have much milder disease than the child or have a different range of symptoms. It would be best to discuss the specific concerns with a physician who has expertise in mitochondrial disease.
Answered by: David R. Thorburn, PhD

Q: Please share with us your experience with the use of Gamma Globulin injections and individuals with Mitochondrial Disease.

A: As you may know, Intra-Venous Immuno/gamma Globulin (IVIG), is a medication that is often used for various conditions, often touted as being effective, but is not completely understood in regards to how it actually works. Theories of how IVIG work do exist - and in general, it is felt to be an immune system "neutralizer." That being said, the single commonality for most conditions that respond to IVIG is that immune system dysfunction is involved in some way and felt to be the primary culprit in leading to the condition. IVIG is often the initial medication for diseases of the immune system being "over active," or in auto-immune conditions where the immune system is felt to attack the body. Since mitochondrial disease is not primarily an immune-system disease -> it is not a standard treatment and has not been studied as such. We know that some patients with metabolic disease become ill more easily - however a specific "immune deficiency" or "immune dysfunction" has not yet been identified. Beyond this consideration, patients with mitochondrial disease may have received IVIG for other secondary problems that are typically treated with this medication. There are currently no cases of a problem occurring in these cases reported in the US medical literature.
Answered by: Sumit Parikh, MD

Q: I was diagnosed with metabolic myopathy. The doctor prescribed 2 150 mg. of CQ10 three times a day. Do you know of any cases that have improved with this? I seem to have more energy but the stiffness in the legs is still there.

A: Ubiquinone (coenzyme Q10) certainly does seem to make people feel better and give people more energy, but does not really improve weakness or symptoms very much. You seem to be getting a similar response to that I observe in my patients.
Answered by: Douglass M. Turnbull, MD, PhD

Q: My 20 month old daughter with Complex 1 defect mitochondrial encephalomyopathy recently had her follow up brain MRI and spectroscopy scan resulting in a normal MRI, but spect. scan showed a decreased NAA level. I know it is synthesized in the mitochondria, but that is really all I know. Does this mean that she has neuronal loss, and if so, why, and is this the reason that despite normal MRI that these kids have cognitive involvement? Are there also supplements to give for this particular issue? Please explain more clearly.

A: I am sorry that your daughter has a complex I disease. I hope that I can explain your question. The two neuroimaging studies are distinct in that the MRI looks at brain structure while the MRS (spectroscopy) looks at biochemical products (chemicals) in the brain. Both are brain scanning techniques that allow us to better visualize structural and chemical levels (which would suggest biochemical function) of the brain. However, both are limited in some ways because they are limited by the resolution of the technique. It is sort of like the difference between looking at, let’s say, the moon with a telescope versus being on the moon itself. Both would allow us to see the very large craters or mountains, but only being on the moon would allow us to see all the really fine detail on the moon’s surface. So, MRI and MRS (spectroscopy) allow us a very powerful telescope view of the brain; they are limited by not actually being able to place the brain under a powerful microscope and visualize the individual neurons and glia cells of the brain. At the sensitivity level of the MRI scan, the structures of your daughter’s brain seem to be normal. However, looking at the different chemical peaks of the MRS or spectroscopy scan, there are lower levels of a marker chemical, NAA (N-acetylaspartate). You didn’t tell me whether the technique used multiple voxel detection or single large voxel volume for detection. But, essentially the answer would be similar. The NAA peak is thought to have two functions in the adult brain (precursor to lipids and is involved in coenzyme A interactions). The NAA peak is higher in the cortex than in the white matter, as most NAA is located in the neuron and its branches. So, we think that a decrease in this peak (or relative reduction in the ratio of NAA to Creatine) is an indicator of neuronal and/or axonal damage. In the developing brain, there is a significant amount of NAA in the myelinating cell, the oligodendrocyte. So, in a brain that is actively myelinating, the NAA peak may be an indicator of normal oligodendrocyte development and reduced levels might suggest oligodendrocyte dysfunction. So, depending on where the MRS detection was located, a decreased NAA peak may suggest neuronal dysfunction or neuron decrease and/or oligodendrocyte dysfunction. Most of the time, the location where the MRS is used is within places where neurons are in high numbers such as the cortex or deep gray matter regions. So, most likely the finding of reduced NAA (in your daughter) suggests neuronal dysfunction and/or reduced numbers of neurons. So, the MRS may be giving a better picture of what is going on in your daughter’s brain. So, although structurally normal at the level of the MRI, the MRS suggests that there is neuronal dysfunction or neuron cell loss. I hope this helps you understand why we like to get both studies in children with mitochondrial cytopathies.
Answered by: Russell Saneto, DO, PhD

Q: I have a 12 year old with a variety of symptoms. • Neurologists are "frustrated” with no specific Mito disease to name and want additional nerve and muscle samples. We are tired of surgeries. Are there less invasive tests recommended? • If this (or part of it is) is mito disease, is he harming himself by “overdoing it”? Doctors want to start biofeedback.

A: Unfortunately, all confirmatory diagnosis in mitochondrial disease still requires an invasive procedure and evaluation of living muscle or other tissue (liver) mitochondria. Even gene testing limited to blood specimens is incomplete and muscle/other tissue need to be tested for genetic abnormalities. A big challenge in the field is that confirming a diagnosis of mitochondrial disease, at this point in time, does not alter treatment (though it could potentially alter genetic counseling for families and the affected individual). So the decision is often based on the family and physician's need to be in a category of "possible," "probable" or "definite" mitochondrial disease. When a diagnosis of mitochondrial disease is not "definite," an important plan of care includes periodically re-evaluating for other diseases or syndromes that may cause such symptoms and making sure they have been excluded. In regards to your question of his "overdoing" it - supervised exercise (within his limits) may help a person make more healthy mitochondria. If he is regressing or completely "wiped out" after exercising - he may need to step-back his level of activity. Treatment of most mitochondrial-disease-associated symptoms is identical to symptoms in those without mitochondrial disease. Thus, biofeedback may very well help with pain management.
Answered by: Sumit Parikh, MD

Q: Is gastrointestinal motility a problem caused by MERRF?

A: 1/4/06 Gastrointestinal dysmotility is an under-recognized problem in patients with mitochondrial diseases and may occur in MERRF. A paper by Dr. Kurenai Tanji and colleagues described a patient with intestinal dysmotility (paralytic ileus) and the MERRF A8344G mitochondrial DNA mutation (Acta Neuropathol (Berl) 2003;105:69-75). The patient did not have the typical features of MERRF (myoclonus, epilepsy, or ataxia) but rather had mitochondrial myopathy, multiple lipomas, hearing loss, and stroke-like episodes in addition to the gastrointestinal dysfunction.
Answered by: Michio Hirano, MD

Q: Is there any research regarding the effects of RSV on children with mitochondrial disease and the prognosis of the child? My son is 5 and was immunized against RSV so I found it strange that he tested positive for RSV. He has a COX deficiency and we live in a place that has been struck by three hurricanes in 14 months. The local health officials are identifying RSV in non-RSV seasons. Also, what are the implications for the long term for a child infected with the RNA RSV?

A: Respiratory Syncytial Virus (RSV) - is a common cause of respiratory infections in children and adults. Almost all of us have been infected by this virus by age 2. The virus is transmitted as most cold-causing viruses are -> from sharing respiratory secretions from person-to-person or person-to-object (so hand-washing is a key to prevention). Infection with RSV usually presents with cold-like symptoms in most individuals (an upper respiratory tract infection). It can cause lower respiratory tract infections such as pneumonia and/or bronchiolitis as well - though this is less common in normal children and adults. In those who have a) a weakened immune system (not necessarily the case for all mitochondrial patients), b) chronic lung disease (premature infants), and c) congenital heart disease-> the RSV vaccine is used as a prevention measure. This vaccine does not prevent an individual from obtaining RSV, testing positive for the virus or from having symptoms. It only "protects" the person by delivering antibodies prior to infection and preparing the immune system - so when infected - the infection is less severe. The consequence of routine RSV infection (cold symptoms or uncomplicated lower respiratory tract infections) are negligible and allow the person's immune system to prime itself. Complicated RSV infection can lead to hospitalization and a need for supportive care, short-term oxygen, and medications to help open the airway. Since RSV is a virus, antibiotics are not beneficial. RSV immunization is not indicated for most patients with mitochondrial disease and is considered on a case by case basis for these individuals. Sumit Parikh, MD
Answered by:

Q: I am a 48 year old female with Mitochondrial Myopathy with deficiency in Complex II and III, particularly isolated in my muscles and "stroke like symptoms". Currently I am experiencing cramping in both thigh muscles and upper arm mucsles, to the point of my legs being stiff - I look like a "scare crow" when I walk because of the stiffness. I am also dizzy, droppy eyelids, foggy thinking, slight slurred speech, difficulty retrieving words, headache, tight chest, and tight throat making it a little difficult to shallow. I have not yet noticed any darkness to my urine. What can I do to get through this, other than rest? Is there something my doctor and I could be doing to get me through these "crises"? Any help would be appreciated, as I want to continue to be mobile and working.

A: 11/29/05 Because you have multiple symptoms and lack a genetic diagnosis, it is difficult to provide you with specific advice. There are a few issues that ought to be addressed. First, it is important to know whether you have deficiency of respiratory chain complexes II and III or deficiency of coenzyme Q10 (CoQ10). Many laboratories perform biochemical assays which measure complexes II+III and complexes I+III rather than the activities of the individual enzyme complexes. Because CoQ10 transports electrons from complexes I and II to complex III, deficiency of CoQ10 will cause low activities of complexes I+III and II+III. Therefore, measurement of CoQ10 in your muscle would be important diagnostically and also therapeutically because patients with CoQ10 deficiency respond very well to supplementation!! As for your muscle cramps and stiffness, I would like to know whether you have true muscle cramps or spasticity due to upper motor neuron dysfunction. I suggest that you ask your internist or neurologist to define your neurological problems because there are very different symptomatic treatments for each condition. Are there any precipitating events that cause your crises? If so, avoiding such environmental triggers may be beneficial. Finally, it may be helpful to know the results of laboratory tests during your crises. During each episode, do you have severe lactic acidosis, elevated serum creatine kinase, or other abnormal blood tests? Do you have brain MRI changes during the "stroke-like" episodes? Have you been evaluated for epilepsy? In summary, I recommend that you discuss your medical problems with your doctor(s) to better understand your condition. With this information, it may be possible to provide more specific therapy.
Answered by: Michio Hirano, MD

Q: Can you tell me the significance if any to my son who has a mito disease deficiencies of Complex 2, 3, and 5 having very elevated aluminium levels in blood?

A: 11/29/05 There are no published studies on the interaction of aluminum toxicity and respiratory chain deficiency. Aluminum is not known to participate in oxidative phosphorylation. Please be careful of aluminum measurements in blood. They are very prone to contamination and there is actually very little reason to measure levels under normal circumstances. There are a variety of labs that make a lot of money testing for "nutritional deficiencies" and "environmental toxicities" and do little but make their owners rich. You should discuss any concerns about metal toxicity with your metabolic doctor. Most have a good knowledge about which labs are reputable.
Answered by: Gerard Vockley, MD, PhD


A: 11/11/05 A liquid Vitamin B2/Riboflavin is made and available in several brands and formulations. One specific brand is not preferred over others. Liquid preparations can be found online if not available locally. It can also be formulated from a pill to a liquid at a compounding pharmacy (which most cities have) or even at some regular pharmacies - and thus can be mixed into a more palatable syrup. Vitamin B2 can change the urine color and smell, but is not known to be toxic to the kidneys. It should not directly affect the kidney's abiliy to concentrate urine.
Answered by: Sumit Parikh, MD

Q: I have a 16 year old daughter that had a muscle biopsy two years ago and has a working diagnosis of a mitochondrial cytopathy complex I defect. She started on all the mito medicines, B2, CoQ10, Carnitor. She hasn't been able to attend school a full year in the last four years. This year has been no exception. She only went to school seven days before she was put out on homebound. My question is will she ever be able to attend school full time, or even work for that matter? Should we be considering disability for her so she will always have her insurance? Will she ever be any better then she is at this time? We are just greatly concerned with what her future holds. Any help you can give me would be greatly appreciated.

A: This question is primarily related to the issue of a mitochondrial disorder being a progressive degenerative disease. Please recognize that most health care personnel regard mitochondrial illnesses as progressive. By this we mean a disorder that progresses each year, getting worse with time and related to the degeneration that is taking place in certain organs and tissues such as the brain, muscle, nerves, etc. And certainly many mitochondrial diseases secondary to respiratory chain deficiencies are progressive neurodegenerative processes. In these instances, the patient may present with weakness, clumsiness or a seizure disorder, but progress with time so that as the years go on, the patient may sequentially lose the ability to walk, stand, see, hear and even eat food and drink liquids. But this is not true for all of the various types of mitochondrial defects. Some patients present in early infancy, progress fairly quickly, but then stop getting worse by age 2 or 3 year. They may be left with ataxia (meaning poor balance) and an abnormal gait, or seizures and delayed development. Other patients may have developmental delay and seizures, but nothing more over the course of a decade. So you see, it is sometimes very difficult to say for sure what the future will bring, and of course therapy with vitamin cofactors and antioxidants at high doses may be beneficial and alter the natural course of the mitochondrial disease process. Given your questions, it is possible that your daughter may not be able to go school anymore, possibly because of weakness alone. But that is not necessarily the case. She may become stabilized, and even be able to engage in meaningful work, especially if she could be close to a family member. My suggestion would be to err on the conservative side. For example, assume that she will not be able to attend school or even work. Even if it is not true! Then you should make arrangements to secure insurance for her and consider obtaining disability benefits. She may get better as time goes on, but we just can't say for sure. I hope this note is helpful for you and the family.
Answered by: Gerard T. Berry, MD

Q: My 5 year old son was recently diagnosed with oxidation phosphorylation disease, complex I defect. Could you please tell me what this means and how this will affect his life?

A: 10/21/05 Complex I is one of the major enzymes of the mitochondrial respiratory chain. It consists of greater than 40 proteins (individual building blocks) and has an extremely complicated structure. Deficiency of complex I is one of the commonest causes of mitochondrial disease. Deficiency of complex I can be due to either a defect in the mitochondrial genome (which produces 7 of these proteins) or of the nuclear genome (which produces the rest and many more involved in assembly). Identifying mutations can be extremely difficult and only a small number of patients have specific genetic defects identified. It is easier to analyze the mitochondrial compared to the nuclear genome and about 20% of patients have defects of these genes. The clinical course of patients with complex I deficiency is extremely variable and likely to be different with different genetic defects. I hope these comments are of help.
Answered by: Douglass M. Turnbull, MD, PhD

Q: Explain to me the Caution to use Tylenol because it depletes glutathione peroxidase levels. My daughter is 16 months old and is teething. Should I give her Motrin instead?? Please explain and advise.

A: 10/13/05 Glutathione (GSH) is an important part of the defense system to help the body combat stress caused by the production of toxic chemicals called reactive oxygen species (ROS) and reactive nitrogen species (RNS), so-called free radicals. As you know, mitochondria provide energy to cells and by doing so function as a “cellular engine.” In addition, mitochondria produce free radicals as a by-product of energy production, similar to a car engine producing exhaust fumes. Car engines that do not work correctly make an abnormal amount of exhaust. Similarly, dysfunction of the mitochondrial respiratory chain can result in an increased production of toxic free radicals (“metabolic smoke”). Although the glutathione system works well to detoxify ROS and RNS under normal circumstances, in cases where there is increased free radical production, this defense system may be overwhelmed. Acetaminophen (Tylenol) is known to cause severe liver damage in cases of overdose. Acetaminophen is converted into a highly reactive chemical, abbreviated NAPQI, that depletes GSH in liver cells. Some researchers think that the net result of acetaminophen toxicity is the creation of free radicals followed by mitochondrial and cell death. If a toxic dose of acetaminophen is ingested, GSH levels fall, allowing NAPQI to cause damage by binding to various proteins inside the cell. Following this damage, free radicals are formed, leading to a vicious cycle of increased mitochondrial and cellular damage. Because acetaminophen causes GSH depletion, increased free radical production, and mitochondrial damage if taken in overdose, some people have raised concerns about the possible deleterious effects this medicine could have if taken by individuals who have decreased mitochondrial function. However, to my knowledge there have been no reports documenting acetaminophen toxicity in mitochondrial disease. At the usual dose, acetaminophen is likely a safe medication for pain relief and lowering fevers. Ibuprofen (Motrin) is also a safe medication when taken as directed by a physician. Gregory M. Enns, M.B., Ch.B.
Answered by: Other Doctor (Noted in Answer)

Q: After 9 years of tests, doctors and hospitilizations my son was diagnosed with a complex I defect by a muscle biopsy. He was 9 years old then. He was able to walk then. Today, he is in and out of a wheelchair because of severe pain to his legs and/or feet; sometimes we cannot touch him due to the pain. He is again in the wheelchair due to pain. We've seen more than 50 doctors at this point. It is now suspected that he has a second disease. Two weeks ago he was tested for Fabry Disease. Yesterday those tests came back negative. Now doctors want to have another muscle biopsy to confirm the original diagnosis. I've read before that a muscle biopsy is 100% accurate in diagnosing mitochondrial disease. Now I'm told this is not true. I'm told with the advancement in technology, having another muscle biopsy now would be more accurate than five years ago. No one seems to be able to get his pain under control. He's 14 now and many nights he's up till 2 or 3 in the morning crying with pain. He bangs his feet on the floor to try to stop the pain (it doesn't work); he shakes his legs to stop the pain (it doesn't work). We've tried so many different medications and nothing works; most cause him to react to the medications. I don't understand how a diagnosis could be made through a muscle biopsy five years ago and now it's questionable. Please offer me some information as to how this works. How many patients with complex I defect actually suffer from this type of pain and to this degree? What methods can be used to stop the pain to allow for a normal life? He can't even go to school because of the pain level. He's home all the time.

A: I am very sorry to hear of how much pain your son is in and the recent diagnostic difficulties your family is having. I will try and answer your questions in several segments: 1) The muscle biopsy is not 100% accurate. We do not have perfect numbers yet as to the absolute accuracy of this test - which is why some of us hem and haw about performing it. There is no good research data on "false negative" and "false positive" results of a muscle biopsy. Each lab that performs muscle biopsies is still trying to further evaluate this. However, until we know all the genes which can cause mitochondrial disease, and then compare an individual who has a known genetic defect and this person's biopsy results - we will not know for sure. Labs that do muscle biopsies have amassed some individuals with a positive mitochondrial DNA mutation -> but not necessarily in enough numbers to report their findings. Our group is still studying this. All in all - like any test - muscle biopsies will have a certain degree of falsely positive and falsely negative results. 2) What do we know about muscle biopsies -> We believe we know that a muscle biopsy is superior to skin fibroblast testing for mitochondrial disease. We also believe we know that a "fresh" muscle biopsy is superior to testing frozen muscle tissue though the actual figures of "how superior" vary. 3) Is there another diagnosis? This question should always be entertained - especially when a diagnosis of mitochondrial disease is not 100% (i.e., no DNA mutation identified/ clinical course atypical/ muscle biopsy not abnormal for all aspects tested). We suspect that there is a concept of "secondary" mitochondrial disease -> a primary disease can interfere with how mitochondria work or it can directly injure mitochondria, so if you test the mitochondria - the results are abnormal. However - the primary disease is still the problem. Treating the mitochondrial disease may help alleviate some of the symptoms, but the primary disease remains. 4) We do not know how many individuals with Complex 1 disease - or mitochondrial disease in general - have pain, though both brain and nerve disease in mitochondrial dysfunction can lead to pain, and pain is a common symptom in mitochondrial disease. Chronic pain, regardless of cause, is difficult to treat. There is no one medication that is more beneficial for pain caused in mitochondrial disease. The care of a physician who specializes in pain management needs to be obtained. All available treatments, including safe alternative treatments (acupuncture, relaxation, meditation, biofeedback) need to be tried.
Answered by: Sumit Parikh, MD

Q: My daughter is 4 1/2 and has cytochrome c oxidase and complex iv with seizure disorder and precocious puberty. Her seizures have never been controlled despite vagal nerve stimulator, ketogenic diet for 3 1/2 years and lots of drugs. She now is going through puberty and we started the Lupron shots 4 months ago and now her seizures have gotten worse. She normally has 4-5 seizures per day (complex partials); now we have been up to 5-11. The doctors say the lupron shot is not what is making her seize but I am not so sure. Have you had this in any other patients? We are flying by the seats of our pants with her and so far have been VERY lucky. Her nurologist has been a HUGE help but we are all running out of ideas and resources. Any help or suggestions would be GREATLY appreciated!

A: I am sorry to hear about your daughter. My experience with Lupron is limited, but I have one patient we used it for the very purpose that it is being used for your daughter. The patient did extremely well and was on Lupron for several years without much in the way of side effects. We just recently stopped Lupron to allow him to go through puberty. What we know about seizures and mitochondrial disease is limited. My experience with VNS has not been good with myoclonic seizures and mitochondrial disease. However, in some other types of seizures it may work better. I have also had good success with the ketogenic diet, although I have had to alter the ratio in many patients to optimize seizure control and bone density. I mention the above to let you know that I think that these two modalities may be beneficial in patients with mitochondrial disease and seizures (with the exception of myoclonic seizures and VNS). Giving Lupron alters the synthesis of sex steriods, that is how it would delay puberty. We think that estrogens are proconvulsant and progestrone is anticonvulsant with respect to seizures. Since your daughter started puberty, these hormones have likely been around in higher concentrations as well. Now that you have started Lupron, they should not be present in the amounts that provoke puberty. That would have altered the brain's environment and might be inducing some seizure activity. In addition, higher levels of steroids would likely alter the liver's cytochrome P450 system and possibly changed the seizure medication metabolism/clearance as well. I would imagine that about now, things should be baseline with medications, ketodiet, and seizures. I would begin the fine tuning of medications to restore seizure frequency to what was baseline before Lupron administration. It might take awhile, but I would imagine that you'll likely be able to get back the seizure control you had before Lupron started.
Answered by: Russell Saneto, DO, PhD

Q: I have a 4 1/2 year old boy with mitochondrial disease (Complex III defect and partial Complex I defect). My question involves the immune system: How frequently do you see mitochondrial disease affecting the immune system? My son's T cells and T cell subsets are at chronic low levels (cd4 is 553: norms are 900-2860; cd3 922: norms are 1610-4230. Cd8 is below normal as well) 1. His B cell immune system is good at this point.I'm concerned b/c I'm under the impression that typically nothing is done for these levels in 'normal' kids, but our son is not normal. Given that it takes energy from the mitochondria to make T cells, I wonder how much energy he will be able to muster to rev up his immune system (and he will have to rev it up more b/c he already is below normal) to fight viral and bacterial infections and I'm quite concerned about the cost this is to him... the energy has to come from somewhere and, according to the research on mitochondrial disease, it will come at a cost to another organ system if not to his immune system. 2. What is the threshold for considering a child to have leukocytopenia or lymphocytopenia? How low do you have to be for this to be considered? 3. Any thoughts on the CD8 increasing while the CD4 remains the same - I'm under the impression that in HIV you see CD8 increasing, while CD4 decreases (that happened in the percentiles this time) when the immune system is breaking down. I know that in some other families there are kids with mitochondrial disease that end up SCID. Luckily, our son still has good B cell levels. These questions come as we face the winter ahead. Our son has taken 'hits' every winter and has had to use the summer to regain strength - unfortunately he is not able to regain all of his previous strength or skills.

A: There is really very little to nothing in the literature regarding immune deficiency in mitochondrial disorders. Bone marrow suppression and reduced blood cell count is well recognized in Pearson syndrome, but I am unaware of isolated T-cell depression in mitochondrial disease. Similarly, children with moderate to severe disease can get worse with minor illness and may not recover to baseline, but there aren't any data that prove an increased susceptibility to disease beyond that related to neuromuscular dysfunction. The definition of leuko/lymphocytopenia is variable and is probably best to focus on function rather than absolute number.
Answered by: Gerard Vockley, MD, PhD

Q: My daughter, 4.5 years old, has been diagnosed with a non-specific mitochondrial disorder because of congenital optic nerve atrophy, mild dilatation of the ascending aorta, macrocytosis and a lactate/pyruvate ratio elevated at 21.8 (6-18). The hemotologist recently evaluated her for the macrocytosis (large red blood cells) and all tests for anemia (iron/folic/B12, etc.) were negative. The hemotologist asked me to advise her if and when I found out the cause of the macrocytosis. Have you ever encountered macrocytosis with mitochondrial disorder and if yes what is the cause/symptoms/results?

A: I am not aware of an association of macrocytosis with mitochondrial disease nor could I find one in the literature. The clinical picture that the questioner presents does not sound particularly like a mitochondrial disease. There are many more causes of optic atrophy than Leber’s. Perhaps they should consider the X-linked optic atrophy-spastic paraplegia syndrome associated with macrocytosis (OMIM #311100). The neurologic findings may be variable.
Answered by: Gerard Vockley, MD, PhD

Q: My son has MELAS. Our doctor is recommending Magnesium Orotate amoung the other normally prescribed vitamins. Has this been helpful for others? And, is there any new research about the use of Mg Orotate?

A: 8/25/05 Magnesium Orotate is still under investigation. It is a drug which is given at lower doses for magnesium supplementation. It was considered as a treatment for mitochondrial disease since it is converted to dihydro-orotate in the body, and an electron donor to Coenzyme Q10 (in theory it helps CoQ10 work better). It is also a potent anti-oxidant and helps the body synthesize more DNA precursors (purines) This drug is not yet standard of care for mitochondrial disease patients since it has not been studied enough. Most studies of this drug have been in animal models, and for treatment of heart disease. In these studies it has shown varying benefit in decreasing cardiac injury in times of stress and increasing exercise tolerance in those with an injured heart muscle. It has also been studied for treating muscle weakness related to "statin" drugs used to treat elevated cholesterol. There are no current US trials of this medicine for mitochondrial disease (or for any other disease for that matter). Dr. Anthony (Tony) Linnane, who spoke at the recent UMDF conference, is a researcher/physician from Melbourne, Australia. He studies the effects of aging, cancer and cardiac disease on the mitochondria, and is studying Magnesium Orotate. But again, these studies are not on individuals with primary mitochondrial disease. So - while there are no obvious contraindications to this medicine, it's true benefits and toxicities for individuals with mitochondrial disease are not yet known. The only obvious risk is that of magnesium poisoning. This has been reported in the medical literature. Sumit Parikh, MD
Answered by:

Q: I have a daughter with Melas.. Recently she has started to have problems with frightful thoughts.. Can MELAS lead to problems like "obsessive compulsive disorder" (OCD)? A dysfunction in the brain and its metabolism is said to be one underlying reason to this disorder.. I also wonder: Are problems like this common among others with Melas? Would it be safe to use SSRI-products?

A: We are not aware of any data that show that obsessive-compulsive (OC) traits are more frequent in MELAS or in mitochondrial disorders in general. From our own clinical experience, OC traits are common in individuals with mitochondrial disorders, including those with MELAS. You have stated the likely reason as well as we can, as MELAS/mitochondrial disorders often result in "a dysfunction in the brain and its metabolism". Selective serotonin reuptake inhibitors (SSRI) medications are widely used in the treatment of depression, and some of them have also been shown to be effective in patients with OC disorder. Many SSRI drugs have names that are widely known, including Prozac, Celexa and Zoloft. However, SSRI medications can induce mania in individuals with bipolar disorder, which like depression may be more common in mito patients. SSRI drugs also have many other side effects. Headaches and nausea are common at least in the beginning of treatment. Side effects are more likely to appear with higher dosages. There is also the recent concern that suicidal thoughts may be more common in depressed children and adolescents on SSRIs, especially at the beginning of treatment. You did not state how old your daughter is, or if she is taking any other medications. Prozac may be a good choice as it is an SSRI agent that has been tested in children and in OC disorder. There are interactions with some other medications that one has to consider, in particular some drugs used to treat seizures. A general advice would be to look at the whole situation (would successful medication usage really improve quality of life?), and if considered to be worth a trial, start with a very low dosage (much lower than usually considered effective) and wait for several weeks before increasing it gradually, if there are no side-effects and a less-than-optimal effect. It is often necessary to wait longer to see if an SSRI is helping when treating OC traits/disorder than in treating depression. In our experience, frequent feedings/fasting avoidance, co-enzyme Q10, anti-oxidants (for example, vitamins C and E), and/or magnesium are often helpful. However, as with any medications or other health-related recommendations, we advise you to discuss whether they are right for your daughter with your physician. Richard G. Boles, MD Ann Gardner, MD PhD
Answered by: Richard G. Boles, MD

Q: My son has a problem with horizontal and vertical gaze. He has had an emg, tinsolon test and myasthenia has been ruled out with various blood test. His thyroid is fine, his vitamin E levels also. He had blood work also for mtDNA deletion and mutation3243 using PCR. That was also negative. His COq levels were fine in the blood. His lactate was slightly raised. (Both times a tourniquet was used, which I understand is unreliable.) He had a fresh muscle biopsy. The results were negative for Ragged Red Fibers, but there was increased staining of enzymes. Can you tell me of any mito diseases that have opthalmoplegia but no ragged-red fibers? Other than his eye problems, he is fine. Could it not be mito at all, and where do I go from here? Should I just leave things be? Can his eyes correct themselves?

A: There are multiple possible causes of ophthalmoplegia. Supranuclear palsy (dysfunction of brain pathways that control eye movements) and cranial nerve dysfunction can also cause ophthalmoplegia. I presume that these possibilities were excluded by your son's physician. As you noted, impaired eye movements can also be caused by myasthenia gravis. Typical myasthenia gravis is an immunological disease and congenital myasthenia gravis is a genetic disorder. You son's normal EMG and Tensilon (edrophonium) tests make myasthenia gravis unlikely. Nevertheless, to be more certain, a single-fiber EMG of the frontalis (forehead) muscle may be useful because this test is very sensitive for detecting myasthenia gravis affecting only extraocular muscles.

As you noted, absence of ragged-red fibers makes mitochondrial disease less likely; however, sometimes RRF are not detected in patients with mitochondrial PEO and multiple deletions of mitochondrial DNA (mtDNA). Therefore, I suggest that your son's muscle biopsy be screened for multiple deletions of mtDNA and, if present, then he should be screened for mutations in the nuclear genes encoding polymerase gamma, ANT1, and Twinkle. In addition, his muscle should be tested for a single deletion of mtDNA which is typically not detectable in blood of CPEO patients. Because your son does not have a diagnosis, I cannot predict whether his eyes will improve.

Answered by: Michio Hirano, MD

Q: I am an adult male diagnosed with MERRF. I have been disabled since 1987 and am much worse now. I also have a lot of fatty tumors for which I have had surgery four times, but they come back. Doctors say it is part of MERRF. My brothers and nephew have this problem also. Have you seen fatty tumors in connection with MERRF? I would like some information on this problem.

A: 7/28/05
As the name implies, myoclonus epilepsy ragged-red fibers (MERRF) is clinically characterized by sudden and brief body movements (myoclonus), recurrent seizures, incoordination (ataxia), and abnormal muscle fibers called ragged-red fibers. MERRF is usually caused by a point mutation in the mitochondrial DNA at nucleotide position 8344 (MERRF-8344). Patients with MERRF often develop fatty tumors called lipomas. The tumors are typically present at the base of the neck, but can arise in other parts of the body including the arms and legs. The lipomas are not malignant, but can be disfiguring. The tumors can be removed surgically, but, as you experienced, they often recur. Sometimes the MERRF-8344 mutation causes lipomas without the more characteristic clinical features of MERRF. A patient described by Dr. Elizabeth Holmes and colleagues in Sweden had lipomas without myoclonus, epilepsy or ragged-red fibers (and we have seen a similar patient). Interestingly, Dr. Holmes found that the lipomas contained a second genetic defect in the nuclear DNA (a deletion in chromosome 6 of the nucleus). Presumably, in addition to causing MERRF, the mitochondrial DNA mutation somehow causes the nuclear DNA defect, which, in turn, causes the lipoma. How a primary defect in mitochondrial DNA causes a secondary change in nuclear DNA is a mystery.

Answered by: Michio Hirano, MD

Q: My husband is 39 years old and has been diagnosed with mitochondria myopathy. He has been having trouble with his jaw this past week and wonders if it has anything to do with his mito. He says that his jaw has occasionally made a popping sound ever since he was a child. That in the last six months he has noticed a quick severe pain almost like a leg cramp, but in his jaw. It was going away as quickly as it came. However, this last time it has been lasting for five plus days. It hurts to open or close his mouth so he tries to leave it in one position. Do you have any ideas if this is related to his mito?

A: 7/18/05
I am not aware that jaw problems have been described in mitochondrial disease unless someone is very, very weak. On this basis it is more likely the symptoms are very long standing and that this has become a little worse recently.

Answered by: Douglass M. Turnbull, MD, PhD

Q: I have a 4 yr old, normal MRI, Complex I, cognitive involvement, who has persistent panic attacks when being in cars/vans and especially when lying down to be diapered in one (even without it running). They began a year ago and have gradually gotten much worse - to severe panic! I have wondered why. Could it be sensory triggers from sound/vibration (but he isn't usually otherwise noise sensitive)? He is disoriented when reclining (but he has not trouble in the house or sleeping)? He has no attachment of a memory to the car that would induce panic. Is this perhaps related to mito disease and is it necessary to manage it (and if so, how)? Could the body chemistry of panic cause more cellular damage? How do we help him?

A: 7/20/05
Anxiety is common in individuals with mitochondrial disease. In a recent study to be discussed in a future issue, it appears that anxiety is somehow a result of the mitochondrial disease and not simply a reaction to having a chronic and unpredictable illness. I have evaluated many children with mitochondrial disease in which panic attacks are present. Thus, there likely is a connection between the mitochondrial disease and this child's behavior.

On the other hand, while mitochondrial disease may increase the risk for developing panic attacks, they are only one factor causing them and certainly not the only one. Other factors would include both genetic(non-mitochondrial) and environment ones. The diagnosis and treatment for panic attacks is the same whether or not a patient has mitochondrial disease, and whether or not this disease is contributing towards the development of anxiety and/or panic attacks. Thus, an evaluation with a child psychologist is prudent.

In extreme cases, severe anxiety and panic can be a high-energy-demand situation, and thus can trigger symptoms in patients with mitochondrial disease in much the same manner as other stressors can, such as fasting, illness, environmental temperature extremes, lack of sleep, over-exercise, etc.

An exception to the second paragraph (discussed in detail in a previous Ask the Mito Doc response, and which does not appear to be present in this particular case), is when panic attacks occur "out of the blue", not associated with emotional or environmental triggers. In that case, the sudden-onset of dysautonomic attacks such as migraine or tachycardia (rapid heart beat) can be misinterpreted as panic, and may respond dramatically to an anti-migraine medication such as caffeine, amitriptyline, or cyproheptadine.

Answered by: Richard G. Boles, MD

Q: My daughter has MELAS, and she was recently diagnosed with Thyroid Papillary Carcinoma (cancer). The radio-active iodine (radiation) treatment (after a complete thyroid, and one parathyroid removal surgery) made her so ill that she had to be hospitalized for a week. Her body scan shows a lot of remaining cancer, and her lymph nodes and lungs lit up, too, so she needs more treatments. Are cancer treatments recommended for mito patients, and how common is cancer in patients with mitochondrial disorders?

A: 7/15/05
This is a difficult question to answer because there are no properly conducted studies of the frequency of neoplasias (tumors) in patients with mitochondrial diseases. I think it is fair to say that there is no obvious relationship between tumors and mitochondrial diseases, but there are certain types of rare tumors (including some affecting the thyroid gland) that are associated with mitochondrial dysfunction. The type of tumor described could be directly associated with mitochondrial dysfunction because some tumors of the thyroid gland - called oncocytomas - are chockful of mitochondria.The field is open to study. It is a little easier to answer the second question. Because patients with mitochondrial diseases, including MELAS, are more vulnerable to any kind of stress, this has to be taken into account when planning cancer therapy, which is rather aggressive.

Answered by: Salvatore DiMauro, MD

Q: Since January 2003 a succession of MRIs has labeled me with Olivoponto
Cerebellar Atrophy aka MSA typeC now. I have no reason to dispute the
diagnosis: but at the same time he requested a muscle biopsy. This is my third one. All initially come back with a first report of red ragged
fibers plus clumping of mitochondria; however, then the follow-up shows
normal Co-enzymeQ10 levels, so the confirmation remains on 'hold.'

My neurologist has inferred that there may be a link between the two conditions. Thus my question is whether any research has inferred this. I am not asking for a second opinion, just research
information as it seems to me very long odds that I should have two very rare illnesses!

A: 7/15/05
Since OPCA (olivopontocerebellar atrophy) and MSA (multi-system atrophy) are neurologic terms for clinical diagnoses that have been increasingly well delineated and differentiated via enzymatic and genetic abnormalities, the presence of ragged red fibers on a muscle biopsy would raise a question of mitochondrial dysfunction, even with a normal Co-enzyme Q level. So our initial approach in this setting, given that this patient has muscle tissue available for analysis, would be to do as complete a mitochondrial evaluation as possible on the muscle, i.e. mitochondrial enzymes, electron chain components, carnitine level, CPT (carnitine palmitoyl-transferase), and mitochondrial DNA.

Alternatively, it is possible the ragged red fibers represent secondary mitochondrial dysfunction and the clinical diagnosis should not necessarily be altered.
Phillip L. Pearl, MD

Answered by:

Q: Recently, my eight year old son has been falling down a lot. Eight months ago he experienced difficulty in walking. He was hospitalized and attending docs thought it to be toxic synovitis. Yet, as they contorted his legs in various positions, he did not show any sign of pain. He finally did come to a full recovery yet it seemed to be much longer that anticipated, even for toxic synovitis plus allotting even a longer recovery time due to his Mito. So, now here we are eight months later and he is exhibiting weakness again to the extent of falling down/collapsing and we have noted times when his ability to walk appeared very difficult for him to control. Now, we are soon to undergo an MRI on the basal ganglia and cerebellum w/contrast.

At the age of 2 ½, upon the diagnosis of complex one, the molecular geneticist prepared us that our son's life would be shortened and to expect a downward progression either over a long period of time or regression could happen quickly. Because this falling and difficulty in walking is occurring for the second time, this brings up great fear. My son is also going to the Ophthalmologist to check his vision again for any changes. Recently he has been bending at the hips and tilting his head as if to see and/or focus better and when you sit next to him he will look at you and turn away, look at you and turn away and do this repeatedly in one span. Another new thing he does is repeatedly go to the full length mirror in the foyer both during the day and one to four times during the nighttime. I have thought perhaps he was sleep walking, or going to the mirror in his sleep out of habit from going to the mirror during the day, or perhaps it is an autistic behavior as he does have autistic tendencies. But even during the nighttime? Also, he has not said any words in about two months. His vocabulary is extremely limited and perhaps only understood by few, but now is only vocalizing sounds low and high. I realize that without him in front of you, it is hard to visualize and understand without knowing his entire medical history. In condensed form, he is globally delayed, incontinent, has minimal speech, has visual impairments, has had low contractility of the heart, has fatty acid oxidation disorder, has had seizures and is on meds, has history of severe constipation, asthma, body temperature control regulation problems, many hospitalizations, and intermittent hypoglycemia. Any information/ experience is appreciated. I fear this is the start of possible regression.

A: 7/13/05
1) From what you have stated so far, it is a bit difficult to narrow down the possible problem in regards to the falling episodes. He is either having worsening gait with bouts of imbalance, worsening tone, or spells of falling. It is reassuring that he does not have pain with these symptoms.

If it is worsening gait with imbalance, I would ask if this is a continuous imbalance or one that comes and goes in "spells." Both could imply structural changes in the brain, and I agree with obtaining an MRI to further evaluate this. If these are periodic spells of imbalance, I would be concerned about a seizure-like event or migranous phenomena.

If he is having worsening tone or strength, again, an MRI of the brain is necessary to exclude structural changes. I would also want to check a CPK, which assesses if he is breaking down more muscle tissue than he should.

If these are spells of falling - especially of suddenly dropping to the ground - I would obtain an EEG to help exclude seizures as an etiology.

2) His bouts of staring in the mirror, and looking back and forth towards and away from you, both come across as behavioral events. I would want to make sure that you can get his attention during such events. If not - seizures are something worth considering.

3) As to your question of whether this is the start of a regression, it is difficult to say. If I can provide any reassurance, it is that even with regression in mitochondrial disease, the decline often stops and even improves for no clear/predictable reason. I would want to look at his "metabolic profile" and make sure there was not a correctable derangement such as worsening acidosis, carnitine deficiency, or CoQ10 deficiency. The latter two can lead to both worsening balance and weakness.

In any of these above situations, I would also ask if he is on any medication which may be causing any or all of these difficulties.

Answered by: Sumit Parikh, MD

Q: I have a 9 year old son diagnosed via muscle biopsy with mitochondrial myopathy. Is there a more specific connection between the brain and learning issues? At school he went from a C average to now an F, especially in reading and math. All of his teachers at school have noticed a lot of regression. I've read that stressors can perhaps cause this. So can his mito cause a loss in knowledge?

A: 6/23/05
Yes, mitochondrial disease can cause brain and learning problems in some people, and from what you describe, that is very likely what is going on with your son.

Not everyone with mitochondrial disease has involvement of the brain. Sometimes a person with mitochondrial disease that doesn’t directly involve the brain can have learning problems if the mitochondrial disease affects vision or hearing, or causes any other problem that might affect the ability to pay attention in school or at work. For example, if a child is depressed or exhausted because of illness, he might have trouble learning and dropping grades. Also, your son is 9 years old, and if he is in regular school he is probably in the 3rd grade. This is a time when schoolwork becomes more complicated, and some children who have always had a little trouble with learning but did okay in the 1st and 2nd grade can begin to have real trouble with schoolwork.

But you and your son’s teachers are using the term “regression”, which we doctors use to describe the loss of previous abilities or knowledge. We have to worry that this could be the result of direct effect of the mitochondrial disease on brain cells. Brain cells need a lot of energy, and in mitochondrial disease they can become damaged and can die. Sometimes this damage is visible on a CT scan or an MRI, but there can be brain damage without visible changes on a scan. The brain damage can cause decreasing ability to learn and actual loss of skills or knowledge. Sometimes there is an up-and-down course, with periods of regression and recovery. Sometimes the cell damage slows or stops, and there may be some recovery or there may be permanent loss of abilities. And sometimes the damage continues to get worse, and the regression continues with further loss of abilities. We can never be completely certain about what to expect in the future, but “regression” is a very serious sign. You should work with your health care providers to try to have the very best possible understanding of what is going on and whether there is anything more you could be doing that might help.

Answered by: Carol Greene, MD

Q: I understand that "induced" high levels of lactate in the brain can cause panic/anxiety attacks. Can resident, non-induced high brain/lactate levels cause the same problem?

Do elevated levels cause differing results at different ages/stages of life?

At this point, all that I have found on-line are brief references, are there any articles that deal (at length) with this subject?

Basis for my questions:

Recently, an MRI revealed elevated lactate levels. In my early twenties there was a sudden and debilitating onset of panic/anxiety with depression. There is no apparent significant physical or emotional trauma/stress that may have contributed to this.

Panic/anxiety attacks are long past and the intensity almost forgotten. Life long depression is treated with medication.

58 years old, CPEO, LVH, Exercise Intolerance, Type II Diabetes, RLS (Etc)

I’m open to solid facts and/or theories about this matter.

A: 6/23/05
Intravenous infusion of lactate (lactic acid) goes to the brain and induces panic in individuals with panic disorder and, to a lesser extent, in people without panic disorder. To my knowledge, chronically elevated lactate in the brain does not cause panic or anxiety attacks.

We are increasingly recognizing psychiatric disorders in mitochondrial disease patients who have chronically elevated lactate in the brain. Dr. Anu Suomalainen noted severe depression in patients with autosomal dominant progressive external ophthalmoplegia and multiple deletions of mitochondrial DNA. Depression has been seen in patients with other mitochondrial disorders. There is a report from Japan, Miyaoka et al, Biological Psychiatry 1997;42:524-526, describing a patient with the MELAS 3243 mitochondrial DNA mutation and panic disorder and agoraphobia. Most likely, the chronically elevated lactate does not cause the psychiatric problems, but rather both abnormalities are caused by mitochondrial dysfunction. There are many medical papers describing lactate-infusion induced panic attacks. If you go to the PubMed website ( and type in the search words "panic and lactate" you will obtain a list of 315 papers which include 57 review articles.

Your clinical features (CPEO, exercise intolerance, diabetes mellitus and elevated lactate) strongly suggest that you have a mitochondrial disease. The diagnosis must be confirmed by laboratory tests. If the diagnosis is confirmed, it is certainly possible that your depression and panic/anxiety are due to your mitochondrial disease.

Answered by: Michio Hirano, MD

Q: My 12 yr old has Complex I deficiency and has problems at times with mood dysregulation including panic attacks, anxiety, depression and hypomania. He has had complex partial seizures with evidence of a focal problem on right temporal and parietal lobes. The last two EEGs were normal, except for generalized slowing. He had been on Depakote, was switched to Trileptal. Some medications have exacerbated the mood dysregulation, to the point of some rage issues. Straterra really caused problems. He tests with superior scores on IQ and processing except with some evidence of atypical attention problems. We think stimulants might send him into mania. His mood problems are keeping him from using his cognitive abilities. What drugs could we try with the least amount of side effects? He is scared to death to try any new meds. He is also on Synthroid.

A: 6/22/05
I am sorry to hear about your son. Behavioral problems are not uncommon in children with mitochondrial disease. I have found behavioral problems very difficult to treat in my patients. We initially try behavioral modification techniques such as routine in the daily schedule, rewards for doing tasks properly, etc. But many times these are not enough. In general we use the same medications that are used in patients without mitochondrial disease to treat psychiatric problems. Most of the time, I try to work together with a competent child psychiatrist or psychologist and find their input invaluable. I would recommend that you enlist their help, if possible. Psychiatric specialists can add other types of non-pharmacological therapies that can really help and add to the overall care of your son. Frankly, they (psychologist and psychatrists) are better equiped to treat behavior problems than I am. I usually try and treat the most serious of the behavioral problems first and try to control these and then see how other behaviors are affected. If they remain a significant problem then move on and try to treat these as well.

We have found that sometimes seizure medications can also help with behavior, in some patients. For instance, Lamictal works well in many patients with partial complex seizures and has been FDA approved for rapid cycling bipolar disease in older patients. I have used Lamictal for treating both problems in the same patient with some encouraging results. Others have found that Tegretol can also help. This does not mean that it will work in your son, but that it might be worth a try. Some of my patients have difficulty with attention or staying on task. Some respond to ritalin, some to Straterra, and some do not. In these latter cases, I have had some luck with Provigil. You must know that Provigil is not approved for this use and may or may not help your son. I give the above examples of other medicines that might help your son. Remember, that you need to work with your primary care physician as well as the others on the medical team taking care of your son.

I hope that you will find the right mixture of medications and possible behavioral therapies for your son.
Answered by: Russell Saneto, DO, PhD

Q: My son is seventeen months old and was diagnosed with Mitochondrial Disease two days before his first birthday and that was after being tested for the past year. I had done a lot of reading and researching but I know no more now than I did before. Nobody really knows anything or most people have not even heard of this disease, and I do not understand WHY. I feel like my son has been given a death sentence and he has done nothing. We were told that he has complex 1, 2 and part 3 and part 4 mitochondrial disease. He has hypotonia, and is mentally and physically delayed. When he was born, they thought that he was deaf and blind. Now after putting tubes in his ears, we know he is not deaf and blind. His sight is delayed about 6 months and his hearing is bout the same - just delayed. He can not walk, stand and can not sit unassisted except for 30 seconds during therapy. He has physical and occupational therapy 3 times a week for 45 minutes, vision therapy 1 hour once a week, speech 2 times a week, and about to start aqua therapy once a week. They can do everything to blood, plasma anything else so why can't they take some of my mitochondria and give to him? I do not understand why they can not fix him. Can I donate something? They told me that it was me and my husband’s genes, not just mine. We have plenty of family that will assist. He takes Cq10, L-carnitine and they have just started B-1 and B-2 which do not seem to be helping. What else can I do? Could you tell me anything? Thank- you.

A: 6/1/05
I am sorry that you have experienced difficulty in obtaining information and answers for your son who has been diagnosed with a mitochondrial disorder. The genetics and clinical features of the disorders collectively referred to as “mitochondrial disorders” may be complex for both health care professionals and parents alike. Unfortunately, many physicians are not familiar with these disorders; however, more recently trained physicians are more likely to learn about these disorders in medical school, than were some of their senior colleagues. A goal of the UMDF is to provide information and education for parents, families and physicians both on the web page and in the form of a yearly conference.

These disorders are rare, perhaps 1:4000 individuals may have a mitochondrial disorder. However, some sources believe the condition may be as common as 1:1000. The disorders may affect multiple body systems or mainly neurological systems. The inheritance may be from both parents (autosomal recessive), or one parent (autosomal dominant, or maternal inheritance, some rarely are X linked).

Although it has been difficult to obtain information about the condition in your son, it appears you are doing everything possible to improve his quality of life. I can only answer in generic terms because I have not had the opportunity to review medical records or examine your son. Hearing and vision may be problems in children with mitochondrial disorders, and early on it may be difficult to obtain accurate testing to determine the degree of impairment. Physical therapy may be helpful to many children with physical and cognitive delays due to mitochondrial disorders.

Beyond that, unfortunately, there are no cures for the condition. Associated medical problems can be treated such as heart rate abnormalities, kidney problems, hormonal problems (which some, but not all patients with mitochondrial disorders may experience). Because these conditions result from changes in the DNA or genetic information in the mitochondria, total cure would require correction of this DNA abnormality in all cells and tissues that are affected. There are no approved therapies involving transfer of mitochondria from one person to another.

Treatment with vitamins is offered as a way to potentially improve mitochondrial enzymatic activities by providing vitamins that may play a role in these reactions. For some patients they may be helpful. Others may find no distinct benefits. There has not been a lot of research in this area, and it is best to make these decisions in concert with your practitioner who is managing your son’s case.

You might find it helpful to visit the UMDF website or consider attending a parent conference to obtain more up to date information and have the opportunity to speak directly with physicians who have managed other patients with similar conditions.

Answered by: Andrea Gropman, MD, FAAP

Q: I am experiencing an increase in severe muscle cramping, to the point where I have difficulty walking. My doctor told me to drink tonic waterand it seems to help; however, some of the cramping was so bad, I now experience numbness in the area. How common is this for someone with Mito and what suggestions would you have for treatment?

A: 6/1/05
Some mitochondrial diseases - especially those confined to muscle (true "mitochondrial myopathies") can cause severe cramping. After experiencing bad cramps, do you ever pass darker than usual urine? It would be important to know more about your condition to be more specific, but unfortunately there is no specific "antidote" to the cramping, except moderate aerobic exercise (even "mitochondrially challenged" muscle can be trained) and - possibly - oral coenzyme Q10 (at least 300 mg daily).

Answered by: Salvatore DiMauro, MD

Q: My 19 month old son was diagnosed with Leigh's disease(through an MRI,spinal tap and muscle biopsy) approximately six months ago. He has the t>g mutation of the disease. We have seen a mitchondrial doctor only one time who did not feel the need to see us back for six months. He did not know a thing about this mutation. He has never treated a patient with this mutation. I was told upon diagnosis that 75% of the children die by the age of 2. Since then, I am finding more children that are alive past this age than I had expected. I would like to know if there is a direct link between mutation and life expectancy. If so, approximately how many years might we have and what kind of things are we headed for down the road. Right now my son has swallowing problems, digestive issues, he still can not sit up (hypotonia?)and high lactic acid levels. He has no seizures, no eye or hearing problems, but has had multiple infections, i.e. colds, ear infections, etc.

A: First of all, I would definitely recommend you find a doctor who has experience with mitochondrial disease.

When you say the "t>g mutation" it is a little ambiguous but I am pretty sure you mean a T to G change in mitochondrial DNA at position 8993. You will know that there are a large number of different causes of Leigh's disease. At the latest count, there were more than 20 different genes in which mutations have been shown to cause Leigh's disease, and no doubt there are quite a few more still to find. That is one of the major reasons why there is a lot of variation between patients. The 8993t>g change is one of the more common causes of Leigh disease, present in about a tenth of all patients. My comments below assume your son has the 8993t>g change.

With mitochondrial DNA mutations, it is not just the particular mutation that is important but how much is present. In patients with the 8993t>g mutation, every cell in the body usually has a mix of healthy mitochondrial DNAs and mitochondrial DNAs containing the 8993t>g mutation. Basically the more mutant mitochondrial DNA there is, then the more likely it is there will be a problem in mitochondrial energy generation. For the 8993t>g mutation, it seems we can tolerate up to about 60% to 70% of our mitochondrial DNA containing the mutation before it has much effect. If more than 90% of the mitochondrial DNA has the 8993t>g mutation, then a patient is almost certain to develop severe symptoms such as Leigh's disease. In between these values, then the risk of symptoms increases with the amount of the 8993t>g mutation. So we refer to this percentage level as the "mutant load" and above the threshold value of about 60% 8993t>g mutation, then the higher the mutant load, the more likely it is that symptoms will be severe.

In Leigh's disease, the particular mutation and the amount of it are major factors that determine disease severity and life expectancy. However, there is also individual variation. Our individual genetic background and things such as childhood infections (how many, what type and when) can have a big influence on disease severity and on life expectancy. That means it is always difficult to give precise information about life expectancy. Hopefully, you can find a physician locally with enough expertise to answer all your questions. If you still have concerns, then perhaps you may want to travel to see one of the national experts.

Answered by: David R. Thorburn, PhD

Q: 2 Questions combined:
I recently read somewhere that taking Vitamin E with CoQ10 may interfere with the absorption of the CoQ10. Is this true? I am currently on the mito “cocktail” and don’t want to waste money if it is. What is the suggestion when taking these two? I’ve also heard that instead of taking the mito “cocktail” stick to only Carnitor, CoQ10, and Vit B2. My diagnosis is mitochondrial myopathy with deficiency in Complex II & III. Any suggestions, as I really don’t want to waste money on a “cocktail” of vitamins when only three of them might be useful.

The suggestion of supplements on your site has already been suggested to me by my neurologist; however, I would like to know the differences in supplements. Such as: is one form better than another as relates to speed of entering body/muscles; are there 'pure' supplements meaning no additives?

A: 5/25/05
1) Different physicians utilize different mitochondrial vitamin/cofactor/anti-oxidant "cocktails" and even different ones for their different patients. A most extensive "mito cocktail" that has been used by several physicians contains thiamine-HCl(vitamin B1), riboflavin(B2), pyridoxine(B6), nicotinamide, pantothenate, vitamin C, vitamin E, coenzyme Q10, lipoate, carnitine and the metal cofactor, selenium. These are all given in amounts that are close to or even greater than 10-times the typical daily dietary intake. Creatine is also used. Some physicians might only use coenzyme Q10 and vitamin E. The important issue that you must recognize is that there is no uniformly accepted way of administering these compounds to patients or a prescribed way that even utilizes common practice across the country.

2) The beneficial effect of these compounds has never been demonstrated in a satisfactory way, nor has a proper study ever been conducted. WE DON'T KNOW IF THEY WORK!

3) The important thing is that they are safe (except that B6 can damage peripheral nerves and nicotinamide produces headaches and flushing).

4) With this type of megadosing, we don't know much about GI absorption either of a competitive or enhancing nature.

There is no definite info showing that coenzyme Q10 interferes with vitamin E absorption or vice versa. However, simultaneous digestion and absorption of dietary fats and vitamin E improves vitamin E absorption. One group of investigators actually reported that intake of vitamin E along with coenzyme Q10 in mice may actually lead to increased levels of vitamin E in tissue mitochondria (Lass and Sohal, FASEB J.,vol 14, page 87, 2000). But this was not the case with Q10. We need to look at effect of megadosing on absorption and tissue levels much more carefully in humans. I would not stop taking the two together at this time, because of this uncertainty. I suggest that you ask your doctor which of the above extensive list is most helpful for a mito disorder that primarily affects muscle.

Answered by: Gerard T. Berry, MD

Q: Our 11 yr. old son began using oxygen and a bi-pap machine over a yr. ago due to CO2 retention and in addition a process in which his cells don't utilize O2 or something about this. I really don't understand the metabolic role of O2 and mito disorders, but while we only noticed small benefits with the bi-pap, we have noticed dramatic improvement in his overall health using the oxygen therapy. He is stronger; endurance and energy is improved, and he fights off viruses much better. These are all unexpected improvements. It hasn't cured him, and he still has frightening symptoms and episodes of chest pain
etc. with activity, but he feels better more often now. Could you explain the role of oxygen usage in mito disorders and do you see oxygen therapy as a possible therapy for all mito disorders to help produce ATP? Would it be possible to do a study of children with mito disorders to evaluate the benefits of O2?

A: 5/3/05
Sorry that your son has to use bi-pap at night. You did not indicate that your son has a mitochondrial disease, but I will assume that he does. In many patients with mitochondrial disease, the muscles used to breath are weak. The frequency that we take our breaths is mostly to exhale carbon dioxide and not to take in oxygen. In fact, for the most part the level of carbon dioxide regulates the frequency of our breaths. A normal and healthy person could probably inhale the amount of oxygen we need in only several breaths per minute. Obviously, we need oxygen for every cell in our body to function properly. The use of oxygen in every cell, with the exception of the red blood cell, is for oxidative phosphorylation or the production of ATP in the mitochondria. Red blood cells do not have mitochondria so they use a different process. (However, red blood cells carry oxygen to every cell in the body.) So, at night when our conscious brain turns itself off and the sleeping centers take over, our breathing becomes less frequent, and for the most part more regular. Pathological muscle weakness (such as in a mitochondrial disease), soft floppy/fatty palates, anatomically narrow throats, obesity, or poorly functioning central sleep centers may decrease the depth of breathing or intake of oxygen. This change in breathing also reduces the amount of carbon dioxide we exhale. Over a prolonged period of time, this increase in carbon dioxode can alter the brain's center that regulates carbon dioxide and the set point for when the breathing centers stimulate the body to breath faster (to remove excess carbon dioxide) and becomes less sensitive to carbon dioxide. Therefore the amount of carbon dioxide remains too high and our breathing can become dysfunctional. Because the stimulation to breath depends on the level of carbon dioxide, loss of senistivity to carbon dioxide may reduce our breathing frequency. The impact of this can be reduced oxygen levels in the red blood cells which would translate into less oxygen delivered to each cell. Since oxygen is need for the mitochondria to make ATP or energy, less oxygen would reduce the amount of ATP that is ultimately produced. In a patient with a mitochondrial disease, ATP is limited to begin with and this process would be more of a problem than for someone without a mitochondrial disease.

Answered by: Russell Saneto, DO, PhD

Q: I have NARP. I experience a lot of muscular pain in my legs from walking. However, I was sharing with my doctor that I have extreme pain in my ankle and knee of my right leg. He said that he thought that it was more joint pain that muscle pain. Can a mito disease affect the joints as well as the muscle? My doctor wasn't sure and he said the only way to know for sure was to do a muscle biopsy. I've already had one biopsy and don't want another. Please let me know what you think.

A: 4/22/05
In my view the pain in your joints is unlikely to be NARP. A patient with mitochondrial disease can get other problems as well and joint pains are common in the general population. Joint pains are also common if there are gait disturbances.
I do not think another muscle biopsy is justified and I would look for other causes.

Answered by: Douglass M. Turnbull, MD, PhD

Q: My 5 year old granddaughter has recently been diagnosed by frozen muscle biopsy to have mitochondrial disease due to complex III deficiency. She has cognitive delay, tremor in her right hand and ataxia. All symptoms are worse during illness, during which she often becomes nonverbal with excessive irritability. For example, she screams, tries to bang her head, bites herself and others, and pulls her hair out. This behavior can last for up to an hour. In addition, during these episodes she is wild-eyed, her pupils are dilated, she doesn't respond to anything, and she often repeats words and phrases. How do we know if these episodes are tantrums? Is behavioral modification adequate? How likely is it that these episodes are a result of the disease and the way it affects this child, and how can that be proven?

A: 4/19/05
Temper tantrums are common in toddlers in general. In children with developmental delay secondary to mitochondrial disease, temper tantrums can be seen in older children as a combination of emotional and speech delays (from frustration in not being able to express their thoughts and needs). Some children have very loud and active tantrums and do not listen to others during them, however, tantrums rarely last an hour. Behavioral modification is the appropriate manner to deal with temper tantrums.

On the other hand, many children with mitochondrial disease have pain crises, in which severe pain can suddenly develop in the head, abdomen, or limbs. If the child is not very verbal, these can manifest as sudden outbursts of screaming and aggressive behaviors that can look a lot like a temper tantrum. These episodes can last up to several hours. In my clinical experience, anti-migraine medications, particularly caffeine, amitriptyline or cyproheptadine, can treat or prevent these episodes.

Both of these situations can be worse during illness. How do you tell the difference? One usually occurs when the child is frustrated (e.g. told that she can’t have something), and the other usually occurs at apparently random times.

Very rarely, behavioral episodes can be a sign of a more serious condition, such as certain forms of epileptic, psychiatric or neurodegenerative disorders.

Answered by: Richard G. Boles, MD

Q: I am a 47 year old woman. It has taken me about 10 years to finally get a diagnosis - for many years doctors believed I had myasthenia gravis. Finally, I found a doctor who did an EMG, which he said looked like a "myopathy", so he did a muscle biopsy last year. (Oh, before this was done, a year ago a serum carnitine level came back on the low side, which the doctor started me on Carnitine, which I did notice a difference, but I still had problems). The muscle biopsy said I had a "proliferation of mitochondria" and the results of the mitochondrial enzyme analysis stated that I had "a profound reproducible deficiency of succinate cytochrome c reductase with modest biochemical evidence of increased mitochondrial content". So, I was told I had mitochondrial myopathy with deficiency in Complex II and Complex III of the Respiratory Chain. What does that mean? I have done some research, but I'm still unclear of what that means exactly. Can you describe it in "simple" layman terms?

Also, I have had a DNA test for Thalassemia and discovered that I have Thalassemia Trait with 2 Thal Genes on ONE DNA strain, which they tell me there is not a lot of research about how that manifests itself. Can that affect the mitochondrial myopathy? AND to make things worse, I am also perimenopausal and find that right before my period my fatigue and stroke-like symptoms are really bad. I usually have to take off work. What is usually recommended for a woman with mitochondrial myopathy and going through "the change of life" - it can get so bad at times, I am crawling on the floor to get around! I would appreciate any clarification to all of this. Thank you.

A: 4/8/05
I understand your uncertainty regarding your diagnosis of "mitochondrial myopathy". The diagnosis is based on your muscle biopsy which reportedly showed "proliferation of mitochondria" and "a profound deficiency of succinate cytochrome c reductase [mitochondrial repiratory chain complexes II and III] with modest biochemical evidence of increased mitochondrial content". I presume that the "evidence of increased mitochondrial content" was increased citrate synthase activity.

You might have a "mitochondrial myopathy" with deficiency of complex II+III. Unfortunately, a specific molecular genetic abnormality (mutation) or biochemical defect was not identified, hence, your diagnosis is vague. A defect of "succinate cytochrome c reductase" (complexes II + III), could be due to several different possibilities: complex II deficiency alone, isolated complex III deficiency, defects of both complexes II and III, or even coenzyme Q10 deficiency (because CoQ10 shuttles electrons between complexes II and III). To better characterize your biochemical defect, it is necessary to review the biochemical activities of all of your mitochondrial enzymes. After your biochemical defect is clarified, then molecular genetic studies might lead to identification of the causative mutation. You may benefit from a consultation by a mitochondrial disease expert who can review the results of your muscle biopsy and determine whether additional biochemical, histological, or genetic studies are warranted.

I am not aware of any relationship between thalassemia trait and mitochondrial disorders. It appears that the stress of menopause is worsening your "mitochondrial myopathy". This situation is not uncommon because mitochondrial diseases often worsen during periods of stress such as infections.

In summary, the results of your muscle biopsy suggest that you have a mitochondrial myopathy. A consultation by a mitochondrial disease expert may lead to a more clear diagnosis of your condition.

Answered by: Michio Hirano, MD

Q: My daughter is 9 years old and was diagnosed as having MELAS (A3243G). Her symptoms started when she was 7. She has high lactic acid, ptosis, and seizures. At this moment (Jan/2005) she is very well. Her mother and her grandmother (mother of her mother) are healthy. I also have a son who is 5 years old. He is healthy too, with no symptoms of MELAS.
I would like to ask if it is possible to evaluate the probability of my son having or not having MELAS.

A: 4/6/05
The issue of whether someone without symptoms or signs "has MELAS" is not a straight forward answer. Does one want to check if he carries the mutation or has the disease or is at risk of developing the disease? For the mutation, it depends on which tissue is checked and how invasive testing is. It MAY also depend on whether the egg transmitted by mom had a high or low percentage mutation. One could check blood, and if that is negative, hair follicles /buccal mucosa and if necessary muscle biopsy, etc. but this will ONLY tell you if he carries the mutation and will not tell you if he is at risk of developing symptoms and if so, which symptoms. That can only be done clinically by monitoring over time although if a high percentage heteroplasmy of the mutation (usually more than 80-90%) is found in a certain tissue, there is a higher risk of developing symptoms related to that tissue/organ at some time but one cannot be more specific than that.
Answered by: Annette Feigenbaum, M.D., FRCP

Q: My question is: with a local anesthetic is a puncture done and if so, is a puncture enough tissue to see enough of the DNA and do the proper tests?

A: 4/6/05
Local anesthesia does NOT imply a needle biopsy; however, if general anesthesia is needed, it can be done safely under the care of an experienced pediatric anesthesiologist.

Answered by: Salvatore DiMauro, MD

Q: My daughter is an 8 y/o with OxPhos disorder: Complex I & IV defect. She is non-convulsive static epilectic. She is now taking Topamax, and Valproic Acid. There are no other remaining seizure medication options we want to consider at this time, and we are seriously considering the Ketogenic diet. She just had the feeding tube put in 2 weeks ago. We are concerned of the safety of administering this strict diet regimen, and also concerned whether the diet would satisfy her nutritional needs, given her disease status. We understand the benefits of the diet with respect to the epilepsy, but what are the benefits/ risks associated with the diet under these conditions?

A: 4/5/05
I am sorry that your daughter has severe epilepsy. We have used the ketogenic diet in several patients with intractable seizures. We have had good success in both decreasing epileptiform discharges as well as producing fairly good control of seizures. All of our children have had West syndrome or infantile spasms. My thought would be that the ketogenic diet should work well with other seizure types in patients with mitochondrial cytopathies. We usually test our patients before starting the diet just to make sure they can metabolize the various fats appropriately. A fatty oxidation disorder would rule out the diet.

The first thing we do is bring the patient into the hospital to start the diet. Many children do not tolerate the initial high fat ratio and either have vomiting episodes or hypoglycemic episodes. We do not fast these children before starting the diet. Depending on the initial pH balance of the child before starting the diet, we tailor the ratio of the diet. We usually use a 3.5:1 to 4.0:1 diet but if the child doesn't tolerate the initial diet, we alter the ratio. We usually start patients with a complex I disorder on a lower ratio. We have had two patients develop renal stones on the diet with coadministration of topamax or zonisamide. We watch children on these two medication very closely for stone formation. We do not limit fluids on the diet and renal stones are the primary reason. We have had one child become very acidotic on the diet and had to use bicarbonate supplementation. We are beginning to do Dexascans to monitor bone mineralization and have had to use a bisphosphonate therapy on one child for severely decreased bone mineralization. It was unclear if the reason was the ketogenic diet or not, but his bone mineralization has gotten better after a single course of therapy. We have had several children not gain weight on the diet and at least two others gain too much weight on the diet. We altered the calories and thus far all these children remain on the diet. As you can tell, it takes close coordination of dietian and neurologist to manage the diet as each child seems to be unique in how they tolerate the diet. Thus far, all of our patients have eventually tolerated the diet fairly well and remain on the diet. Our numbers are not large, so there is likely a bias.

Answered by: Russell Saneto, DO, PhD

Q: My son is 15 months and undiagnosed but probably has a mitochondria disorder. He started with Ataxia and MRI showed lesions in the Basal Ganglia. All the tests were coming back normal. Following a recent metabolic acidosis, he became floppy and has lost lots of skills, dystonic, MRI showed changes. Also behavior changes- irritability, lack of sleep, only tolerates being in motion like in the stroller and he has a sweaty head. Few questions:
1. He has been put on Ubiquinone, Vit. E, Vit.C, Thiamine, Riboflavin, Biotin. What other vitamins/co-factors can we put him on? What are good doses for the above vits?
2. As advised we are doing a muscle biopsy, but I feel a bit nervous because I have been warned about possible set backs due to anesthetic. Is there any precaution we can take before, during or after the procedure? How much closer does a Muscle biopsy put us to a diagnosis?

A: 4/1/05
Your child seems to have many features of Leigh syndrome, which has many different causes, but all related to mitochondrial dysfunction.
The doses of the vitamins are not crucial, as these are only palliative measures. The muscle biopsy is going to be very important for a precise diagnosis. The biopsy is usually done under local anesthesia and presents very few risks.
Answered by: Salvatore DiMauro, MD

Q: We have a 15 month old boy undiagnosed but with probably a mitochondria disorder. We would like to know about having the following tests done:
Complex II (SDHA and SDHB subunit)
Complex III (BCS1)
Complex IV ( SURF-1, SCO1, SCO2 and COX10) of the OXPHOS system as well as for E1 alpha E2 and E3 of the Pyruvate Dehydrogenase complex, ANT1, ANT2 and CPT II

A: 4/1/05
Your question covers the sequencing of ALL nuclear genes associated with respiratory chain defects to date. I hope you realize that this is a formidable task. It is also a tremendous waste of energy (and money) and an exercise in scientific "brute force" if conducted "blindly" in search of a molecular diagnosis. These tests have to be chosen and "targeted" according to (i)symptoms and signs; (ii) laboratory exams;(iii) muscle biopsy; (iv) biochemistry. If biochemical data show complex I deficiency, then it may be important to sequence the complex I genes that you list.
Answered by: Salvatore DiMauro, MD

Q: We have a 3 1/2 year girl with partial complex 1 deficiency, and has associated mitochondrial encephalopathy-seen on MRI and presenting with mental and motor delay- but stable and no overt regression. She gets a cocktail via the PEG of anti-oxidants, carnitine and creatine, but as yet we have not given her Co Q.Is Co Q contra-indicated in complex 1 disorders? If not, what are the recommendations-when and how much should be given? Are there any further suggestions regarding supplementation and treatment? Your advice would be appreciated.

A: 3/15/05
The use of ubiquinone in mitochondrial respiratory chain disease is somewhat variable between centers. As yet there are NO trials of ubiquinone in complex I deficiency, and some clinicians add it to the cocktail of therapies and others do not.
The timing is variable as well - sorry to be so vague, the treatment protocols in mitochondrial disease are not established.

Answered by: Douglass M. Turnbull, MD, PhD

Q: My 19 year old son has been diagnosed with Kearns Sayre (KSS) in 1998. We took him to a mito specialist for a second opinion and he confirmed the diagnosis. Here are my concerns;
1.We recently found out that his heart has many episodes where it beats 266 beats/min. He is thought to have atrial tachycardia. Is this KSS related?
2. He told us that he is having a hard time talking. It is getting more difficult. What does this mean?
3. Our son does not ever say much about his health; however, recently he made the comment that he knows his body is changing a lot. He has been on the cocktail of vitamins and COq10 but he feels like it has done nothing for him in regards to slowing the progression down.
5. When we took him to the mito doctor in 1998, the doctor made a comment to us that our son was lucky because he is only missing the "common deletion". I thought that this meant that it would not change his life too much. However since 1998, many things have been dropped, changed or altered in his life and it appears things are not getting any better for him. My husband and I are noticing some major things happening in his life. He seems so different then when first diagnosed. I know that every situation is different, but I was hoping you could shed some light on this disease and what could possibly happen to him in the future. We really are trying to deal with this and understand and help him as best we can. I would rather have a better understanding to what might happen instead of not feeling somewhat prepared when or if it does happen.

A: I am sorry to hear about your son. From what you have written, he has the mtDNA deletion and not the mtDNA point mutation that causes KSS. One of the problems that is common with this disorder is heart arrhythmia, specifically heart conduction block. Some patients need cardiac pacemakers. There have been reports of patients presenting with cardiac conduction disturbances being manifest 6-8 years after ptosis was noted and some patients more than 15 years. I would suggest that you make sure your son is followed by a cardiologist.

Unfortunately, mitochondrial disease is progressive. This varies from patient to patient (see above), but is likely present in all mitochondrial patients. There are no large studies showing that the use of coenzyme Q10 and other antioxidants are beneficial in mitochondrial disease treatment. Theoretically, they should help in preventing or slowing down the process of oxygen radical damage to mitochondrial membranes and further mitochondrial dysfunction. There have been small studies showing both benefit and no benefit with antioxidant usage. In your son's case, what we don't know is how he would be doing at this point, if he didn't use the antioxidants. Some patients may only experience the decrease in progression (therefore, would not subjectively feel better) and not mitochondrial function improvement (subjective better feeling). Some patients may not have any benefit. We really need to do more work in this area to understand if the use of antioxidants really helps patients.

Since your son has been diagnosed with the deletion with previous testing, further testing would likely not yield a different answer or finding.

The variation in the way a particular patient will progress with any given mitochondrial disease makes prognostication of how a particular person will do over the next several months to years impossible to predict. Clearly, as the disease progresses the patient begins to notice the advancement of symptoms. One reason to be followed by someone who has an interest in mitochondrial disease is to track disease progression and what may help or not help that particular patient. New things are being tried and it would be those physicians who are interested in this disease, who would know what is new to try. This would be another reason to see someone who has an interest in this disease.

I am sorry that there isn't a magic treatment that will help your son. Manipulation of the small things that we can control, such as diet, rest, use of wheelchairs, etc are things that will likely help but not cure you son's illness.

Answered by: Russell Saneto, DO, PhD

Q: My brother's daughter (my niece) has Leigh's Syndrome and I am now expecting my first child. I was wondering if any research was being done with Cord Blood Cells and helping find a cure? If there is any chance that in the future these Cord Blood Cells may help my niece then I would like to know so that I can begin the paperwork process of storing the Cord Blood Cells for when I deliver in June.

A: At this time, I am unaware of research being done on cord blood cell transplants for mitochondrial disorders. Leigh's disease can have many causes and depending on the cause, the cord blood cells may or may not be useful. I would suggest that you ask your brother to check with the specialist treating your niece to see if your baby’s cord blood cells could be used to help your niece. The treating physician should be able to guide you with this decision.
Answered by: Susan Winter, MD

Q: My son has been diagnosed with Pyruvate Carboxylase Deficiency. He is now 1 year old. I have a question:
The gene responsible for PC is located on the long arm of chromosome 11. Can other family members' DNA be tested for PC to see if they are a carrier or is the only way a skin biopsy?

A: 1/11/05
The diagnosis was presumably made by growing up skin fibroblasts and measuring the activity (or amount) of the pyruvate carboxylase enzyme. Measuring enzyme activity is usually the way to investigate patients suspected of having this disease but as a generalisation, it is usually not possible to detect carriers by enzyme analysis. With only a few exceptions, carriers of most enzyme deficiencies have an enzyme activity that is similar to any other healthy people.

Your son will have two copies of the pyruvate carboxylase gene, each carrying a mutation, one of which has come from mom and one from dad. It is necessary to find the two mutations (sometimes it is the same mutation in both copies) before relatives could be tested for carrier status. If the mutations have already been found in your son, then it would be possible to test blood, or perhaps a cheekbrush sample, from other family members. If not, then your doctor would need to find a lab that could do mutation analysis on his skin fibroblasts.

This may be worth trying to organise, particularly if you and your partner are thinking of having further children. However, you should discuss it with your doctor. There may not be much to be gained from testing family members. There is no reason to think that being a carrier for pyruvate carboxylase deficiency will have any impact on one's health. All of us are carriers for about 10 diseases, but most have no impact on health. Since there are over 30,000 different genes that we may be carriers for, it is only when our partner happens to be a carrier for the same disease that we are at risk for having a child who will develop the disease. In that case, as with your partner, there is a 1 in 4 chance for each pregnancy of having an affected child. The risk that any of your other relatives would have a child with pyruvate carboxylase deficiency is very low, much lower than the small risk that any couple faces of having a child with some type of genetic disease. The only exception is if one of your relatives had children with a relative or with one of your partner's relatives.

Answered by: David R. Thorburn, PhD

Q: My daughter is 30 months old and she has been diagnosed with mito complex 3 severe and 1 mild. She is g-tube fed, experiences some dysmotilty, dysautonomia, seizure activity, and hallucinates at times. She is always failure to thrive, has lactic acidemia, low bicarbs, ketosis, hypoglycemia, muscle pain, weakness, rotten teeth, a lesion on the right front lobe of the brain like a noodle, and sometimes gets blood infections. She eats some by mouth and only needs a mobility stroller when fatigued. She is on: neurontin 75 mgs twice a day, CoQ-10 175 mgs a day, 600 mgs a day of carnitor, B2 50 mgs a day,chlor hydrate as needed for sleep, needs oxygen when sleeping and as needed throughout the day. Do you think she would benefit from a central line and hyperal? It has been mentioned but I do not know what to do. Who is the best doctor to go to and how would I base my decsion? Do you think my child has a good prognosis? She is a very smart child. What would you do if this were your child to improve the quality of her life and also quantity? She stays on feeds about 16 to 18 hours out of the day. Do you think that lesion on her brain is from her disease?

A: 11/8/04
I am sorry to hear that your daughter has a mitochondrial disease. I will assume that when you mention that she is on continuous feedings, that there is a G-tube present. If this is so, then she has an access for fluids using the G-tube if she gets dehydrated due to illness. However, there are some good points for having a central line. The central line is a ready access for IV hydration, port for TPN if IV nutrition is required due to GI dysfunction, and site for blood draws if medication levels or IV medications are necessary. If her GI tract is working well and allowing her to meet her nutritional needs, the need for TPN is likely not necessary. However, if this is not the case, then having a central line may be necessary. Any invasive device increases the possibility of infection, which has to be carefully followed. Depending on how sick your daughter may be, having a central line may be of benefit. This is a decision that depends on how sick your daughter may be and the risks and benefits of the central line that you and your daughter's physician will need to carefully discuss.

The best physician for your daughter is someone who knows you and your daughter medical condition, someone who will be available to answer your questions and respond to the medical needs of your daughter. This is usually the pediatrician, as most of the time there isn't a mitochondrial disease specialist close by. However, many times there is a mitochondrial specialist within your region of the country that can serve as a consultant to help your local physician take care of your daughter. You can find a specialist list in your area through the UMDF.

Prognosis for a particular child is extremely difficult without knowing the child better. There is a range of possibilities, as you might expect. Basically, if a child is making developmental gains the outlook is better than if a child is stagnated or regressing in development. Without better knowledge of your child, it is not possible to give you a prognosis concerning your daughter.

Overall, the physician tries to give/allow the child the greatest chance to reach his/her potential. For most patients this entails cognitive and motor functioning and relationship with his/her family and society. However, there are other issues dealing with "quality". Quality of life issues are different for particular families and their child. As an epileptiologist, I always try and balance seizure control and seizure medication side effects. For example, complete seizure freedom with a child that is completely sedated and non-responsive may not be optimal medical care for a child with respect to quality of life. One has to balance control of any particular medical condition, there is a balance with medications/procedures and the child's ability to respond to his/her environment. There is also the issue of family dynamics. For example, some children may have long uncontrolled seizures that force a family to take the child to the emergency room for treatment. However, using a rectal medication that can be given at home has helped many families stop seizures at home, and therefore saving a 911 call and emergency room visit. This increases the quality of life for both the child and the family. Working with your physician and other medical providers, both the overall and particular issues involved with your daughter will hopefully be addressed.

I can't answer whether the "lesions on her brain" are from her disease, since I haven't seen the MRI scan and know under what context the MRI was performed.

I hope that your daughter is doing well. Hang in there and keep being your daughter's advocate.

Answered by: Russell Saneto, DO, PhD

Q: Could sex, specifically an orgasm, cause an increase in the symptoms of mito in an adult with the disease?

A: 11/4/04
Mitochondrial diseases are caused by defects of oxidative phosphorylation, the final pathway that uses oxygen to convert fats, sugars or proteins into energy. Any physical activity which requires a lot of energy (e.g. vigorous sex) can be stressful for patients with mitochondrial diseases and, in theory, might worsen symptoms. Nevertheless, many adult patients are able to participate in sexual activities and experience orgasms. Because mitochondrial diseases are very heterogeneous, each patient should discuss the issue of sexual activity with his or her physician.

Answered by: Michio Hirano, MD

Q: I have been told that my 11 month old daughter has hypomyelination throughout the brain and that there is atrophy of the cerebellum and volume loss also in the pons about 4 months ago. And now I was told the other day that she has a Complex I defect. Are the two related? Can a mitochondrial disorder cause the brain to shrink?

A: 11/4/04
Some people with disorders of the respiratory chain do not have any neurologic problems. However, we do know that disorders of the mitochondrial respiratory chain can cause brain damage in a variety of ways. Sometimes this brain damage cannot be seen on radiologic studies like CT or MRI. Other times the CT or MRI shows visible changes including findings called "hypomyelination", "volume loss" or "atrophy". As the words "volume loss" and "atrophy" suggest, the brain can get smaller or "shrink" in some people as a consequence of mitochondrial disorders. In addition, the structures in the brain (pons and cerebellum) that you mention in your question can specifically be affected by disturbances of mitochondrial energy production. So the answer to your question is yes, the brain findings you describe as being seen in your child can certainly be related to problems with Complex 1 function. It is important to understand that there is always the possibility of some more complicated explanation, but the simplest explanation here - assuming that the diagnosis of Complex 1 deficiency is correct! - is that the Complex 1 deficiency is the cause of the brain findings.

Answered by: Carol Greene, MD

Q: At around age three my son started having difficulties sleeping at night. He also became very hyper and was later diagnosed with ADHD. The sleeping problems have only gotten manageable with multiple medications. He is too hyper to put himself to sleep, and even with the meds doesn't sleep very 'soundly'. We are about to consult with Dr. Richard Ferber, the sleep expert, as a pre-requisite to doing a sleep study. I am very convinced that this is NOT a behavioral issue, but a biological problem. Do you have any insight as to sleeping problems and mito disease? My son (age 7) has MADD and damage to cortex and basal ganglia; he is also legally blind.

A: 11/4/04
I am sorry to hear you are having so much difficulty getting help for your son. As you know, mitochondrial disorders can affect the brain in different ways; by causing developmental delays, mental retardation, learning disabilities, attention deficit disorder, seizures, sleep disturbances, and neuropsychiatric disturbances. Trying to separate behavioral vs. biological problems as if they are black and white is very difficult; they are so closely linked that at times they are one and the same thing. There are many times that a biochemical imbalance in the brain causes a behavior problem as a symptom.

Dr. Ferber is a world-renown pediatric sleep expert, and not many have the chance for a personal consultation and must read his book for advice. I would take advantage of this opportunity!

If necessary, a sleep study could then evaluate other causes of sleep disturbances (apnea, reflux, seizures, restless legs/periodic limb movements,etc.) Most centers have a pediatric pulmonologist or neurologist that specializes in sleep disorders.

Finally, you did not mention if your son was on any medications which could be causing the sleep problem, such as stimulants used to help ADHD.
Answered by: Amy C. Goldstein, MD

Q: My son is 3 1/2 years old with oxidative phosphorylation disease (specifically Complex III defect and possible Complex I defect). He has had hypotonia and muscular weakness since birth but, with physical therapy, he has met many motor milestones. My questions concern his gastrointestinal system. He developed severe gastrointestinal dysmotility following a virus last fall and has had a g-tube since March 2004. He is fed by pump with Alimentum as he cannot tolerate much food by mouth. In addition, he is unable to have a bowel movement (no matter how soft!) without a suppository to stimulate the nerves and muscles. I have heard of children with mitochondrial disease experiencing regressions and yet regaining skills - can the gastrointestinal system heal and become 'normal' again? Or once the GI system damaged, is it always damaged? Lastly, is there any prognostic data on Complex III, particularly in a child who remains very bright but has muscular weakness and GI dysmotility?

A: 10/26/04
One cannot say for sure what the natural progress/history of each system is in mitochondrial disease for any specific individual although it seesm he is doing quite well now, which is good news. The GI problems in mito diseases are often very difficult to manage as they may result from a combination of muscle and neurological/autonomic problems. However I would ask if a more specific diagnosis could be made which may help or if mitochondrial DNA change has been looked for - e.g deletions/cytochrome b mutation or, if indicated, thymidine levels for MNGIE? In MNGIE, therapy with thymine, and in others, coenzyme Q10 may be of some help as well as checking carnitine levels and supplementing that as needed.
Answered by: Annette Feigenbaum, M.D., FRCP

Q: Our daughter who is two and a half is suspected of having a metabolic disorder. The geneticist is leaning toward the mitochondrial area. Our daughter is hypotonic, has severe reflux, global development delays, heat intolerance, abnormally high pain tolerance, major regression after an illness and has balance problems. She cannot sit alone or stand alone. She has shown low carnitine levels and had elevated methomylonic acid levels during an illness. It has been suggested that we have a fundoplication. We would like to have more information from doctors who deal with these types of issues and how they will affect this procedure. What are the positive and negative issues. Our daughter can have bouts of vomiting sometimes up to forty times a day on a bad day. We have had a scope done of the esophagus and there was no damage. She does have a hiatal hernia. Any information you could share would be very valuable to our family.

A: 9/17/04
There are at least 2 issues. The first one is the need to establish in your daughter the correct diagnosis. And the second is the need to provide the optimal treatment for gastroesophageal reflux (GER). The latter is most important as it is possible that a specific diagnosis cannot be made, but she needs the proper symptomatic treatment.
All of her clinical problems are compatible with a primary defect in mitochondrial oxidative (Ox-Phos)metabolism. The intermittent elevation in methylmalonic (MMA) acid levels may also be seen in mitochondrial Ox-Phos disorders. However, the MMA phenomenon may increase the likelihood that a specific diagnosis will not be made. As an aside, it is important that a primary defect in vitamin B12 metabolism be ruled out as well since they can be associated with intermittent elevation of urine MMA. Finding a high level of MMA and the amino acid, homocysteine, in plasma would indicate a defect in vitamin B12 as the cause of her problems. The main reason for finding the underlying metabolic cause, be it Ox-Phos or Vitamin B12, is that a specific therapy might help the vomiting and GER get better or even disappear.
Metabolic problems of many different types are associated with recurrent vomiting. And hypotonia from any cause may predispose an infant or child to GER and hiatal hernia. It is imperative that you work closely with an experienced pediatric gastroenterologist in making the decision whether a fundoplication is performed. It would be the logical procedure to do for GER alone or associated with minimal to moderate regurgitation. But if the vomiting is truly relentless and violent, it may, at the least cause the fundoplication to break down and, at the worst, cause tears or rupture of the stomach, if a natural outlet has been artificially obstructed and is necessary to expell the stomach contents during the course of uncontrolled vomiting. You all must use good judgment.
Answered by: Gerard T. Berry, MD

Q: My daughter (8 years old) has MELAS, mutation A3243G. The syndrome started in July, 2003 with a severe stroke-like episode that involved the occipital region but with no consequence. From August, 2003 to April, 2004 she had no symptoms. From May, 2004 up to September, 2004 she had 5 stroke-like episodes, none with consequences. Now her symptoms are: stroke-like episodes, ptosis and high lactic acidosis. She takes CoQ10, L-carnitine, Vit. C and E and folic acid.

- Could I consider her as having heteroplasmy ?

- Could I consider that the percentage of nonmutant mithchondria changes in a random pattern ? Even in the brain cells ?

- Could the medicine that she takes improve the percentage of nonmutant mitochondria ?
- Could I consider the lactic acid as responsible for all these episodes ?
- Could I use the lactic acid as a marker for the treatment, meaning that if the lactic acid goes down everything is going well; on the other hand, if it goes up something is wrong ?
- Could I use RIBOFLAVIN to reduce the lactic acid (in my country, DCA is not available) ?


A: 10/12/04
I am sorry to hear that your daughter has MELAS syndrome. As you describe, she possesses the most common mtDNA mutation associated with the disorder, and unfortunately, has experienced the most common and troublesome features, namely lactic acidosis and strokelike episodes.

Heteroplasmy describes the state where both normal copies of the mitochondrial genome and abnormal copies (ie harboring the A3243G mutation) can coexist in the same person. Most individuals with mito disorders have heteroplasmy, however, that is not determined clinically, but rather by assessment of the number of normal and abnormal mtDNA genomes on a tissue sample submitted to a molecular genetics laboratory.

In cells that do not divide anymore, such as brain and skeletal muscle, the ratio of normal and abnormal genomes are not expected to change.

As you know, while many patients with oxidative phosphorylation disorders are placed on cofactors, there has been no scientific study to assess the effectiveness of this. The cofactors are selected for their ability to possibly enhance the activity of an enzyme (or enzymes) that are not working to maximum capacity in these disorders and thus potentially overcome a deficiency or metabolic block. It is not expected that the medications will alter the levels of mutant and normal copies of the mito genome.

While lactate is often elevated in patients with MELAS, it is not clear if lactic acidosis is the cause or the result of the neurologic dysfunction. It is a marker of impaired aerobic metabolism, as anaerobic metabolism results in elevated lactate due to diversion of metabolic pathways to those not requiring oxygen, when energy metabolism or aerobic metabolism is disrupted. Elevations of lactate can be observed in other conditions, thus is not specific for a mitochondrial disorder, such as those associated with inadequate blood flow—vascular strokes, tumors, seizures, hypoxic injuries, and other inborn errors of metabolism. Lactate levels may remain elevated after the acute event. Lowering of lactate levels don’t always coincide with clinical improvement, but can be used as a marker for a therapeutic intervention.

Some patients with MELAS who have mild symptoms or gene carriers who appear asymptomatic, may not have elevated lactate at rest, may require a stressor, or may have lactate detected only in cerebral spinal fluid, but not other areas of the brain when assessed with magnetic resonance imaging ( a specialized application of Magnetic resonance imaging, MRI).

Elevations of lactate may indicate impending change in neurological function. Blood lactate levels do not necessarily correspond with the lactate level in the brain or CSF.

Riboflavin is often used to lower lactate levels. DCA, while a lactate lowering agent, has not yet been shown to significantly alter the clinical course of individuals with mito disorders and lactic acidosis, except perhaps in select instances. Thus, you may continue to use riboflavin, which is safer than DCA in terms of the probability of side effects.

Answered by: Andrea Gropman, MD, FAAP

Q: My son was diagnosed with mitochondrial myopathy when he was 8 yrs old. 3 yrs ago, when he was 12, a neurologist prescribed carnitor. After using this for a year and no improvement, we decided to discontinue the meds. Now I have been reading about co enzyme Q10. Should we try this? And is a patient supposed to take the carnitor along with the co enzyme Q10? How much of the co enzyme Q10 should one person take? Also is there a way to help my son to gain weight? He is 5'9" and weighs about 100 lbs. What is a good nutrient supplement to take?

A: 9/24/05
I am sorry to hear about your son. For those patients with a defined deficiency of a particular supplement, such as carnitine deficiency, we usually will see improvement when the supplement is added. However, for the most part, we try different supplements in "hopes" of helping the patient (when the patient does not have a defined deficiency of a vitamin or other supplement). There have been few studies looking at whether supplements help the clinical picture in patients without a particular deficiency. Several small studies have shown either a benefit or no benefit to using added vitamins or supplements in mitochondrial patients. The numbers needed to prove a benefit are large and until there is such a study, it is difficult to recommend or even not to recommend taking vitamins or supplements.

My opinion is likely biased, similar to most physicians who suggest that their patients with mitochondrial disease take vitamins. My thoughts on this subject may not be universal among mitochondrial experts. Using supplements in this patient population was part of my training. I have continued to suggest vitamin usage in my patient population. However, there is no conclusive data showing that vitamins help improve the clinical status of patients with mitochondrial disease, except for those patients who have a defined vitamin deficiency. I do so, for the theoretical rationale of decreasing the oxygen radical load or oxygen radical production that occurs with mitochondrial electron transport chain dysfunction. There seems to be some evidence that decreasing the production of oxygen radical formation or species might reduce the possible further damage to mitochondria function. Whether using vitamins helps perserve mitochondria function in our patients is not fully studied (see above). Certainly, a large study should be done in the future, but whether one will ever be done is questionable.

To answer your question about Coenzyme Q10. This is a vitamin that is found in membranes and within certain structures within every cell; one organelle is the mitochondria. It is involved in helping the electron transport chain function to produce energy or ATP. It is also a very strong anti-oxidant (meaning that it detoxifies oxygen radicals). Depending on the type of Coenzyme Q10, I usually recommend somewhere between 1 mg/kg/day up to 5 mg/kg/day divided in two doses per day. I also recommend to take vitamin E with the Coenzyme Q10 dosing. However, there are no studies showing that Coenzyme Q10 universally helps mitochondrial patients, unless they have a Coenzyme Q10 deficiency.

Concerning gaining weight, I would recommend that you see a nutritionist to evaluate his diet, caloric intake, and possible absorption problems.

Answered by: Russell Saneto, DO, PhD

Q: My son, Joe, is 41 and might have a mitochondrial disorder. Unknown. He is legally blind, deaf, has ataxia, and is in a wheelchair. He reads and writes braille and uses tactile sign language. He was a normal baby and has slowly deteriorated these 41 years. He has optic atrophy and nerve deafness. Does anyone else have the same? He also has severe pain in one ankle due to a slight sprain 10 years ago, has had four surgeries and the nerves burned, but nothing helped.

A: 9/24/05
Yes, a mitochondrial disease is a consideration in your son. Have we
seen anybody with a similar condition? Yes, we are following a
middle-age man who has become blind, has severe hearing impairment, and peripheral neuropathy (which your son may also have), but no ataxia.
Answered by: Salvatore DiMauro, MD

Q: My 23 year old daughter was just recently diagnosed with IgA Deficiency. When she was twelve, she was diagnosed with Borderline Disorder. Thatt was changed to Bi-Polar when she was 15, and back to Borderline about 2 years ago. She's always suffered from hypersensitivity to bee stings and mosquito bites. She freqently gets boils that last for months at a time. She has asthmatic bronchitis and slight hayfever type allergies. She also, a couple of times a year, suffers from blind spots in her right eye and tingling in her fingers and toes. A friend of mine has suggested that this combination of mental and physical issues could be mito related. Is that possible? Should we have her tested for any of the mito diseases? Is there a direction we should head first?

A: 8/26/04
As you probably know, patients with mitochondrial diseases have diverse medical problems. We are increasingly recognizing psychiatric manifestations, such as depression, in mitochondrial diseases and loss of vision in one eye is the usual presenting feature of Leber hereditary optic neuropathy, therefore, it is possible that your daughter has a mitochondrial disease; however, I think that this diagnosis is unlikely. Her physical problems seem to be related to abnormalities of her immune system: IgA deficiency, hypersensitivity to insect bites, asthma, and hay fever allergies. In addition, her neurological symptoms, transient loss of vision in one eye and intermittent tingling of her fingers and toes, could be due to immunological abnormalities (e.g. inflammation of her nerves). I suggest that your daughter be evaluated by a neurologist for her vision and sensory problems. Since the diagnosis of a mitochondrial disease is remotely possible, I recommend that her blood lactate and pyruvate be measured. If the lactate is elevated, then further evaluation for mitochondrial dysfunction should be considered.

Answered by: Michio Hirano, MD

Q: I will try to be brief, but I feel you need a little bit of background info to answer my questions. I have a little guy who was diagnosed at 18 months as Autistic. Over the past 4 years, he has had many serious 'episodes' of physical and vocal aggression. At times he suffers from some minor delusional thoughts. He's been hospitalized twice because of his out-of-control behavior. His episodes can come on, literaly, in seconds. When they end, it's as if nothing has happened...he doesn't even seem to realize that he was so totally out of control. He, at one point, had a potential diagnosis of schizophrenia, but is too young for a formal diagnosis.

Recently, he was diagnosed as having one of the Mitochondrial Diseases, not yet specified which one. Someone suggested that the family have him tested for heavy metal toxicity. His results came back very disturbing. He is in the 93% for high lead. He is in the 2% for Calcium (he is experiencing loss of vision in his right eye). His manganese was over 85%. His fatty acids were over 99%. Mercury did not showup in the results.

Now to the questions... 1)is this typical of Mitochondrial Diseases? Could the Mitochondrial problems be the reason for the extremely high levels of heavy metals? 2) We've been told that once the lead has been chelated, the mercury will probably show up as very high also. Is that typical? Why is that? 3)What's the prognosis once he's chelated? How long will it take for chelation? 4) We've also been told that any damage/regression is permanent. Chelation will stop future deterioration, but not repair any damage already done. Is this accurate? 5) Once chelated, will the high levels likely return in time?

A: 8/24/04
Sorry to hear that you have been having such difficulties with your son. While autism/autistic spectrum disorder has been seen as a feature of some mitochondrial disorders, many mitochondrial disorders do not feature autism. The severe episodes of physical and vocal aggression would be atypical for autism, and I agree that investigating a possible other etiology such as chromosomal (Smith Magenis for example if the features fit), psychiatric (ie bipolar disorder) or seizure disorder should be pursued.

You did not provide any information as to how the diagnosis of a mitochondrial disorder was made; thus I can only answer your question in a generic way. While some features of mercury overload can recapitulate an autistic disorder, there is no consensus about the role of heavy metals and testing for such play in neurodevelopmental disorders. Some children with mercury overload can experience language and social regression, and intolerance to light and sound; however, more controlled clinical studies need to be performed in order to address this issue.

Biochemically, mercury is known to bind sulfhydryl groups, and since mitochondria are rich in SH groups, can impair cellular respiration. Impaired mito function has been suggested in some cases of autism due to frequent association of lactic acidosis and carnitine deficiency; however, other pathways are also potentially important in autism such as serotonin, in which mercury may be involved.

Cases of heavy metal overload do not appear to be a common problem seen in mitochondrial disorders. Thus, I cannot comment about the role of chelation in the setting of mitochondrial disorders.

Answered by: Andrea Gropman, MD, FAAP

Q: I am aware that there are different medications that people with mito disorders should avoid; however, I am not familiar with all of them. In my concern to avoid potential problems, is there a "list" of medications to avoid?

A: 8/20/04
There are certain medications to take cautions with when you have a mitochondrial disorder. This is not an exhaustive list and does not pertain to every patient with a mitochondrial disorder. Review your individual disorder and medications with your personal physician.

Prior to any surgical procedure, review your medical history with the anesthesiologist. Certain anesthetics used in surgical procedures should be used with caution, and these should be reviewed with the anesthesiologist. The decision about whether to use specific drugs must be based on your disorder, your age, and the surgical procedure being performed. A review is provided in "Think Mitochondria" by Drs. Bruce Cohen, John Shoffner, and Glenn DeBoer, reprinted from the Spring 1998 UMDF Newsletter, and is available by calling the UMDF office. Patients with mitochondrial disorders could be at risk for a condition called malignant hyperthermia, and there is a protocol for the anesthesiologist to follow for this condition.

Valproic acid (Depakote) has been used as an anti-seizure medication in some patients safely; however, it has led to serious and fatal consequences in other patients. It should be avoided in the very young patient, especially when the diagnosis is uncertain. However, if a patient has been on Depakote without problems, with careful monitoring, it is generally safe to continue on this medication. Depakote can deplete the carnitine stores, so Carnitine should be supplemented while on Depakote.

If IV fluids are necessary, Lactated Ringers solution should be avoided as it contains lactic acid.

Antiretroviral drugs (anti-HIV drugs) are toxic to mitochondria and should be avoided if possible.

Doxorubicin, a chemotherapy medication, causes cardiomyopathy as a side effect, most likely through mitochondrial damage, and should be avaoided.

Aminoglycoside antibiotics, such as gentamicin, streptomiycin and tobramycin, can incduce hearing loss by damaging mitochondria. This accounts for 5-10% of drug-induced deafness and 0.6% - 2% of the deafness population. These antibiotics should be avoided if the cause of the mitochondrial disorder is unknown. There are specific point mutations in the mtDNA that make one more susceptible to this ototoxic damage.

Certain antipsychotic medications can increase the risk of diabetes and should be used with caution and frequent monitoring.

Medications can be essential to your health and well-being. Please review any concerns you have with your physician. More information can be obtained from the UMDF website and through literature available from the UMDF office.

Answered by: Amy C. Goldstein, MD

Q: My 6 month old was just diagnosed with Pyruvate Carboxlyase Deficiency. If the muscle biopsy wasn't fresh, is this a true diagnosis? Also, have you ever had a patient with this that has lived past 1 year old?

A: 7/30/04
Thank you for your question, and I hope your little one is doing well.

Let me answer your second question first. I certainly have taken care of patients with pyruvate carboxylase deficiency who have lived well past their first year of life. However, every person is different, and life expectancy is not always predictable. Sometimes we can predict life expectancy based on the kinds of problems that led to the diagnosis. For example, in some children, pyruvate carboxylase deficiency has been reported to cause a pattern of neurodegenerative disease called "Leigh Syndrome", which is diagnosed using MRI scan of the brain, and most of those children have a very short life. Other children with pyruvate carboxylase deficiency can be quite healthy so long as special care is taken when they have childhood illnesses. The doctors who have worked with you to make the diagnosis will be in the best position to help you understand what the future might hold for you and your child.

Your question about the diagnosis is also very interesting, and turns out to have a complex answer.

First, like many other enzymes, the enzyme pyruvate carboxylase can be measured in a number of different tissues, and it can be measured either in fresh tissue or in tissue that hase been properly stored. It isn't necessary that tissue be fresh in order to make the diagnosis of pyruvate carboxylase deficiency - but how the tissue was stored does matter. If the tissue was properly handled, the results of the pyruvate carboxylase enzyme assay in stored tissue may be quite accurate.

Next, when making a diagnosis of pyruvate carboxylase deficiency, it is necessary to know the results of other enzymes tested in that person. Results of other enzymes tested on the same sample are helpful because, if the tissue was not properly handled, other enzymes besides pyruvate carboxylase might also have reduced activity measured in the laboratory. It is also important to know whether the pyruvate carboxylase deficiency is the only biochemical problem, or whether the low pyruvate carboxylase activity is part of another condition - for example, the condition known as "multiple carboxylase deficiency". If pyruvate carboxylase deficiency turns out to be part of a disorder affecting other carboxylases as well, that would change the diagnosis and possibly the treatment.

If there is any doubt about the diagnosis, sometimes it is appropriate to examine the activity of the enzyme pyruvate carboxylase in other tissues, like certain cells from blood or skin fibroblasts, or to examine other enzyme activities. In some cases the pyruvate carboxylase enzyme acitivity can be variable depending upon what tissue is sampled (but so far as I know, having that kind of information does not tell you what symptoms or life span to expect).

So as you can see, it is important to have a lot more information about how the sample was handled and about how the test was done in order to know whether you have received a "true diagnosis". I hope this information will help you - and any other families - to know what questions to ask your own doctors about the accuracy of any diagnosis made by laboratory tests of enzyme activity.

Answered by: Carol Greene, MD

Q: I have been reading a lot lately about mitochondria diseases and muscular dystrophy. Our son has a mito disease (COX IV deficiency), but I was wondering what the link is to mito diseases and MD...I understand the mitochondria aspect, but I am confused...

A: 7/21/04
Muscular dystrophy is a condition that occurs when the normal structure of muscle breaks down. A number of proteins that normally reside in the muscle membrane have been associated with these destructive changes. The best-known example is a protein called dystrophin, which is abnormal in a disease that effects boys called Duchenne muscular dystrophy. Although mutations in the gene that directs the manufacture of dystrophin can be identified, the exact function of dystrophin in the muscle cell membrane is unknown. When there is an abnormal dystrophin molecule, muscle tissue starts to break down slowly leading to progressive weakness and eventual complete muscle failure.
In mitochondrial diseases that affect muscle (not all do), the basic problem is that the muscle cannot generate enough energy to be able to function normally. This leads to muscle weakness that is described as a myopathy. Myopathy may be progressive or static. There isn’t always a chronic loss of muscle tissue in mitochondrial diseases as there is in the dystrophies but occasionally there is acute loss of tissue due to a process known as rhabdomyolysis. Here, muscle cells break down rapidly when there is stress such as muscular exertion. Acute loss of muscle tissue can result in kidney damage due to sudden release of muscle contents (proteins) into the blood system.
Both dystrophies and mitochondrial myopathies result in muscle weakness but the mechanisms that cause these changes are different.

Answered by: Michael J. Bennet, PhD, FRCPath, DABCC

Q: Early this year I underwent surgery to plant scaffolding in to my arteries [stents x 2] because of coronary cholesterol. I was actually in the hospital in the pulmonary unit when I became unwell and was transferred to the coronary unit where I underwent testing. A short while later I had this operation as above. A few weeks later back at the pulmonary department I had another period of sickness and was sent back to the coronary department for observation and eventually another operation to confirm that I was ok. I was told I needed medication for cholesterol and that statins were not good for me as they would destroy muscle which is the last thing I need. I am now waiting research to establish the best form of medication for me.

A: 7/16/04
Statins do not actually "destroy muscle", but in some individuals and
at certain doses they do seem to damage muscle, as manifested by
exercise intolerance, muscle pain, and increased levels of serum
creatine kinase (CK). In rare occasions, muscle damage has been
extensive, resulting in myoglobinuria (discoloration of the urine due
to the passage of the muscle pigment myoglobin). So, as often in life,
one has to find a balance between risks and advantages. If - as it
sounds - your cholesterol problem is serious, statins are wonderful
drugs. If you take them, however, you should also take coenzyme Q10
(CoQ10) by mouth because CoQ10 levels in blood decrease during statin
treatment. Also, have your blood CK checked at regular intervals.
Answered by: Salvatore DiMauro, MD

Q: I am 43 years old and was diagnosed with Mitochondrial Neuroencephalopathy about 3 1/2 years ago. I have had a stroke (TIA) on the left side and have regained most of the use on that side. I also have what is called focal seizures that affect the speech and memory part of the brain. When I have a seizure it can take one or both of these. I am on Lamictal 150mg qh and Topomax 200qh and Klonipin at the onset of the seizure. Is there anything that we can do to prevent these seizures or any help that we can be given? It has been suggested that I go into a power wheel chair due to the problem that I am having walking and standing. Is this a good move for me?

A: 7/16/04
It is difficult to answer your questions without more specific information about your illness and treatment. Since you have had persistent left-sided weakness, you probably had a stroke rather than a transient ischemic attack (TIA, which by definition does not cause neurological dysfunction that persists more than 24 hours). The stroke lesion is likely to be the cause of your seizures. As you know, it is particularly important to treat seizures in mitochondrial diseases, because seizures cause metabolic stress which may worsen the problems caused by the underlying mitochondrial defect. Clearly, this is evident by the worsening of your speech and memory after seizures. Conventional anti-epileptic drugs such as Topamax and Lamictal are usually effective for seizures in mitochondrial diseases. I cannot recommend changes to your anti-epileptic drug regimen without more specific information about your seizures and past response to medications. In general, we recommend that mitochondrial patients avoid valproic acid (Depakote) because this medication can cause carnitine deficiency. Zonisamide has been useful, particularly in mitochondrial patients with myoclonus epilepsy.
Answered by: Michio Hirano, MD

Q: My 7 year old son has a unspecified mitochondrial encephalomyopathy resulting in seizures, ataxia, and other neurological deterioration which began as a toddler. My 5 year old son (I only have two children, and no plans for more) is just showing signs of possible mitochondrial disfunction including reflux, fatigue, digestive troubles, headache, and muscle pain. His EEG is abnormal in the same way his brother's was early on. Neither shows any signs of cardiomyopathy.

My father passed away from complications caused by hypertrophic cardiomyopathy. He developed diabetes and hearing loss as an adult, which was assumed to be caused by the medications he was on. I have three siblings, one of whom died from SIDS, and another who has advanced hypertrophic cardiomyopathy, reflux, and severe muscle cramping. My sister and I have possible mild, asymptomatic hypertrophic cardiomyopathy. I recently have experienced some trouble with walking.

My husband's maternal grandmother had severe migraines, and his mom has neurological problems including dystonia and ataxia, and many other health problems, especially gastrointestinal ones. Other than reflux, my husband has no significant symptoms.

What are some possible inheritance patterns to explain our sons' problems? I have read that mitochondrial DNA (vs. nuclear DNA) cause varying degrees of disease and at various rates of progression. Is that exactly true or is there room for some variation with nuclear DNA?

How could I, and some or all of my siblings, have inherited this from my Dad, and then both my kids have inherited it from me? (My mother shows no signs of mitochondrial disease.)

Is it possible for my husband to pass on mitochondrial DNA?

Could we both have contributed defective mitochondrial or nuclear DNA to result is mitochondrial problems in our children?

A: 7/14/04
With a complicated story like this involving perhaps four generations, both sides of the family and a range of different symptoms it is very difficult to work out exactly what is going on. Even knowing the details of all the investigations on each individual, it may not be possible to make a definite conclusion. If you haven't already done so, the best thing I can recommend is that you seek out one of the top experts in mitochondrial diseases in your country and have them look over all the details. This may involve a visit interstate but is likely to be more useful than just seeing a specialist neurologist or cardiologist who is not an internationally recognized figure in the mitochondrial disease field.

Your father and siblings are presumably not related to your husband's family, except by marriage, so there is no genetic link and it seems extremely unlikely there is one single explanation to link together all the symptoms in your children, your relatives and his relatives. There are several possible explanations for symptoms that may or may not be caused by mitochondrial disease affecting multiple generations.

1) Mitochondrial DNA
Some mitochondrial DNA mutations can cause hypertrophic cardiomyopathy in one family member and other symptoms such as seizures, ataxia, neurological deterioration, diabetes or deafness in other family members. It is possible that the symptoms in your 7-year old son (and perhaps in your other son, yourself and your siblings) are caused by a mutation in mitochondrial DNA. If that is the case then it is extremely unlikely that the symptoms in your father and your husband's family are caused by the same mutation. Mitochondrial DNA is normally inherited only from the mother. There has been one report of mitochondrial DNA passed from a father to a child but this has now been looked for in lots of other families and appears to be an extremely rare occurrence.

2) Autosomal dominant inheritance
Ignoring mitochondrial DNA, we all have 46 chromosomes. This includes 22 pairs of "autosomes" plus two sex chromosomes (XX in females, XY in males). We inherit one copy of each autosome and an X chromosome from our mother and the other copy of each autosome plus an X or Y chromosome from our father. So for most genes we have 2 copies, and autosomal dominant inheritance refers to diseases where a mutation in one of the two copies is enough to cause disease. Autosomal recessive inheritance refers to diseases where both of the gene copies must have mutations in order to cause disease. An autosomal dominant disorder can cause symptoms in multiple generations and be passed on by either parent. There are a number of genes that cause autosomal dominant hypertrophic cardiomyopathy by interfering with efficient contraction of the heart muscles. If your father, sibling and possibly your sister and you have hypertrophic cardiomyopathy, then it is very plausible that one of these genes is involved. That wouldn't account for any symptoms in your husband's family and probably isn't related to your son's illness.

3) Autosomal recessive inheritance
It is possible that the symptoms in your son(s) are due to an autosomal recessive disease but it is very unlikely that this type of inheritance could explain symptoms in any other family members.

4) X-linked inheritance
X-linked diseases usually affect males more severely or more often than females, and cannot be passed from father to son. It is possible that the symptoms in your son(s) are due to an X-linked disease but it is very unlikely that this type of inheritance could explain symptoms in any other family members.

So there isn't any obvious type of inheritance that can explain everything. I think it is almost certain that some of the symptoms in the family members you mention are unrelated to those in your sons. Mitochondrial diseases can potentially cause almost any symptom so it is tempting to blame everything on them. However, some symptoms like migraine, fatigue, gastrointestinal symptoms, etc are very common. Although one thinks of conditions like hypertrophic cardiomyopathy as being uncommon, it could well be that this is unrelated to a mitochondrial problem and present in the family coincidentally. We have seen several families where the family history appears to be quite confusing and ends up being shown to be due to two different diseases affecting different family members.

My best advice is to see a leading mitochondrial expert and have them evaluate all the investigations done on your 7-year old son and other family members. Since the family history is confusing I would recommend putting it aside and focus on the clinical symptoms, imaging, metabolic investigations and enzyme results (if tested) for your son. We rely heavily on enzyme results to guide further molecular investigations to try to identify the genetic cause. If a genetic cause can be found, then they can sort out how much of the family history is relevant.

Answered by: David R. Thorburn, PhD

Q: My little girl is 2 years old and she is diagnosed with complex I and III. with suspected myclonic seizures. Please, in simple English, explain to me these complexes. My other questions are: why does she say her eyes and various parts of her body burn? Why does she sweat so badly when sleeping? Why doesn’t she eat well and gain weight? (She is 18lbs 30in long, head cir. 47cm, and wears 3-6 months clothes.) Why does she have the following symptoms: headaches, really sandy frequent stools, hardly urinates, hot and cold sensitive, chronic sepsis, lactic acidosis, autistic-like episodes, bites and hurts herself? She will have a seizure or stroke-like episode and go to sleep, wake up with a 107.4 fever, and we’re off to the hospital. Why the fever? Her hair falls out. She is on Co-Q-10 16mgs bid and carnitor 2.75 tid. I feel like I am in the dark.

A: 7/14/04
The mitochondria have been referred to as mini powerhouses, where the energy production of our body cells takes place. The are present in our body cells, and in increased numbers on those cells that require a lot of energy (ie muscle cells, heart muscle cells, brain cells, eye cells, kidney cells). The food we eat is the fuel for this energy. Depending upon the content of the food—fat, carbohydrate, and protein, different enzymatic reactions take place in various parts of the cell and the byproducts of these reactions or reducing equivalents enter the mitochondria to be converted into energy, called ATP. This energy conversion occurs along a powerplant comprised of 5 different substations—called complexes 1-5 of the electron transport chain. Each of these substations or complexes is made up of many proteins that are needed to get the job done. If any of these proteins are not working, there is the possibility that the whole substation will not function, and impair energy production. One clue of this impaired energy production is the build up of lactic acidosis, as the cell has to figure out other, but less efficient ways to make energy—anaerobic metabolism.

The clinical manifestations of impairments of this mitochondrial energy production process (referred to as oxidative phosphlorlyation) are many and varied and depend upon many factors—mode of inheritance of the defect, cells and parts of the body affected (ie brain, eye, heart, etc), type of defect at the molecular or biochemical level, other factors including environmental, other genetic mistakes in cells, etc.

Thus many of the symptoms you describe in your daughter can be ascribed to this breakdown in energy production. For example, lactic acidosis, stokes, and myoclonic seizures are common in certain kinds of mitochondrial disorders termed MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes), as is poor weight gain and linear growth. Abnormal sweating and fevers can be due to dysfunction of the hypothalamus, a type of control center in the brain for autonomic function such as temperature regulation, feeling full after eating, etc.

The burning and abnormal hot and cold sensations could be due to problems in the nerves, which can also be seen in mito disorders. Some children with mitochondrial disorders have developmental delay, mental retardation and/or autistic features. Many of these children will hurt themselves (ie biting) as self stimulation, or because they don’t perceive pain as you and I do. It may give them some type of sensory feedback. Physical and occupational therapy may be useful in such cases.

The best management of the many symptoms involved in mito disorders is that of a multidisciplinary team of doctors and other health professionals and therapists who can contribute their expertise to managing the day to day issues associated with a multifaceted disorder. Parent support groups may be useful for education and advocacy, as well as to learn how other parents have learned to manage particular aspects of the disease.

Answered by: Andrea Gropman, MD, FAAP

Q: My adopted nephew has been diagnosed with mito complex 1&4 and he has about 3 to 30 seizures a day. He is g-tube fed and wheel chair bound with low tone. He is having some type of crystalizing coming out of his penis and it usually happens with a seizure. He is only 21 months old and we are checking his sugar three times a day. It never gets over a 90 and never below 65 so he is right on target. What is it? What should I do? I am asking this at his mother’s request. He is on Kepra and Co q 10 and carnitor. Nothing is helping the seizures. They just get worse. Please help.

A: 7/14/04
I am sorry to hear about your adopted nephew. I am not sure what to tell you concerning the "crystalizing" substance that comes out of his penis during seizures. Urinary incontinence is common during generalized or secondarily generalized seizures, but not a"crystalizing substance". My thought is that you should have him seen by a pediatric nephrologist. It might be that there are other kidney or bladder issues that might need to be addressed.

Seizures in mitochondrial disease can be difficult to control. If Keppra is not effective in controlling the frequency of seizures then another medication may be warranted. If Keppra has helped but not completely stopped the seizures from occurring, then dual therapy might be an option, with another medication that can synergize (has a different mechanism of action) with Keppra might be an alternative treatment. Each patient can be unique so it is best to work with your pediatric epileptologist in designing an appropriate plan to stop your nephew's seizures. The trial of medications can take some time to evaluate, so try and be patient. If medications do not seem to be controlling his seizures, then there is the possibility of the ketogenic diet and maybe even the vagus nerve stimulator as alternatives or additional mechanisms to control his seizures. This should be discussed fully with your epileptologist.

Answered by: Russell Saneto, DO, PhD

Q: Our ten yr. old son has an unspecified mito disorder, and in the past year and a half has had symptoms such as hallucinations and sleep walking within the first few hours of sleep, then a very deep sleep that he doesn't want to wake from. He is also very, very pale, occasionally grayish, has changes in his pupils, and during the day has had confusion, very pale skin, and a range of other symptoms. This has progressively worsened becoming more and more frequent over time. He was found to have high CO2 retention in the daytime and at night. Bi-pap was started at night, helped somewhat with the night episodes but daytime symptoms kept on as well as night troubles. We then saw a pulmonologist (who is very good) and has experience with mito disorders, and he told us that the CO2 is a secondary problem, the primary problem being oxygen troubles with the cells. His breathing muscles are in the 90% for his age, so that is not the problem during the day, though we think it is a problem at night. Our son is now using oxygen full time through the bi-pap and it has helped tremendously. He is even sleeping through the night. However, he still has occasional symptoms if he is active at all. When monitored, he was found to have saturation drops, particulary with even light activity, and his saturation was always lower during these episodes than when he is feeling good.
What is the correlation in mito disorder to cells not oxygenating, and is there a name for this problem? Also, what does this mean for a prognosis? We are very optimistic and believe firmly in holding onto hope, which we are doing, but also know that needing oxygen full time at ten years old is not a good thing, and we want to know what we are up against. I guess we don't quite know the seriousness of this or if it is just a common "mito thing". How many mito disorder patients require oxygen, and is it often mistaken for weakened breathing muscles?

A: 6/30/04
There are a number of causes of high C02, low oxygen saturation. Causes
like lung infection/disease or cardiac heart disease (cardiomyopathy and rhythm problems)need to be excluded. In children with mito disease this could also be due to muscle weakness (sometimes helped by Bipap or may even need ventilation) or a problem in the central drive for respiration due to neurological or brainstem involvement in some with mito disease. It seems he is also having some autonomic nervous system symptoms which are seen in those with neurological involvement by mito disease. The cells in mito disease do not 'use' the oxygen properly to make ATP etc but that should not cause high CO2 or low oxygen blood levels- rather it causes build up of lactate levels in the body and /or brain and if this causes acidosis there may be breathing problems- usually episodes of rapid or deep breathing with
low C02 levels. The lung function tests, oxygen saturation monitoring,
lactate levels and MRI scan may give more information on these. Confusion states etc are sometimes caused by low oxygen levels - I cannot be sure that is the problem here but if it is improved by giving oxygen and avoiding low oxygen saturation it seems this may be it. I do not know what his cognitive state is, but some children with sleep walking symptoms may have anxiety as a contributing factor and this could be considered too. Without the full picture it is hard to give a prognosis in any child with mito disease and even so, each child is different and the picture may change over time -it depends on the progression if any, or plateau of the disease and also of course what the family and physicians decide about further interventions if
they are needed. I suggest this is better discussed with his physician

Answered by: Annette Feigenbaum, M.D., FRCP

Q: Taking the high levels of vitamins and minerals, especially B6, that are in what is referred to as the "mito cocktail" leads me to wonder how to determine whether it is meat or poison for each individual. I have also wondered why the formulations of B-complex vitamins are called B 100 or B 50, generally specifying that capsules contain 100 mg. or 50 mg. of several B vitamins, which results in highly disproportionate quantities relative to the RDA. A more physiologically safe formulation would seem to be capsules containing 50 or 100 times the RDA of each of the B vitamins contained therein.

A: 6/17/04
Yes, Physicians specializing in the field of metabolic diseases always prefer to administer vitamins in amounts that are 10-100 times the RDA. The reason is that authentic vitamin-responsive inborn errors of metabolism (biochemical genetic diseases) often require that the tissue levels of vitamin-cofactors (the name given to vitamin derivatives that actually kept cells alive and functioning) need to be 10X or higher than normal for the cellular function that depends on the particular vitamin to begin to normalize. For example, if a PDH defect could be corrected with thiamine (a B vitamin) megatherapy, it would probably need to be given in amounts that are 10-100X the RDA (e.g.. 10-100 mg instead of 1 mg per day).

However, certain vitamins are poisons when given in high amounts. These include vitamin B6, vitamin D and Vitamin A. The latter two are very dangerous and are not B-complex vitamins. Vitamin B6 is the only B vitamin that can cause problems when given in high amounts. But all of our information is from adults! If adults ingest 500 mg per day they may develop perpherial nerve disease. It may occur at doses that are greater than 200-300 mg per day but this is less well documented. In fact, there is not enough information on the dose that can cause perpherial neuropathy in infants, children and adults. A very conservative estimate in infants and children would be no more than 3 mg vitamin B6 per Kg weight per day or 210 mg per 70 Kg body weight as in an adult. This would mean no more than 30 mg in a one year old. Most of us would empirically use higher doses such as 50-100 mg in a one year old, but it must be done carefully and not for an indefinite period of time.

I hope this helps, but obviously there is still much to be learned .

Answered by: Gerard T. Berry, MD

Q: I have a 17 mos old daughter, who was diagnosed 3-12-04 with complex 1 and 4 deficiency. She has seizures, is peg tube fed, blind {just recently}and her MRI shows severe white and grey matter disease. We were told that there was no treatment for her; just treat the symptoms. Does this sound right to you? She is responsive, very sweet and beautiful. She was sitting in December; now she does not. I would like to find out some more info.

A: 6/17/04
In an attempt to directly treat mitochondrial disease, many specialists advocate various co-factors and other agents such as co-enzyme Q10, carnitine, anti-oxidants, DCA, etc. While the routine use of these compounds in mitochondrial disease is a matter of debate, most experts will agree that most mitochondrial patients do not dramatically respond to them. Thus, unfortunately, at present there really is not much that can be done to treat mitochondrial disorders such as that your daughter has, other than by treating the symptoms.

However, treating the symptoms can sometimes make a difference in an individual child with mitochondrial disease. There are several conditions that are both common in mitochondrial disease and amendable to treatment, at least in part, including seizures, migraine, reflux, constipation, hypothyroidism, hypoglycemia, diabetes, cardiomyopathy, strabismus, hearing loss, depression, attention deficit disorder and developmental delay.

I will elaborate on but one example: Migraine headaches are common, often severe, difficult to diagnosis (if one does not look for them), and treatable. In young children or older children with developmental delay, migraine can often manifest as nausea, vomiting, or simply as episodes of screaming. A useful hint in many cases is that the manifestations of a migraine episode in a given child are generally similar in terms of symptoms and time of onset. Successful treatment regiments vary from child to child, and include juices (sugar), caffeine, ibuprofen and/or amitriptyline.

Answered by: Richard G. Boles, MD

Q: I have Cricopharyngeal Achalasia and have had not recently had success with dilatations. It was suggested that I consider Botox injections and I'm wondering if this could potentially cause more problems with my Mitochondrial Myopathy. I am also immuno-compromised from Lupus related treatments. Are you aware of any Mito patients having this procedure with adverse effects ? I'm concerned that my cells might consider this an infectious process.

A: 6/12/04
Botox treatments, which are becoming increasingly popular with physicians and patients alike, need to be very carefully considered in patients with disorders of mitochondrial energy production. Botox works by paralyzing tight (spastic) muscles, and the major benefit is an alteration in the relative balance of the tight and weak muscles in a limb, which can improve posture and function. Botox does nothing to help weak muscles: it makes them worse, because it works by weakening a tight muscle.

The Botox effect is usually relatively short lived: it typically lasts about 3 months, and then has to be re-given. In a mitochondrial patient, the balance of weak and strong muscles in a limb can change even during that time frame: so the physician using Botox needs to carefully re-evaluate the pattern of muscle balance before each treatment.

However, a more serious concern is whether Botox is, in fact, always reversible when injected into a muscle that is not actually normal in the first place: Botox works by blocking transmission of a chemical message from the nerves coming from the spinal cord to the muscle: if this block is too intense, or the muscle injected already weak from mitochondrial disease, the injection may actually make the limb balance worse.

Botox is a potent toxin that is used at very low concentrations in these treatments: however, in even moderately higher doses, especially when it enters the blood stream, it can cause weakness and even paralysis. Physicians using Botox are trained to avoid injection into blood vessels.

In years gone by, we used to see children presenting with paralysis after eating raw honey, in which the bacterium that produces this toxin had grown: they presented with weakness and respiratory failure, and (to many doctors) would have looked very similar to the way in which some patients with mitochondrial disease present.

There are several other drugs which should be considered by the doctor for treatment of spasticity as part of the overall treatment decision for or against Botox. Use with caution!

Answered by: David Whiteman, MD

Q: I would like your thoughts on the use of a Ketogenic Diet for seizure management. While my daughter's seizures are fairly well controlled by Keppra 1000 mg bid and Neurotin 900 mg tid, she is sleepy and lethagic throughout the day; some days sleeping 3 hours in school. We miss seeing our daughter interactive and excited by life. This is something we are looking into with the support of the pediatric neurologist with the hopes we can reduce her meds and wake her up.
She will be evaluated to determine if a Ketogenic diet is appropiate for her in July. I have been reading about it and am now wondering if it is a reasonable consideration. The limited carbs and protein, fluid restriction, the possible low blood sugars, etc. make me concerned we may tip the balance on a stable child.
Would you please share your ideas on the positive and negative aspects of this treatment in a child with Leigh's, clinical diagnosis not confirmed through testing done 14 years ago?

A: 6/12/04
I am sorry that your daughter seizures are difficult to control. Whether to try the ketogenic diet depends on several factors:

(1) The diet is very regimented, meaning that strict account of all foods eaten is required. The diet is very bland in taste; although there are many ways to enhance taste in the diet, it still remains somewhat bland. This may cause a child not to eat the diet, which defeats the purpose of the diet.

(2) If a child is mobile and capable of getting into other foods in the refrigerator or pantry, then this would sabotage the diet and could enhance seizure activity. We have seen patients go through the garbage to find food as well as even eating their pet's food.

(3) The diet requires a commitment of the family. This is necessary as other siblings will need to be aware that certain foods are "off limits" to the child on the diet. Sometimes other foods not on the diet will need to be out of the vision of the child so he/she is not aware or tempted to eat the forbidden food, i.e. cookie.

(4) A full metabolic workup is needed to make sure that the child does not have a beta oxidation problem (metabolizing fats for energy).

(5) Most ketogenic diet centers would like the patient to stick with the diet for at least 4 - 6 months for an adequate trial.

(6) There are some children who just do not tolerate the diet-vomiting, severe constipation, or lack of seizure abatement.

I have good success with the ketogenic diet and mitochondrial disease, with respect to seizure control. My patient population consists of electron transport chain complex dysfunction, mitochondrial DNA mutations, and pyruvate dehydrogenase deficiency. Most of my patients are on the 4:1 diet but several are at 3.5:1 or 3.75:1 ratios. The variation in ratios is due to the caloric needs of the patients and ketone levels. Most are growing well, albeit a little slower than their peers (most of my patients are infants and young children). I have not had difficulties with increased lactic acid levels or patients becoming too hypoglycemic on the diet (after the initial phase of starting the diet). Seizure frequency has been from seizure-free to significantly reduced (>75% seizure reduction) in my patient population. Unfortunately, most have continued on their seizure medications. The majority of parents tell me that their child is brighter or at least more interactive on the diet. I think the reduction in seizure frequency has a large part in this subjective view of the parents. I hope this helps in your decision-making process.

Answered by: Russell Saneto, DO, PhD

Q: We are currently living in the UK. Our 3 year old daughter has been diagnosed with a mito disorder. She had an initial diagnosis of Leigh's Syndrome but now the doctors are not convinced of this particular one. Her symptoms are: hypotonia (can't walk or sit up), poor growth and weight gain, peripheral neuropathy, abnormal eye movements, ataxia, losing clarity of speech. However her mental development is normal.
We have been reading about IVIG infusion and Stem cell transplantation and wondered if either of these two treatments may be of use to our daughter. We have asked our UK doctors about this and they do not have enough information to comment. Do you have any more information we can act on or anyone you could put us in contact with regarding this?
At the moment she is not on any medication or suppliments whatsoever. Would you recommend a particular regime we could follow?
It appears to us that the UK is far behind the US in terms of knowledge and treatment in Mito disorders. We would be keen to bring our daughter to the US to benefit from this advanced knowledge. Do you know of any doctors undertaking trials or treatment therapies that might be of benefit to us?

A: 5/19/04
I am sorry to hear that your daughter has been diagnosed with a mitochondrial disorder. As I do not know the exact diagnosis (mitochondrial DNA mutation, electron transport chain abnormality or substrate dysfunction) it is not possible to give specific treatments. I will try and give you my prespective on the use of IVIg and stem cells in mitochondrial disease. The use of stem cells in mitochondrial disease is not well studied and likely will not be used in the treatment of mitochondrial disease in the near future. Theoretically, it would be a way of providing "normal mitochondria" to specific organs within the body. Unfortunately, currently much study is still needed before its use in general clinical practice.

My experience with IVIg is limited. The first use came during my fellowship training and was accidental in some ways. We thought we were treating a demyelinating condition named chronic demyelinating polyneuropathy. The usual treatment for this disorder is IVIg, in many instances. The use of IVIg reversed the muscle weakness. This disorder is episodic, multiple uses of IVIg are required. It was used multiple times with great benefit in this patient. It turns out that the patient really had a mitochondrial disease. Although it was beneficial in this single case, I have used it in another similar case without much success. Whether the effectiveness in the initial patient and the lack of benefit in the second patient was due to type of mitochondrial disease is unclear. Both had features of spotty demyelination by EMG studies as well as increased protein in the CSF. The second instance that I have seen IVIg have a benefit is "pseudo-obstruction" of the bowel. Often a hyperosmotic electrolyte solution is used to induce rapid bowel transit. I have used and seen the benefit of IVIg when hyperosmotic solutions fail to work. It is not clear the etiology of how IVIg works in this situation.

I am sorry that my experience with IVIg is rather limited. I am not aware of any particular studies using IVIg in mitochondrial disease.

Answered by: Russell Saneto, DO, PhD

Q: I am a 51 year old woman, diagnosed with POTS in 1996. But additional symptoms that appeared both before and after this diagnosis were not consistent with POTS, and a facilitator on their website ( suggested I look into the possibility that mitochondrial disease might be the problem. I had Graves disease in ’90, followed by total thyroidectomy, take synthroid, and in 1994 developed an eye movement problem, causing terrible pain and requiring that I wear an eye patch for eight years because of pain associated with trying to use both eyes. This was later described as ophthalmoparesis. Initially, I was thought to have MS, as I presented with what appeared to be a stroke, with difficulty speaking and swallowing, but the brain MRI was negative, and has remained so. During this described episode, I developed a tremor in my extremities, worse on the left. This has become worse over time. I developed gastroparesis, requiring TPN initially, then a j-tube, which I have had for eight years and run a feeding for 13 hours at night. I must sleep 11+ hours/ day. I am cold and heat intolerant, no longer sweat, and have had temperature instability in the past. I wear compression stockings, yet cannot stand for very long without feeling extremely fatigued and ill; fatigue being a profound limitation overall. Unlike most POTS patients, my blood pressure goes up going from a supine to standing position, and I never have bouts of syncope or near-syncope. I have air hunger, requiring a fan at night, even in winter. I must sip on a slightly sweetened decaff ice tea (2.5L) throughout the day, or I become agitated and shaky. I have urinary frequency, without any structural anomalies; that has become a significant problem. My sister and two of my four sons, ages 13 and 29, have also demonstrated some symptoms now, one son being disabled with chronic daily migraine. My neurologist initially agreed to do testing for mito disease. The blood work and urinalysis were negative, as well as an MRI spectroscopy, and my insurance (Medicare and Medicaid) would not cover any further testing. Are there any valid reasons to pursue a muscle biopsy/ LP/ skin biopsy at my own expense? My sons’ physicians know little about this, and are not willing to investigate their situations at this time. Are there any treatments that would result, if these tests were diagnostic of mito disease that could improve my life, or that of my sister or sons? I am no longer physically able to travel for specialists’ evaluations, and any suggestions you might have would be invaluable.

A: 5/11/04
Often, patients like this woman with complicated medical problems are suspected of having a mitochondrial disorder. POTS and other severe autonomic system abnormalities are not common in mitochondrial disorders. Nevertheless, in Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE) gastrointestinal dysmotility has been attributed to both autonomic dysfunction and smooth muscle abnormalities.

Certainly, this person has clinical manifestations that are typical of a mitochondrial disorder: ophthalmoparesis, an atypical stroke at a young age, tremor, gastrointestinal dysmotility, hypersomnolence, and fatigue. The "negative" blood work and MRI spectroscopy make the diagnosis of mitochondrial disease less likely. Nevertheless, muscle biopsy would be important to further evaluate the possibility that she has a mitochondrial disorder. Ideally, the biopsy should be performed at a major medical center with expertise in evaluating muscle for mitochondrial abnormalities. A less optimal option is to have the biopsy performed at a local hospital and samples shipped to a major mitochondrial clinical center.

There are very few therapies that directly treat mitochondrial dysfunction. For example, patients with primary deficiencies of coenzyme Q10 or carnitine can be treated with nutritional supplementation of these compounds. Nevertheless, it is important to make the correct diagnosis of a mitochondrial disease for proper genetic counseling and for symptomatic management of the disease manifestations.

Answered by: Michio Hirano, MD

Q: Is there any evidence that children with mitochondrial diseases are more sensitive to medication side affects. Our daughter seems to develop the low incident side affects to seizure medications and ADD medications. We wondered if any of this could be related to her having a mitochondrial disease?

A: 5/4/04
To answer your question directly, I am not aware of any published studies that indicate that patients with mitochondrial disease are more sensitive overall to the side effects of medications. Having said that, because I do not know specifically which medications your daughter had difficulties with, and what type of side effects she is experiencing, my answer can only be in general terms.

Some patients who have seizures associated with mitochondrial disorders can experience intractability, ie the inability to control the seizures on usual dosages of anticonvulsants. It is possible that such patients may require higher dosages of medications or combinations of more that one anticonvulsant given together. This certainly increases the chances of experiencing an adverse effect. I don’t know if this is the case with your daughter. Also, valproic acid (Depakote) can lead to mitochondrial dysfunction and may result in adverse effects. Likewise, other drugs that have the potential to interfere with oxidative metabolism involving the mitochondrial pathways, can theoretically lead to adverse effects even at low end dosages.

There is a UMDF monograph detailing the risk of certain anesthetics that should be avoided in patients who have mitochondrial disorders due to suspected or known inhibition or interference with mitochondrial function.

Because there is such clinical, biochemical, and molecular diversity in mitochondrial disorders, it is likely that some patients will experience difficulties with certain medications.

Answered by: Andrea Gropman, MD, FAAP

Q: My 8 year old son has mitochondrial myopathy via a muscle biopsy. He has 10 teeth that have very bad decay, and also needs his top 4 teeth removed. Is there a connection between mito and poor teeth? If so, please explain. I have always brushed his teeth but it didn't help the decaying of his teeth.

A: 4/22/04
I am sorry to hear about your son. I do not know of a direct connection with mitochondrial induced dental decay. There may be a problem with pooling of secretions and poor swallowing mechanics due to muscle weakness and incoodination (from the mitochondrial disease) which may lead to dental problems. Some patients with mitochondrial dysfunction often have immune problems, not able to fight certain bacteria or viruses well. This might also have an impact on dental caries, albeit indirect. I have seen severe caries happen in some of the patients that I am allowed to care for. So, although you brush your son's teeth faithfully, the poor swallowing and pooling of his secretions, and maybe poor immunity may foil your good intentions.
Answered by: Russell Saneto, DO, PhD

Q: Our son has been diagnosed with complex I and complex II mito. Now our 24 year old daughter is having issues. She had cataracts on both eyes by age 21; she has migrane headaches and now last week she came down with some serious stomach virus and was very sick for two days. While she was still sick she complained of her legs going numb and now having recovered from this virus is having extreme pain in the front of her lower legs when she walks. She also is having trouble writing. This has all come on just in the last week since she contracted this virus. What should we be doing from here for her?

A: 4/22/04
I suspect that her symptoms are due to peripheral neuropathy. She could have had a pre-existing (peripheral) neuropathy that was worsened by the viral syndrome, or the neuropathy could have been caused by the infection. Febrile illnesses (e.g. viral infections) can cause acute worsening of mitochondrial disorders such as MELAS. I recommend that the patient be evaluated by a neurologist with experience treating mitochondrial disorders and peripheral neuropathies. There are many potential treatments for painful neuropathies.
Answered by: Michio Hirano, MD

Q: My daughter has mitochondrial encephalopathy. When she has an exacerbation she has psychosis. Even when she is not in "crisis" she is showing symptoms of dementia. Does anyone have experience with Idebenone as a treatment for mito? How much is used and how often? How effective is it? Does it replace CoQ10 or is it used in addition to it?

A: 4/22/04
Cognitive signs are not unusual in mitochondrial diseases. I would not
recommend replacing coenzyme Q10 (CoQ10) with idebenone. CoQ10 is
safer and probably more effective. However, CoQ10 has to be taken in
high doses (minimum 400 mg/day). The dose can be increased up to 1,000
mg/day if necessary. There are no known or reported side effects of
CoQ10, even at high doses.
Answered by: Salvatore DiMauro, MD

Q: My question is, How do you know when it is time to start considering getting a Medical Stroller? My son, who is almost 5 years old, has an unspecific Mito disease. He can walk yet has AFO's and has always had a awkward gait. Yet in the last couple of weeks he is having to be carried around more than not. If he walks more than just a short distance, his legs buckle, he falls and then is just exhausted the rest of the day. He tells us "his batteries are run down". That is really hard to hear at his age. He is too big for normal strollers and to ride in the shopping carts. He weighs 41 pounds, which realy makes it hard to carry him around, but we do. I knew we would get to this point sooner or later, yet I thought it would be much later. How do we know when it is time?

A: 4/21/04
When the neuromuscular handicap reaches a point of severity, even intermittently (but persistent), that it interferes with daily living or the well-being of mother, father or other caregivers, then it is necessary to obtain a medical stroller or comparable device. By neuromuscular, we mean that the muscle strength is decreased because of poor metabolism in muscle mitochondria, the nerves in the arms and legs are damaged and/or the messages coming from the brain or spinal cord to the muscles are absent or uncontrollably exaggerated. Sometimes, all of these malfunctions are going on at the same time, but one or all may be especially out of control on certain days leading to an almost state of muscle paralysis. We can't always predict when this might happen, but in some children the "leg buckling" or "exhaustion" may appear or get worse during an infection. It is important to have those helper-devices at home during those times to allow the child to get around, participate in activities, etc. and to prevent exhaustion and disability in mom or dad. Don't wait until the child is persistently paralyzed to get help even if that is the natural course of events in a particular patient.
Answered by: Gerard T. Berry, MD

Q: I am an early intervention therapist and have 2 kids on my caseload who have been recently diagnosed with as of yet unspecified Mito. Disease. Two questions: 1) Are there usually distinguishing features in toddlers who are diagnosed with the disease and 2) Is a global lack of language/following directions common with this disease? Both of these children have made fairly good gross motor improvements, but they are both so delayed in language and cognitive development.


A: The question is a very general one and without more specifics I can only state that mitochondrial diseases can present in many ways, even in toddlers, from pure myopathy to neurological deterioration (Leigh disease type) to systemic disease. The UMDF website descriptions would give some ideas on this variability. The speech delay is common in affected infants and may be due to central neurological, neuromuscular or pure muscular problems and may be global or more expressive or receptive. The prognosis is very variable depending on the child, the severity of disease and of course the therapy instituted. It is possible that the prognosis may vary depending on the underlying specific cause but I don't think we have the data for that. In this cases it seems the language delay is part of cognitive impairmant but of course, hearing loss may be a factor in mito diseases and ABRs(BAERs)/audiograms should be monitored as this may affect speech progress.
Answered by: Annette Feigenbaum, M.D., FRCP

Q: I was diagnosed with mitochondrial myopathy (probable) three years ago. I have been fairly healthy until this December. I was diagnosed with mono and have not been able to bounce back. I have high calcium and magnesium in my 24 hr urine tests and my Taurine, histidine and ornithine are all low, and my phosphoserine is high. Could these levels have anything to do with mitochondrial myopathy? I have contacted my mito doctor who wants me to have a muscle biopsy but will not even be scheduled for another 4 wks. I have already lost my job.
I am also very weak, I get shaky, anxious and uneasy feeling and being in a car makes me feel very sick.

A: 4/15/04
The important issue here is to establish a diagnosis - without a definite diagnosis advice is difficult. The muscle biopsy would seem appropriate and important with the information I have been given if advised by a physician. I am not aware that mitochondrial myopathies induce changes in calcium or magnesium, or the changes in amino acid metabolism. These could be unrelated or suggest an alternative diagnosis.

Answered by: Douglass M. Turnbull, MD, PhD

Q: I am getting ready to get my son's kindergarten shots in the next couple of weeks. I have read that immunizations can cause problems in Mito kids. We have always done fine in the past, just ran a pretty high fever of 103 for about 24 hours. Is it just a fluke thing that happens in some Mito kids, or can it be common? I am really kind of concerned. We do not have a Mito doc that could explain it to me.
I would like to know what to watch for.

A: 3/24/04
The medical literature has absolutely no articles on immunizations/vaccinations in individuals with mitochondrial disease. In the absence of any studies, there is only clinical experience and opinion. Personally, I know a few cases of severe complications following routine immunizations in children with mitochondrial disease, generally in those who were later diagnosed as such. However, in almost all of these cases the child stopped eating because of feeling ill, and I believe that most of the complications were actually provoked by fasting. Fever may be more common following immunizations in mito kids than in children in general, possibly because abnormal autonomic nervous system responses (dysautonomia) are very common in mito disease. Of course, febrile children are fussy and may not want to eat much. Since immunizations protect against serious diseases that could really cause complications if a mito kid were to get them, and because of my own clinical experience in that over a hundred mito kids safely received immunizations when certain precautions were taken, with my own patients my practice is as follows:

Immunizations act like common viral infections in that they can cause a child to have fever, nausea, poor appetite, and/or malaise (generally feeling bad). At these times, pay extra attention that your child is getting adequate calories. Fruit juices are one option to get quick calories in a child who is eating poorly. Fever increases energy demand, and should be treated with the proper amount of acetaminophen (Tylenol, etc.) or ibuprofen (Advil, Motrin, etc.). Seek prompt medical attention for continued vomiting, inability to take almost any calories for over 24 hours, and especially for lethargy (excessive tiredness) or an otherwise altered behavior (including excessive fussiness, confusion, etc.). Occasionally, IV fluid with D10 (10% sugar) may need to be given.
Any mito kid with a severe immunization reaction in the past should probably avoid immunizations altogether.

Answered by: Richard G. Boles, MD

Q: Is spasticity a symptom of mitochondrial disease? I am asking because I thought it was hypotonia.

A: 3/5/04
Certainly spasticity can be a feature of mitochondrial disease - it really depends which part of the nervous system is affected. If the brain is affected then it usually leads to spasticity, whereas if the muscles are affected it leads to hypotonia.

Answered by: Douglass M. Turnbull, MD, PhD

Q: The field of mito disorders is one in which not many medical professionals specialize. This makes it frustrating as a parent when new progression of this illness occurs. The local pediatrician refers on to the neurologist, who after finally getting in refers to the mito specialist, who is hard to get an appointment with because of all of the referrals. If it is not an immediate life-threatening issue, but serious indeed, what should a parent or adult mito patient do to resolve the situation? Should we research and find a solution ourselves or call the local pediatrician or neurologist or specialist? Do you feel more Doctors will begin to specialize in this field in the future? What could parents do to get the word out to more physicians about patients’ needs without coming across as pushy?

A: 3/3/04
I am sorry that you are having difficulty in finding physicians who both understand and try to care for patients with mitochondrial disease. Unfortunately, you are among a growing population of patients and their families. When I was a fellow in Cleveland, the nurses and physician assistants who worked for Dr. Bruce Cohen did a survey which suggested that the average number of physicians that a patient with a mitochondrial disease went to before a diagnosis was made was seven! From what I have seen in my practice, it seems like the diagnosis requires fewer physicians today then when I was a fellow (which isn't that long ago). However, the number of physicians actively taking care of mitochondrial disease is still limited. Reasons for this state of affairs are numerous. The disease as an entity is young, the first mitochondrial DNA mutation was only discovered and described in 1988. It is so young, that there isn't even a specific ICD-9 code (what we physicians use for billing and the government and researchers use to track diseases) for mitochondrial disease (there was a nice article in Newsweek several months ago describing this fact). There are no specific fellowships for young physicians to get quality training. Things are beginning to change. For instance there is a proposed Fellowship to be created between Stanford University and Oxford University in England to train quality fellows in this area. Things are evolving and in time, I believe that more physicians will track into this field of medicine. We in the field need to address these issues more aggressively, creating an atmosphere of creative and intellectual curousity that attracts more people into the area, providing more funding for young physicians to attend meetings where mitochondrial disease is discussed, and giving of our time and energy to help organizations such as UMDF to spread information concerning the disease.

However, this doesn't answer your current needs for your child. I think there are several ways to approach the medical care of your child. One is to meet (however long it takes) a mitochondrial specialist who will work with your primary care physician to help manage parts of your child's medical care as it pertains to mitochondrial disease. Read as much as you can, ask as many questions as you have, and learn what kind of medical care pertains to your child's particular mitochondrial disease. Develop action plans when illness occurs, such as IV hydration during an illness or glucose containing IV fluids during catabolic states. Since you probably know more about the particular mitochondrial disease your child has, gently begin teaching your primary care physician concerning your child's disease. Care is needed as the information needs to be factual and not just "what you got over the internet". Certainly, you will find resistance. Most physicians have a desire to care for their patients and you will find that many will educate themselves in this disease as they take care of your child.


Support the physicians and researchers who are interested in mitochondrial disease, such as UMDF or local interest groups. Develop parent support groups. The task is endless, and in the end one can only do his/her best. As you take care of your child, others will notice your care and love. That will be the most attractive ingredient to gain support for this disease.

Answered by: Russell Saneto, DO, PhD

Q: I have been diagnosed with Leukemia. Is that common to have a mito disease and cancer?

A: 2/16/04
To my knowledge, there is no published evidence for a mito patient with cancer. However, given the basic science of mitochondria it is possible.

Answered by: Keshav Singh, PhD.

Q: Can you please address some issues in regards to behavioral problems related to mito disease?

A: 2/16/04
I have a broad response to this issue which is this: mitochondrial disorders can affect the brain, which can cause anything from headaches to encephalopathy to seizures to dementia to learning disabilities to behavior problems to sleep disturbances, etc. The problem that some psychiatrists have in treating these children and adults is that they do not neatly fit into a DSM-IV criteria (Psych Diagnostic Manual), and the drugs have been designed with these criteria in mind (i.e. major depression, anxiety disorder, etc.). In neurologic disorders though, it is important to treat the symptoms even if they do not neatly fit into a psychiatric category of diagnosis. These symptoms include aggression, self-stimulatory behavior, insomnia, hyperactivity, and inattention. These not only occur in mito disorders, but commonly in epilepsy, tuberous sclerosis, Rett's syndrome and many other disorders that affect the brain.

It is going to be hard to recommend certain drugs because each case is so individual. For aggression, I have used tricyclics which also treat sleep problems, neuropathic pain, GI symptoms and headaches; alpha-agonists such as clonidine and tenex which also treat hyperactivity and sleep but can cause rebound hypertension; SSRIs such as Prozac; antipsychotics such as Risperdal or Zyprexa which can help with comorbid movement disorders and sleep but can cause weight gain. For sleep I try melatonin, chloral hydrate, Tranxene, or Ambien.
If a patient has a seizure disorder that is not well controlled, I first try to see if an anti-epileptic drug can be used for the problem first; Neurontin is a good example because it can be used for sleep, mood stabilization, neuropathic pain, GI symptoms. Tranxene is another good example. I continue to avoid Depakote for seizures and behavior. If the behavior problems are really severe, I try to refer the patient to a child psychiatrist rather than sub-optimally treat him/her myself.

Answered by: Amy C. Goldstein, MD

Q: Our son has an unspecified mito disorder. He has difficulty with hearing, not profound - but enough to interfere with his daily life. He has atrophy of both cerebellum and had an episode of non-specific swelling, fluid and lesions on his brain when he was four. An EEG/hearing test was done after recovery and it showed a slowing of the signals when it reached the brainstem. We would do something to help his hearing if we could, so my question is: would hearing aids or anything else be helpful since the problem is at the brainstem and not the ears themselves? Is this common among mito disorders, particularly if the brain is affected?

A: 2/16/04
Hearing loss is not rare in mitochondrial disease. Regarding treatment options, you need to contact a hearing specialist (ENT). Cerebellar atrophy is common in congenital defects of glycosylation - were these disorders tested for in your child?
Answered by: Richard G. Boles, MD

Q: Our ten year old son has an unspecified mitochondrial disorder,
with possible dysautonomia. He has had high levels of CO2 during
the day and at night. This has been causing frightening symptoms,
particularly at night. He is now using a bi-pap machine at night,
but we have not noticed a difference. Should we be more concerned
and aggressively going after this or will the bi-pap help in time?
Is high CO2 harmful to his development? Among the symptoms we have
noticed, he is mentally regressing in his academics and physical development. Is CO2 in mito disorders related to lactic acidosis?

A: 2/11/04
Children and adults with muscle disorders, including mitochondrial cytopathies, will often experience difficulty with retention of C02 in sleep due to weakness of the diaphragmatic muscles. For this reason CPAP or Bipap is often recommended. These patients may come to clinical attention due to increased day time sleepiness, snoring, or multiple night time awakenings. On examination, there is evidence of muscle weakness and sufficient evidence and concern to believe that the respiratory muscles may be involved. There is also a condition known as central apnea independent of muscle weakness, in which the brain does not handle CO2 signals properly and does not tell the lower brain centers to breathe in certain way in response to an elevated C02. In these conditions, CPAP or BiPap may not be as helpful. Since I do not know your child’s history in detail, I can only answer on generic terms.

CPAP/BiPAP acts as a pneumatic splint to the upper airway, serving to maintain airway patency, preventing the airway collapse associated with obstructive sleep apnea. A sleep study can determine to what extent a central or obstructive apnea is present, and follow up sleep studies on BiPap should be done to determine if there is reduction in number of apnea episodes. Hypopnea or insufficiently taking deep breaths (either due to aberrant brain signals in central apnea, or weak muscles, or obstruction) leads to CO2-retention with consecutive loss of consciousness demanding mechanical ventilation. Patients with Mito disorders tend to have lactic acidosis, which is related to difficulties with aerobic energy metabolism on a cellular level.

Answered by: Andrea Gropman, MD, FAAP

Q: I was recently diagnosed with a mitochrondrial myopathy via a muscle biopsy. The muscle had been rapidy frozen and stained with H&E, modified Gomori Trichome which indicated there were these ragged red fibers suggestive of a mitochondrial myopathy. I have had muscle fatigue and cramps for months, and just overall fatigue. I have had an issue with my kidneys dumping protein in my urine for about two years. I also had a reflux problem corrected by surgery about 9 years ago. Do I get another biopsy for a second opinion? Can a sample of this recent biopsy be used for further genetic studies or tests?

A: 2/6/04
It shouldn't be necessary to get another biopsy. If you haven't done so already, you should get a referral to a specialist in mitochondrial diseases rather than just a regular neurologist or physician. I would recommend doing this even if you have to travel interstate to do so. They should be able to evaluate your symptoms and the results from your biopsy to determine whether they are just "suggestive" or definitive. It may be that further testing for mitochondrial DNA mutations or respiratory chain enzymes is required to confirm your diagnosis or to make it more specific. Hopefully the lab that did your muscle biopsy will have retained some of the sample. If so, that should be suitable for DNA testing and perhaps for enzyme testing. If not, then you would need to discuss with a mitochondrial disease specialist whether further testing could be done on blood or if you did need a second biopsy.

Answered by: David R. Thorburn, PhD

Q: I am a 47 year old female who is positive for 3432 mutation, MELAS, and recently they have found lactate levels in my basal ganglia on MRI,spectroscopy. I also had a blood test for lactic acid which was 15 (normal is 3-12). My question is: is this indicative of impending full blown MELAS or, in you opinion, have you seen this before in someone without the disease?


A: January 28, 2004
I would like to reassure you that many people with the 3243 MELAS
mutation have elevated lactate levels in blood and in the brain
(based on magnetic resonance spectroscopy [MRS]); however, few of
these individuals develop "full blown MELAS". My colleagues, Drs.
Petra Kaufmann, Salvatore DiMauro, Dikoma Shungu, and Darryl De Vivo
will soon publish a paper describing increased lactic acid in the
brains of patients with MELAS and their oligosymptomatic (i.e. less
affected) relatives. Furthermore, the fact that you are 47
years-old, and presumably have not had any stroke-like episodes,
indicates that you are unlikely to develop MELAS. Nevertheless, you
should be followed carefully by an internist, since you could
develop milder symptoms including hearing loss and diabetes.
Answered by: Michio Hirano, MD

Q: My son who will be 5 years old in March,has been diagnosed with a Mitochondrial Disease, yet what kind is unknown.
My Question to you is how do you diagnose each specific disease?
My son who was born full term, healthy we thought, left the hospital after two days, as normal, yet started showing signs right away.

The following are his symptoms:

chokes on liquids, GERD, Stridor, diagnosed with Larynomalamia(floppy voice box),
Profuse sweating at night, Colic, Awkward Gait, falling, AFO's, Speech delays,
O.T delayed, Sensory Integration and Crossing Midline problems, Hypotonia,
Had Tonsils and Adenoids removed at 10 months of age, spent 6 days in I.C.U on respirator,
Muscle biopsy showed: elevated Citrate Synthase, Succinate Deydrogenase, Lactic Acids were at 3, Pyruvic Acids were.210
But normal Acylcarnitine and Organic Acids, Developmental delays, Acid Reflux, Lordosis,
Asthma, Has Heart Arrythmias, yet heart on Ecco looks normal,
Very low energy as day goes on, worse after therapy, light sleeper,
Heat intolerence, severe, will run high fever, Has had two minor seizures, Leg cramps,
Poor body awareness and ability to negotiate obstacles, Auditory processing problems, Headaches.
I'm sure I am missing several but this is what has come to my mind.
Does any of this or all of this sound like a specific Mitochondrial Disease?
Are Arrythmias common? And what are they caused by if the heart looks fine?
Is Larygiamalcia common? Is Stridor common?


A: January 28, 2004
Each specific disease can be difficult to diagnose. Some of the disorders have specific features, but we have learned that each person with a disorder is unique. Not all people affected with the same disorder will have the same symptoms. We call this a genotype-phenotype correlation. The differences are due to factors such as the number of affected mitochondria, what the specific defect is (deletion, point mutation, etc.) in the mitochondrial DNA or in the part of the mitochondria not working, and what organs are affected. When three or more organ systems are involved, as in your son's case, (GI, Neurodevelopmental, cardiac) mito disease should be suspected. Many of his symptoms are typical. His laboratory investigation suggests mito proliferation (higher in number) with the elevated citrate synthase, but is non-specific to one disorder. Sometimes the disorder can be identified further, through testing for complexes in the electron transport chain, or in further genetic testing.
Arrythmias can be seen with mito disease, as can cardiomyopathy. Arrythmia is an electrical problem in the heart, so it is not unusual for the heart to look normal. When structural abnormalities are seen on echocardiogram, it can lead to arrthymias. It is similar to the brain having seizures even if the MRI of the head looks ok.
Laryngomalacia can cause stridor due to narrowing of the airway. This may be secondary to the GERD, but can be seen in many children without mito disease. It is more unusual for the airway and pulmonary system to be directly involved in mito disease, but can be seen.

Answered by: Amy C. Goldstein, MD

Q: I have a son who is 4 years old with an unspecific Mito Disease. He has had a Heart Arrythmia appear on two different EKGs, constant through a sleep study and in his Ecco just last week. Our doctor said the heart looks fine other than the Arrythmias. He doesn't seem to know much about Mitochondrial disease, and did not do anything about the Arrythmia. Should we be more concerned? I hear it is common in Mito kids, but everyone I have talked to is being treated for their Arrythmias. What should we do???

A: January 23, 2004
I am sorry to hear about your son's cardiac arrhythmia. Yes, many mitochondrial patients have cardiac arrhythmia. Whether or not your son needs treatment depends on the type of arrhythmia found on examination and the possible etiology. For instance, arrhythmia may represent rates that are too fast, or too slow. An example of a heart rate that is too fast is atrial fibrillation. This is characterized by an extremely fast atrial rate and irregularly irregular ventricular response with normal QRS complexes. This requires treatment, which may be medical or shock treatment. Arrhythmias may represent subtle changes in the shape of the P wave (one of the waves seen in cardiac conduction) and PR interval (the time between the P wave and QRS). This latter is called a wandering atrial pacemaker and is benign and does not need treatment. Another type of abnormal rhythm is called premature ventricular contraction (PVC) and is a bizare, wide QRS complex appearing earlier than anticipated and the T wave points in the opposite direction (types of electrical waves seen during the time the heart contracts and relaxes). There are various types of PVCs. They may appear in otherwise normal children, up to 50% to 70% of normal children may show PVCs on a 24-hour ambulatory ECG. So, the type of cardiac arrhythmia dictates the treatment or if treatment is necessary. It may be that your son has one of the types of arrhythmias that does not need treatment. If you are concerned, you might want to have a further discussion with your pediatric cardiologist.

Answered by: Russell Saneto, DO, PhD

Q: In the booklet "Think Mitochondria" page 3, under lab evaluations, it states "low BUN indicates failure of urea acid cycle, (either primary or secondary)". I was diagnosed as having mitochondrial myopathy and a carnitine deficiency in 1999. During a recent hospitalization (had a virus) my BUN was 2, (range 8-25), creatinine 0.6 (range 0.6-1.4) and B/C ratio was 3 (range 10-28). At different times during the hospitalization the BUN ranged anywhere from 2-4, creatinine ranged from 0.4-0.6, the ratio ranged from 3-10. The hospital physician indicated that he had no idea why the BUN was low and what, if anything, it meant. Is having a consistently low BUN something that indicates a need for further evaluation and if so by what type of doctor? Where can I find more information on the urea acid cycle, what it is and what it does?

A: January 20, 2004
There are many causes of low urea. One of the most common is poor Nutrition, especially poor protein intake/stores- a common problem in people with chronic conditions. I see the creatinine is also low- an indicator usually of poor muscle bulk/stores but it in itself will not cause a problem. I think it unlikely that an adult would have an undiagnosed urea cycle defect as this usually causes major problems- more information is on the web at If your doctor mentioned urea cycle defect perhaps he already checked for it - this is relatively easily excluded by doing a plasma ammonia level, amino acid analysis and if there is still suspicion a test called a urine orotic acid level. Otherwise without further details I do not consider it a cause for concern.

Answered by: Annette Feigenbaum, M.D., FRCP

Q: Our 10 month old son was diagnosed with Leigh's Disease at 5 1/2 months (he is our first child). His pediatrician sent us to specialists because of his somewhat sudden weight loss, severe hypotonia, and developmental regression. A diagnosis of Leigh's Disease was made from a head CT and MRI. He has continued to regress since then and has severe infantile spasm seizures that have not responded to Topomax or Zonegran. We now sedate him with Clonazepan 3x a day and use Diastat when his seizures are prolonged. We are attempting to identify the cause of the disease and have so far had not had any success.

A muscle biopsy (thigh muscle) was examined via electron microscopy. The mitrochondria appeared normal. No abnormalities were found in the respiratory chain complexes.
The blood test for mitochondrial DNA mutations: MELAS, MERRF, NARP, KSS, and LHON, were all normal.
A skin biopsy tested negative for PDH & PDC (E-alpha 1,2,3).

We understand that the muscle biopsy does not rule out a mitochondrial cause due to 'load & distribution', and aside from post mortum examination of affected tissue (i.e. brain- basil ganglia/thalamus) we have been told that at this point no other clinical testing is available and further testing would be on a research basis. Are there other tests that you are aware of? If not, and we are left with the 'research' possibility only, how does one go about pursuing that? We understand this will not affect the outcome of our son's situation, but we would like to identify the cause to better understand the potential for reoccurrence and potentially to pursue PGD (pre-implementation genetic diagnosis).

A: January 14, 2004
The diagnostic work-up performed to date appears rather complete. However, some additional testing, either established or investigative, might be appropriate. I recommend that you consult an expert in mitochondrial disease to review the case, including the history, family history, biochemical laboratory testing, biopsy results, neuroimaging, and DNA analyses.

However, your questions do bring up several general issues that may or may not apply to your family. First is whether mitochondrial disease is the appropriate diagnosis for your son. In your son's case, as in many others, there is evidence both for and against a diagnosis of a mitochondrial disorder; the imaging is read as Leigh disease, a mitochondrial disorder, but the normal muscle enzymology (respiratory chain complexes, PDH & PDC) suggests otherwise. In some other cases, a positive DNA or enzymatic test by itself establishes the diagnosis. However, in many other cases, there is no "smoking gun", and the diagnosis is made by an experienced clinician based upon the preponderance of clinical, biochemical, enzymatic, imaging and molecular data. Often, this issue is not fully resolved even following extensive testing, and a diagnosis of a "possible" or "probable" mitochondrial disorder may be given. Unfortunately, sometimes the experts themselves cannot agree. Thus, it may not be currently possible to determine with certainty whether or not your child has a mitochondrial disorder.

Research testing is itself a broad topic. The term applies that the researchers are performing the test as part of an ongoing scientific investigation, and not for a fee. There are many practical limitations, including that the patient must meet eligibility criteria approved by a Human Subjects committee. These criteria are usually preset and can be rigid. What research studies are available depends a lot on timing and what ongoing investigations that your doctor is aware of. Much research is being performed on Leigh disease, but given the normal enzyme studies, this one doctor is not aware of any studies that your child would qualify for given the information presented here.

Based upon the limited information available, recurrence risk estimation is very difficult, if not impossible, in your family. The infantile onset of severe disease is often thought of as indicating autosomal recessive inheritance, and with it a 25% recurrence risk per additional full sibling. However, maternal (mitochondrial DNA-related) and other inheritance models can still apply. A few years ago, I co-authored a paper on infantile spasms and mitochondrial disease. I mention this because a set of identical twins with severe infantile-onset disease, and what appeared to be an otherwise negative family history, turned out to have the A3243G (MELAS) mitochondrial DNA mutation. Thus, I would tend to be cautious regarding the determination of the inheritance pattern in your family. Unfortunately, this may mean that the recurrence risk estimate is as broad as near zero to near 100%. Details in your family history not listed here (such as multiple normal siblings) would potentially modify this risk.

Answered by: Richard G. Boles, MD

Q: I am just curious your explanation for a patient that has had 2 fresh
muscle biopsies in known mitochondrial labs, and one showed defects in
all complexes (although no known mutation was found), and the other
showing completely normal. This is a patient with severe developmental
delay, seizures, GI issues, etc. One lab claimed there might have been
mishandling of the lab and the other claimed their lab was correct. Can a patient of mito have no defects shown if they have mitochondrial
disease? In the positive lab, the complex one level was 0. In the
negative lab the complex 1 level was high. This seems confusing to me
and leaves me wondering where to go.

A: January 13, 2004
It is clearly very frustrating to get results from two different labs that appear to be in total disagreement. Unfortunately, this is not the first time I have been asked about such an occurrence and without seeing the lab reports and having a detailed knowledge of the labs and methods used it is impossible to determine which lab is correct, or (at least in theory) if both may be correct. Your best option is probably to ask an independent lab expert whether they will look at the clinical story and both lab reports and see if they can give an opinion.

In general there are several possible reasons for discrepant results of respiratory chain enzyme assays. Some possibilities are:
1) Real biological variation. If the patient does have a mitochondrial DNA mutation, it is theoretically possible that two biopsies obtained from different muscle sites or at different times could have a large difference in heteroplasmic load. For example, in one the proportion of mutant DNA might be above the threshold needed to cause an enzyme defect and in the other there could be enough healthy DNA to maintain normal activity.

2) Methodological variation. Different labs often use very different methods to do their assays. For example, we measure complex I directly using the "NADH-CoQ1 reductase" assay. This assay uses an electron acceptor (CoQ1) that is more water soluble than the natural electron acceptor (CoQ10). Some labs use a different assay, "NADH-cytochrome c reductase", which measures both complex I and complex III together using the natural electron acceptor (CoQ10) present in the muscle biopsy itself. There are advantages and disadvantages to both assays. We feel our assay is more robust and less prone to artifactual low activity, particularly in frozen biopsies, if the sample handling has not been optimal. However, since it uses an artificial electron acceptor, it is theoretically possible it could give normal activity for an abnormality that affects binding of just the natural electron acceptor.

3) Artifacts caused by improper sample processing or inexperience in
testing pathological biopsies. One has to be alert to problems with sample processing leading to aberrant decreases in enzyme activity. An experienced lab tends to know the patterns of enzyme activity that suggest this may have occurred. For example, we are always somewhat wary of samples that show low activity of complex II or of all complexes. Although such results can be real, they may be more likely to be an artifact, and should prompt reconsideration of whether there could have been a problem.

4) Human error. Although diagnostic labs have stringent procedures to
minimise the risk of mistakes being made it is unlikely that any system can be 100% fool-proof. Even with really good staff this has to happen occasionally, eg. when someone is interrupted at a crucial stage and perhaps leaves out a reagent (giving a false positive enzyme defect) or mixes up samples (potentially giving a false positive or negative enzyme defect). Most labs try to be alert to this, for example by doing replicates in different runs, always having a normal control, keeping leftover sample (in case an assay needs to be repeated &/or confirm it is from the expected patient using a forensic kit). But often there is not enough sample to repeat assays. So one might expect human error to contribute to an incorrect result, but probably in less than 1% of samples tested in a lab with proper pathology accreditation.

So unfortunately I haven't been able to give you a very satisfactory
answer. Mitochondrial enzyme diagnosis is a highly specialised area. The enzyme assays require considerable expertise to perform reliably and false positive and false negative results are both a concern. My impression is that false positives are a worse problem in labs without a major diagnostic and research emphasis on mitochondrial disorders, since such labs tend not to gain the experience of obtaining enzyme results on large numbers of patients also found to have nuclear or mitochondrial DNA mutations. It could be argued that false negative results occur in all labs, since the available methods don't allow us to recognise every type of mitochondrial problem. Our attitude is that it is very difficult to absolutely exclude a mitochondrial disorder and we like to use diagnostic criteria that emphasise the need to obtain strong evidence from at least two independent sources (eg. clinical, enzyme, pathology, DNA, metabolic) for a definite diagnosis.

Answered by: David R. Thorburn, PhD

Q: I was recently told by another parent that mito patients should avoid a type of antibiotic called an aminoglycocide antibiotic. I was never told this by any of my doctors and am wondering if this is the case for all mito patients and also what are the household names of this type of antibiotic so I can be aware of those to avoid?

A: This is an excellent question, with a somewhat complex and multipart answer.

It is known that some specific mitochondrial DNA mutations found in some families do increase the risk of developing hearing loss when exposed to aminoglycosides. This appears to be due to the similarities between our mitochondria and some important systems in bacteria. Aminoglycoside antibiotics fight bacteria by damaging bacterial systems that are similar to mitochondria. Some people have mitochondrial DNA sequences that make their mitochondria more susceptible to damage from the aminoglycoside action. Those individuals should therefore avoid aminoglycoside antibiotics whenever possible.

Of course this does not mean that all people with mitochondrial disease are at increased risk if exposed to aminoglycosides. For example, we do not know a mechanism that would increase the risk of aminoglycoside exposure for those people in whom mitochondrial disease results from changes in nuclear genes.

Despite concerns about risk, it is not always possible to avoid aminoglycosides. They are used intravenously for treating a variety of serious infections. Sometimes there is no substitute, and these drugs may need to be used intravenously in a hospitalized patient to save life.

Aminoglycosides are sometimes used orally to sterilize the intestinal tract, but since they are poorly absorbed this has not been reported to be associated with deafness. They are also commonly used topically (on the skin) or as an ointment for infections of the eye and again they are poorly absorbed; there are no reports of deafness resulting from use on skin or eye.

There are more than one kind of aminoglycoside, and there are many brand names and chemical names including streptomycin, gentamicin, tobramycin, neomycin and amikacin. Preparations of gentamicin and neomycin especially may be found for use on the skin or the eye, and neomycin is especially used to sterilize the intestines. Not all antibiotics that end in "micin" or "mycin" are aminoglycosides.

Aminoglycosides are not the only antibiotics that can cause deafness. It is important to remember that all medications (and all natural or "herbal" products from which many of our drugs are derived) have a risk of side effects such as hearing loss. Every individual is unique and genetic factors - including mitochondrial variations - help determine how we react to drugs. In addition, some individuals with mitochondrial disease can develop hearing loss even if they have never been exposed to any of the antibiotics known to increase risk of deafness. Only time and further research will help us to understand better exactly which people with mitochondrial disease are most at risk for deafness, and what we can do to minimize that risk.

In order to know whether or not an individual with mitochondrial problems should or should not avoid aminoglycosides, very specific information is needed. For aminoglycosides - as with any medication or other therapy - each person should consult with a specialist who is familiar with their individual medical history.

Answered by: Carol Greene, MD

Q: I am 42 years old and was diagnosed with Mitochondrial encephelomyopathy. Next month will be three years. I have very bad joint pain and weakness on the left side and seizures. After the seizures, I lose the ability to vocalize and with very violent seizures I lose my memory for an indefinite period of time. I am on a host of meds for seizures and other meds. When I lose my memory it is like someone turns a switch off and turns it back on when my memory returns, and I lose that span of time. I can't remember anything that happened. Can you tell us anything that may be causing all of this or why it is happening or what we can do about it? It is so frustrating for my wife and myself.

A: I am sorry that you suffer from both seizures and mitochondrial disease. We have found that within our cohort of patients with mitochondrial disease, about 40% have epilepsy. As your question demonstrates, seizures can be very disabling. It sounds like you have what we call focal seizures; that is, seizures that start focally in one area of the brain and then spread. The speech area seems to be affected as you cannot talk after the seizure is finished. This is called postical aphasia. Very rarely can generalized seizures cause this phenomenon. Near the same area of expressive speech (Brocca's area), the structures (hippocampi) for imprinting memory are located. When a violent seizure happens, these areas are part of the "electrical storm" of a seizure and your memory is affected. We think that new memories have to be imprinted into our limbic/memory system by forming new synapses (connections between neurons). Seizures prevent this process from happening and newly formed memory may be lost. Most of all seizures that affect these areas (hippocampus) cause memory loss. When both hippocampi are affected, memory is lost to a variable extent. Memory can also be lost in generalized seizures as both hippocampi are affected as well as both cortical hemispheres. That is probably why you lose memory when a real violent seizure happens; both hippocampi are involved (and likely both cortical hemispheres). The only way to prevent this from happening is to prevent the seizures themselves. We rely on seizure medications to help prevent seizures. Often, many trials of various seizures medications are needed to find the specific medication that works the best. If seizures always start from the same small area then epilepsy surgery may be an option.
Answered by: Russell Saneto, DO, PhD

Q: I have mitochondrial myopathy and a carnitine deficiency. When my symptoms become severe and I am unable to walk or move my extremities, I have an unusual body odor that is also present in the urine. Increasing bathing from once a day to several times a day helps. The odor disappears when the symptoms get better. What causes this odor and what if anything can be done about it?

A: I do not know what causes the odor. Two possibilities exist in my mind:
1. The cause of your mitochondrial disorder is an organic acidopathy. I would suggest getting urine organic acids done when the smell is present.
2. The odor is a fishy odor due to carnitine conversion by bowel bacteria to trimethylamines which your body does not break down further. If this is the odor, a treatment of metranidazole 250 mg once daily for 10 days will likely get rid of the odor and hopefully for good. If not, you can repeat the treatment when the odor appears.

Answered by: Susan Winter, MD

Q: My family was diagnosed this past August by the southern blot test as having a Mtdna mutation T8993G Atpase 6. I am a few days shy of 31, and I have a 24% mutation and appear symptomless. My daughter is 5 and has a 84% and also appears symptomless. My son is a month from being 3 and has 82%, he has some developmental delay, speech delay, muscle weakness, hyptonia, but is very smart and functioning well. My other son is 1 and has a 95% mutation. He is the most affected with at first failure to thrive. That has changed, MRI abnormal-t2 weighted basil ganglia area, EEG abnormal, some seizure like activity but no med needed, developmental delay, hyptonia, but does appear to be gaining strength along with good weight gain, three pounds this month. My boys have OT, PT, home school teacher, soon aqua therapy. All my children are taking B50, coQ10, carnitine, Dha juniors, poly visol. With the supplements came improvement. Also diet change and increased calories for my 1 year old.
Here are my questions:1. Is there a good kids chewable or melt coQ10? 2.How do you feel about idebonone and who does it most benefit? 3. How do you feel about creatine and who does it most benefit? 4.My 1 year old seems to have this look close to Morrow Syndrome...his arms go up, he makes this little squeak, and his eyes look upwards and he has a frightened or freaked out look on his face. The EEG showed it not to be a seizure (2 hour EEG) and no one can explain it really besides just being brain abnormal function. Do you see this often in Leighs, or can you tell me what his little body is doing or thinking?

A: The mtDNA mutation T8993G (ATPase6) causes a change in Complex V, the last of the complexes of the respiratory or electron transport chain. A full review of the many symptoms of this mutation can be found on the OMIM web site, as it can be a cause of Leigh's phenotype (pathologic changes in the basal ganglia) and NARP (neuropathy, ataxia, retinitis pigmentosa). This mutation can be present in high amounts without becoming symptomatic, as seen in your asymptomatic 5 year old daughter. The reason for this is threefold: there is variation in mutant loads among tissues; (2) the mutant load in a tissue may change over time; and (3) the genotype/phenotype correlation is not clearly understood. (OMIM) A thorough pediatric ophthalmology examination is recommended as is a cardiac evaluation to rule out cardiomyopathy (dilation of the heart).
The most bioavailable form of Coenzyme Q10 on the market is a liquid available from Tischon company in New York. I usually prescribe half the dose to account for this increase in bioavailability (4 mg/kg/day instead of 8 - 10 mg/kg/day, divided in two doses). Idebonone most benefits children with Freidreich's ataxia, but the reports of using this as well as creatine is anecdotal in other patients with mitochondrial disorders. On creatine, kidney functions must be monitored closely. One of our goals is to scientifically investigate the usefulness of the supplements we prescribe.
The event that your one year old is having does sound similar to a "Moro reflex" or a startle response. The best thing was to rule out this being a seizure. It is probably myoclonus (a single body jerk which can be full body or isolated, commonly seen around the head and shoulders) which can be seizure or a movement disorder. Since he has changes on his MRI in the basal ganglia, I would think it is related to a movement disorder (like myoclonus) due to these changes on his MRI (Leigh's). Children with Leigh's can manifest different movement disorders (tremor, dystonia, myoclonus) since the basal ganglia are responsible for this function. If it greatly interferes with developmental progress or sleep, treatment may be possible (check with your treating physician).

Answered by: Amy C. Goldstein, MD

Q: How do I know when I have entered the "lactic acidosis zone"? What are the basic symptoms that are associated with high or toxic levels of lactic acid in the muscles?

A: It is difficult to know when you have high levels of lactic acidosis. The acidosis itself might make you a bit breathless. In the muscles people often feel pain and fatigue. Often patients with mitochondrial myopathy tolerate high levels without many symptoms over and above the fatigue and weaknes.

Answered by: Douglass M. Turnbull, MD, PhD

Q: My son is 27 and was diagnosed with Mitochondrial Complex III Deficiency soon after puberty. For several years now he has had chest pain and his fingers turn white and often purple splotches. He has been on meds for esophageal dismotility/heartburn and wears stockings for Lymphodema. He also goes to physical therapy regularly which has done wonders for him. But now, the coloring in his fingers and toes - even with the stockings - is getting worse. They turn very dark purple & cover most of his fingers & toes and his hands & feet are always icy cold. His primary care physician feels he may also have Reynauds Syndrome. Is this usual with Mito disease? Is there anything I can do about it? We live in the north & I have thought about moving to a warmer place but he cannot tolerate heat & humidity either. Should we see a specialist?

A: We sometimes see mitochondrial patients with a dysautonomic picture, which can include changes in blood flow to the extremities. This may result in changes in skin color: white to blue to red and finally back to flesh tone. Like in frank Raynaud Syndrome, it is often brought on by cold environmental temperatures, emotional stress or local trauma. This would also be manifested as the area being cold to the touch. Treatment is to avoid the triggers, if possible. Often the etiology of frank Raynaud's disease is not clarified in a particular patient. However, one needs to have the possibilities investigated and a visit to a rheumatologist is a good idea.

Answered by: Russell Saneto, DO, PhD

Q: I am 48, have had a myopathy for 9 years, which is now thought to be probably a mitochondrial myopathy (yet to be confirmed). Can massage be helpful in alleviating muscle ‘irritability’ and pain? What other treatments can you suggest to alleviate these symptoms? Endone can help with the pain but not always with the ‘gnawing’ feeling that comes with it.

A: In my experience, muscle pain is not a common feature of mitochondrial myopathies. Nevertheless, I have encountered a few patients with well-documented mitochondrial myopathies and severe pain. Sometimes the pain is associated with muscle cramps. Massage and stretching of muscle certainly can be helpful for muscle pain, particularly when it is due to cramps. Cramps can be alleviated by quinine. Pain medications (analgesics) such as Endocodone, are often useful. Generally, it is better to start with a non-steroidal anti-inflammatory drug (e.g. aspirin, ibuprofen, or celecoxib [Celebrex]) before using an opioid (e.g. meperidine [Demerol], morphine, or oxycodone [Endocodone]). Patients have tried to obtain pain relief from alternative medicine therapies such as acupuncture and herbal treatments with inconsistent results.
Answered by: Michio Hirano, MD

Q: I have 2 girls.My older one died of Leigh disease with point mutation T8993C a year ago at age 8. She had lots of symptoms throughout her life, but none were severe enough I am assuming to have led to mito diagnosis. She had weak sucking reflex, walked late, inguinal hernia, RTA, lost head control for about 2 months at age 8 months, fussiness, mimimal growth, hypotonia, small stature, sensory integration disorder, ADD, farsighted, learning problems, poor balance and coordination, stuttering, endocrine imbalance, but looked fairly good overall. She never had seizures or acidosis. She got sick a lot, and it took her a long time to recover. I spent her entire life looking for a diagnosis and saw many neurologists etc. No one ever mentioned mito disease all those years. Finally, the neurologist was convinced she and her younger sister had a rare "metabolic condition" but still never mentioned mito. I am wondering what are the most important criteria in considering mito disease? Now that we know what she died of, it seems like all the signs were there. Was she just not severe enough? She had 90-95% mutation according to autopsy. My younger daughter has 92% mutation from blood mDNA and I have 54% mutation. It seems like my girls beat all the odds of this disease with such high % mutations and doing as well as they did. Is this true? Is it so rare for this to happen? My daughter got sick with a mild virus and died 2 months later. It was a very quick deterioration. My other daughter is doing very well, but also has mild neurological symptoms like her sister. Is it most likely that the same quick deterioration will happen to her too with such a high mutation, even though she looks so good now? I would appreciate your take on this bizarre event.

A: I'm very sorry to hear about your daughter's death and can empathize with your concerns. You have asked some very challenging questions. I need to point out up front that I am a scientist who has studied the link between the amount of some mtDNA mutations (including T8993C) and clinical symptoms, but I am not a physician. I was unclear from your email whether you have been able to discuss these issues with a physician who specializes in mitochondrial diseases or just with a regular neurologist. If the latter I would strongly encourage you to seek out a mitochondrial disease expert, and UMDF can hopefully give you some ideas on that. Mitochondrial diseases are very complicated disorders, and I'm sure your experience tells you that most pediatricians and neurologists find it hard to get their minds around them and stay up to date.
There is no simple answer to what are the most important criteria in considering mito disease. Some children and adults have a group of symptoms or signs that should immediately raise the suspicion of mitochondrial disease. There is a section on this on the UMDF website that puts it more eloquently than I can. In many cases though, the initial symptoms may be things that could be caused by a range of other causes (e.g. viral, endocrine, immune system, other neurological diseases) and mitochondrial disease may not be suspected since it is often thought to be relatively uncommon and perhaps unfamiliar to the primary physician. Unfortunately, I think many UMDF members have had the distressing experience of taking their sick child to a range of doctors for several months or years before the idea of mitochondrial disease is first raised. This may ultimately occur because they finally find the right doctor or because new symptoms keep appearing, making other diagnoses less likely. From your description, and with the benefit of hindsight, it is easy for a scientist like me to think that your daughter's symptoms sound quite typical of mitochondrial disease. However, in terms of knowledge about clinical symptoms I fall into the category of "a little knowledge is dangerous". That is I can believe almost any sick child could have a mitochondrial disease but don't know enough to say what other conditions may have seemed more likely at the time. Thus I cannot know whether the suspicion of mitochondrial disease should have been raised earlier.
You ask about whether it is unusual for your girls to have done as well as they did, given their high % mutations. There are a lot of things that can influence this, for example some mtDNA mutations tend to show much higher % mutation in brain or muscle than blood. Some individuals have stronger immune systems than others, and may fight off viral illnesses better. The child's diet, sex and the number of viruses they are exposed to at an early age may also make a difference. Our genetic background (both mitochondrial and nuclear genes) is also likely to be important. So for most mtDNA mutations it is very hard to find a close correlation between the % mutations and the severity of disease. The T8993C (and also the T8993G) mutation is a little unusual in that it does tend to show a fairly strong correlation. In 1999, we published a paper reviewing all the published information on patients with the T8993C and T8993G mutations. Of the two, T8993C is a milder mutation, and it appears that symptoms are usually not present unless there is more than 90% mutation. For T8993G, the cutoff is closer to 70%. Some people with >90% T8993C mutation were reported to be well or had only mild symptoms, so there is still some variation between individuals.
So that means that the symptoms in both your daughters are consistent with those of patients reported previously. We cannot predict what the future holds for your other daughter with any accuracy. Unfortunately, it is not uncommon for viral illnesses to cause sudden deteriorations in children with mitochondrial diseases. However, that is not inevitable. Your two daughters were born with the same mitochondrial genetic background. However, about half of their nuclear genes are different and there would also be some subtle differences in their "environment" and exposure to illnesses, etc. These individual differences give grounds for hope that your second daughter may have much milder disease.
In closing let me stress again that I am not a physician and I would encourage you to seek out a clinical mitochondrial disease expert, to ensure you are getting the best advice about managing your daughter's health.

Answered by: David R. Thorburn, PhD

Q: I am suspected of having a mitochondrial disease (adult 49), based on the abnormal results of a cardio pulmonary exercise test (plasma levels of carnitine were extremely low). Heart rate too high, and air hunger and fatigue are major issues. I'm in the process of being scheduled for a "flash frozen" biopsy at a local hospital. I've been told that a fresh biopsy (one read within an hour of the procedure) would have a better chance of showing some of the complex respiratory chain problems. I was told my hospital has a way of freezing the biopsy to preserve it (as good as fresh).

Since I am in the process of scheduling this within a couple of weeks, would it be more advantageous to have it done here and possibly start treatment sooner? (I've been suffering from air hunger for five months and some days are pretty bad.) Or would I be better off in the long run to wait and try an out-of-state lab for a better result?

A: This is a hotly debated question that needs to take into account both technical and patient related aspects. As the technology has improved, results obtained from flash frozen muscle biopsies, subsequently analyzed for biochemical abnormalities, is becoming increasingly reliable.


Some assays, however, can only be performed on fresh muscle including screening for biochemical defects in complex V of the respiratory chain. Freezing of muscle prior to mitochondrial evaluation increases the probability of inactivating the more complex and fragile enzymes of the respiratory complex such as complex I, NADH dehydrogenase, or the NADH:ubiquinone oxidoreductase.


Thus the decision for fresh versus frozen biopsy should take into account convenience factors, technology, and what conditions the physician is interested in ruling out. If using a frozen biopsy method, care should be given to freeze appropriately to avoid sample breakdown, which will influence results.

Answered by: Andrea Gropman, MD, FAAP

Q: Are there any indications/contraindications of Botox use in a Complex I, Mitochondrial patient? My 6 year old daughter is a candidate for Botox in her calf muscles, to release her heel cord spasticity. Some doctors worry how the Botox might break down in her system from a metabolic standpoint. We have tried orthotics and weekly PT but she continues to weaken.

A: The indications for Botox include spasticity and dystonia, two common problems in patients with neurologic disease. The decision to use Botox must be made carefully in a patient with mitochondrial disease, because although Botox is usually reversible (and therefore must be given about every 3 months), it blocks the neuromuscular junction and may not be easily reversible (the same reason we do not like to use succinylcholine as an anesthetic). It may make her weaker, as Botox does not help the muscle strengthen, rather it paralyzes the tight muscles. There are other treatments for spasticity, including oral drugs, that can be tried as well.

Answered by: Amy C. Goldstein, MD

Q: My 30 year old daughter is suspected of having a mitochondrial disease based on excretion of alanine, glycine and alpha ketogluterate. For the past 19 years, she has had cognitive, behavioral, and motor regression following a viral or bacterial infection. After each “crisis” she would recover but not return to pre-illness baseline. She has stroke-like episodes. In December 2001, following a cold, she went into one of these “crises” and has never recovered. She now has significant dementia with psychosis. Are there any medications that have been found to help with the dementia and psychosis in mitochondrial patients? When she visited her neurologist recently, we wondered if Aricept or similar medications have been used with mitochondrial patients? Were they effective?

A: To my knowledge, no medications including cholinesterase inhibitors such as Aricept, have been shown to improve dementia in mitochondrial patients. I ran a PubMed search using the key terms "mitochondria" and cholinesterase inhibitor" as well as "mitochondrial disease and cholinesterase inhibitor" and did not identify any papers describing the use of this class of drugs in patients with mitochondrial diseases.
Psychosis in mitochondrial patients is treatable with anti-psychotic drugs. These drugs should be used cautiously because there is a paper claiming that antipsychotic drugs inhibits a mitochondrial enzyme in rats (Inhibition of pyruvate dehydrogenase complex (PDHC) by antipsychotic drugs.Biol Psychiatry. 1991 Jan 15;29(2):176-82)

Answered by: Michio Hirano, MD

Q: I have been seriously ill since 1986. I am now 51 years old. Two years
ago, I was told I had megamitochondria with extensive crystalline
inclusions. I have non-alcoholic steatorea hepatitis, pancreatic enzyme insufficiency, enlarged spleen, extreme muscle weakness, hypertension, hypothyroidism, neuritis, etc. No specific diagnosis has been given. Are crystals in mitochondria something that is normally seen in mitochondrial diseases? If so, which ones? My docs have no interest in pursuing what mitochondrial disease I may have. I believe that it is essential for a treatment plan. Do you have any suggestions?

A: It is diffcult to be sure without seeing the pictures. "Crystals" would be an unusual descriptor in primary mito conditions - there are usually changes in number, size shape and 'inclusions' with "abnormal cristae." I would suggest she find a pathologist comfortable with mitochondrial conditions and ask him/her to review the slides and biopsy pictures. There are changes of mitochondria seen in NASH but they are secondary only and she also has features not classical of a primary mitochondrial condition, e.g. the splenomegaly.

Answered by: Annette Feigenbaum, M.D., FRCP

Q: Could you please tell me if Atrial Tachycardia is related to a mito problem?

A: The first question to answer is what is the age of the individual. Tachycardia (> 100 beats/min) in adults does not apply to infants (> 160 beats/min) and children (> 140 beats/min). The heart rate usually is lower than 200 beats/min in sinus tachycardia (which is different from supraventricular tachycardia, > 240 in an adult). The heart rate can be episodically increased by anxiety, fever, hypovolemia or circulatory shock, anemia, congestive heart failure, mediation, high thyroid, and myocardial diseases. A patient with a mitochondrial disease certainly can have many of these conditions. Probably the most pronounced and worrisome problem would be when the mitochondrial disease is associated with a myocardial disease, such as in a cardiac myopathy that is seen in many mitochondrial mutations and electron transport chain disorders. Certainly, any of the other factors may contribute to episodic tachycardia as multisystemic problems arise in mitochondria disease. The syndrome of Wolff-Parkinson-White can be seen in some mitochondrial diseases (preexcitation that induces episodic attacks of puraventricular tachycardia). What we have also seen in many patients is episodic "racing of the heart" where the patient experiences the feeling of rapid heart rate. In many patients, this remains of undefined etiology.

Answered by: Russell Saneto, DO, PhD

Q: I have a diagnosis of mitochondrial myopathy or cytopathy. In the most recent issue of Quest in an article about non invasive ventilation it is quoted ‘Supplemental oxygen (that is taking in oxygen concentrations of more than the 21% that is usual in room air) is a very bad idea in neuromuscular disease for a variety of complex bio-chemical reasons.’ Do you feel this would be the case in mito patients? During a recent sleep study my oxygen level went very low, 52% at one point. I am now on supplemental oxygen but continue to feel very fatigued. Provigil has been prescribed for me but I don’t feel as if it is helping. I’m wondering if I would be better off with a BiPap or another type of pressure-cycled ventilator at night, either with or without oxygen. Also, a recent pulmonary function test said there is a possibility of weakened respiratory muscles.


A: I have a number of patients who require overnight ventilation because of respiratory muscle weakness due to mitochondrial disease. This is very similar to my patients with other muscle diseases. In my experience patients do not require addditional oxygen over and above the assisted ventilation at night. It will be important to discuss this with your respiratory physician who will be able to give you advice by measuring your oxygen saturation.

Answered by: Douglass M. Turnbull, MD, PhD

Q: My son has had some encephalopathy due to demyelination. Is demyelination caused by an inability to metabolize long chain fatty acids? Would a high protein diet to produce a sate of ketosis (fat burning) be helpful for children suffering from demyelination?

A: Myelinogenesis is a scheduled process that depends on properties of the cell as well as extracellular signals. In human brain, myelin development is an essentially pre and post natal event. Myelination starts in early gestation and continues even after birth. Thus intrauterine and environmental interferences could affect myelin synthesis. Nutrition plays an important role, since severe postnatal malnutrition and essential fatty acid (EFA) deficiency cause hypomyelination. The dietary effects are ore pronounced in the postnatal period.

For some children, a genetic or metabolic disorder which affects a component of myelin production can lead to dysmyelination or demyelination. Such a component of myelin that may be affected include cholesterol, proteins, or fatty acids.

Unfortunately, there is no proven dietary therapy that can reverse a genetic or metabolic disorder of myelination. Many of the substances that can be taken orally cannot cross the blood brain barrier--the complex of blood vessels and membranes that allow substances to be taken up into the brain.

Essential fatty acid deficiency has been well studied for its role in visual system development. The observation that dietary fatty acids can affect membrane composition has led to the use of modified diets in some conditions that affect the central nervous system. For example, preterm infants fed with formulas enriched in the C22:6 fatty acid, show a recovery of visual function. The administration of C22:6 has also been tested in patients affected by peroxisomal disorders which are associated with very low levels of this fatty acid in the brain and abnormal myelin in the brain and nerves.

During treatment, C22:6 content increases in red blood cells, and probably in the brain membranes. Studies suggest neurologic improvement . In Adrenoleukodistrophy, a peroxisomal disorder which is characterized by an abnormal accumulation of very long chain fatty acids (VLCFA) in tissues and fluids, such a diet is able to lower VLCFA levels in plasma, but its effect upon myelin damage is less certain. It has been hypothesized that a diet which reduces the intake of saturated fatty acid and increases the quantity of polyunsaturated fat may benefit multiple sclerosis patients who have demyelinating disease. A decrease of linoleic acid in their plasma and erythrocytes has been noted.

There are no current recommendations regarding such a diet in patients with mitochondrial disorders who manifest with demyelination or dysmyelination. There is not enough data to suggest that dietary manipulations will correct for damage already accumulated in myelin. Good nutrition, in general, is required for all mitochondrial disorders due to impaired energy. The content of the diet is best determined on the basis of the underlying biochemical defect if that is known.
Answered by: Andrea Gropman, MD, FAAP

Q: My daughter was diagnosed with Mito, and passed away last summer. We never got a specific diagnosis. Doctors told us we may never know what she actually had beside lactic acidosis, cardiomyopathy, and unknown Mitochondrial disease.

We were told we have a one in four chance of future children being affected with this disease. I am ten weeks pregnant, and I am wondering at what point after the baby is born can you test lactic acid, and can we test the umbilical cord rather than putting the baby through so much testing? Can we find out any further info from this, with regard to a diagnosis? I am wondering if this would work like a muscle biopsy. We are looking into banking the stem cells and hope this may help.

A: Having lost a child with mitochondrial disease, and being pregnant again must be a mix of joy, hope and concern. Your obstetrician and pediatrician should certainly develop a management plan so you know what tests can be done on your new baby and when. This will presumably be done in discussion with a physician who is an expert in mitochondrial diseases. Without knowing the details of your daughter's illness and what tests were done, it is not possible for me to make any definitive statements about this. So the best I can do is make some general comments and hope these may be helpful to discuss with your pediatrician.

I think that testing lactic acid levels in umbilical cord blood is unlikely to be useful. I have not seen "normal ranges" for such samples and suspect that at least for a vaginal delivery the stresses of childbirth on any mother and baby would likely lead to high levels of lactic acid. So I doubt if the results could be interpreted in a meaningful way.

In terms of other tests on the umbilical cord, it is possible to set up a skin fibroblast culture. However, on the available information, I can't really say whether this should be recommended. It really depends on how extensive the testing had been on your daughter. For example if she had had a muscle biopsy and was found to have normal respiratory chain enzyme levels, there would be no point in doing the same tests on cord fibroblasts. As a general rule, fibroblasts are not a good sample for investigating a mitochondrial disorder as most of the time the disorder cannot be detected there even when it is found in muscle or heart samples.

It is likely that your pediatrician will recommend testing lactic acid levels in blood from your baby within the first few days. They may also want to have the newborn Guthrie card tested for an acylcarnitine profile, which can detect some of the mitochondrial fatty acid oxidation disorders that can cause "mitochondrial cardiomyopathy". This test is becoming a routine part of newborn screening and may already be standard practice in your hospital. It is also likely that tests such as a cardiac ECHO and ECG may be warranted, and I imagine that your obstetrician will be recommending one or more top quality ultrasounds during the pregnancy to check on the developing baby's heart and brain.

Sorry I can't be more definitive about what tests should be done and when, but this can really only be planned by your doctors in light of all the clinical and laboratory information about your first daughter. I'm afraid I also feel unqualified to comment on whether banking of cord blood is likely to be helpful in the event of any health problems. Except for diseases of the bone marrow, cord blood banking is very much in the research realm at the moment.
Answered by: David R. Thorburn, PhD

Q: My daughter with complex IV deficiency has recently been diagnosed with POT syndrome. Could you explain what this syndrome is and what it has to do with her mitochondrial disease or dysautonomia? How common is it in mitochondrial disease?

A: Individuals with POTS (Postural Orthostatic Tachycardia Syndrome) have symptoms (often light-headedness, blurred vision, the feeling of a fast heart rate, tremulousness and weakness) when changing position, such as with rising from a lying to a standing position. This is a disorder of autonomic nervous system control, and the underlying cause is often unknown. Although only described in a few medical papers, in my own clinical experience abnormalities of autonomic nervous system control (dysautonomia) are fairly common among individuals with mitochondrial disease. Very little is known regarding just how common POTS and others dysautonomias are in patients with mitochondrial disease, and this is an area which can benefit from additional research.
Answered by: Richard G. Boles, MD

Q: My son is three years old, has been diagnosed with Complex I Deficiency and has recently been put on a Bi-Pap at night. The ENT says his soft palatte collapses over his airway when lethargic from seizures and when sleeping deeply. How common is this?

If he does not tolerate the Bi-Pap, our doctors are suggesting a trache. What other options do we have? How risky is this procedure?

A: Children who have low tone in the body may also have low tone in the airway. These children are at risk of airway compromise when heavily sedated from medications, or in the aftermath of a seizure which leaves them sleeping deeply. Because heavy sleep or sedation limits one's ability to protect the airway from aspiration, doctors will recommend different options. One option is bipap which provides positive distending pressure to the small airways so they do not collapse. There are also other factors, such as whether there are other sleep anomalies such as hypoventilation, etc. or results of a sleep study. I don't have exact numbers to say how common this is, but it is not uncommon.

If the bipap doesn't work a tracheostomy may be next. This is when a hole is made into the trachea and a small tube is inserted which is a conduit to the outside world. I don't know what other options are available because I do not know more about your son's history (i.e. premature, history of airway problems, sleep problems, sleep studies, and manifestations of his mitochondrial disorder--i.e. any neuromuscular compromise). The risks of the tracheostomy are related to the risks of sedation, and infection because the tracheostomy can communicate with the outside of the body. Also, if a patient has thick secretions, the secretions may clog the trach tube, requiring replacement. Also, patients with a tracheostomy are generally unable to talk, but there are some tricks and devices the therapists can teach to get around this. The family would need to learn tracheostomy care, how to suction secretions,and CPR. If your son receives a tracheostomy, you may be eligible for home nursing services.
Answered by: Andrea Gropman, MD, FAAP

Q: My daughter has been diagnosed with Complex IV deficiency and has always had slightly elevated lactic acid levels. Several of her amino acids were also high. What does that mean? She had never had her amino acids checked before.

A: In patients with a lactic acidosis, the level of the amino acid alanine is frequently elevated. This is because alanine and lactate are both derived from pyruvic acid which is the first compound to build up in respiratory chain disorders. Other amino acid abnormalities may be non-specific and include a generalized increase in many amino acids in samples collected after a meal. Elevated levels of Tyrosine, Phenyalanine and Methionine indicate that there may be some involvement of the liver in the disease process. Elevated levels of Leucine, Isoleucine and Valine indicate that the patient may have been fasting for a prolonged period.
Answered by: Michael J. Bennet, PhD, FRCPath, DABCC

Q: My 25 year old son has been diagnoised with C.P.E.O. and has lost all movement in his eyes. There is no evidence of pigmentary deposition in the retina. EKG was performed and the readindg is normal. A tensilon test was performed looking for neuro-muscular junction disease but was negative. Testing for MELAS, MERRF, and NARP wer negative. A muscle biospy was done and was positive for mitocondrial myopathy.

Is it possible that the disease could effect his eyes and no other parts of his body?

Other than fatique, he has no other signs and he works an average of 55-60 hours per week. Also, when I was pregnant I suffered from severe morning sickness and was given the drug bendictin (which has since been removed from the market due to birth defects) in large doses (6-8 tablets per day). Could this be related to the disease since a complete investigation into family background shows no sign of the disease?

A: By this I presume that you mean it showed evidence of mitochondrial accumulation and cytochrome C oxidase negative cells. My question would be has the muscle biopsy been screened for deletions?

If he has no signs of other involvement the outlook is very good. Many mitochondrial disease patients with eye involvement, have no other involvement of tissues apart from muscle. With C.E.P.O. there is evidence that the more active you are the better you do. The vast majority of cases of this condition are sporadic - and there is no family history of mitochondrial disease. I think it is very unlikely that the mitochondrial abnormality was due to bendictin. At some point your son might need surgery to his eyes to help with the drooping. If this is needed it is important that he goes to an opthalmologist with a major interest in this form of surgery.
Answered by: Douglass M. Turnbull, MD, PhD

Q: It would seem that there is a big trend to give injections of pig secretine to children with autism. Is there any scientific research supporting using pig secretine in children with Mitochondria disease? What do you think about this practice?

A: Secretin is a neuropeptide (a protein that has functions in the nervous system) and it also behaves as a hormone in the body to control digestive processes. It helps the pancreas and stomach excrete digestive enzymes, and forces the liver to make bile, which helps absorbing fats.

A few years ago Secretin was given to children with Autism in order to see if it improved function. Although there were some children that improved, the results of the study were less than impressive. There have been a number of criticisms of the trial design, but Repligen Corporation feels that the problem was that the Secretin was not the correct form, and they are doing a clinical trial using synthetic human secretin. Secretin is available to any doctor in the USA, but it got bad press within the medical community because it was being used without adequate study and the doctors that were giving it profited enormously. (A doctor does not profit one penny by telling a patient to take CoQ10, for example, but can make $500 plus, from each dose of secretin with almost zero work, so there were doctors that had clinics of patients receiving Secretin, making thousands of dollars a day and not studying the results. This behavior does not fly with other doctors that will spend 5 years of their life studying and reporting data with no financial motive).

I know of no trial using secretin in any form to study children with mitochondrial disorders. However, Repligen does have a trial open for Autism, you can find information at the following link:

I found the following link an excellent source of information about secretiin, with other excellent links:

I am 100% supportive of what Repligen is doing. They are studying the use of Secretin in a responsible fashion. The patients do not have to pay to be in the study (they get the drug free) and the doctors do not earn any money for having patients in the study. If the results are positive or negative, the results will be reported. Because medical journals are a bit like newspapers, positive results will more likely end up in a big medical journal. Negative results will place the drug in the same pile of other therapies that have not been helpful, although most of these "other therapies" have not been studied in a rigorous fashion.

You may ask, "why has no one studies Secretin in Mitochondrial disorders?"

1) You need a doctor to have interest.
2) That doctor must write a proposal and have it funded by a drug company and approved by their institution.
3) There must be clear objective endpoints to the trial.

Point number 3 is the most difficult in mitochondrial disorders. I have addressed this issue in the article written by Dr. Gold and myself, which is on the UMDF web site thru links. Because every person with a mitochondrial disorder is different, and because there are a dozen main aspects that could be studied (seizures, intellect, heart function, strength), and because statistical models require enormous numbers of patients if you study more than one aspect in a study, it is almost impossible to do a study. Dr. Robert Naviaux has been working on this problem for a decade, and Repligen is helping us actually design a trial in mitochondrial diseases.
Answered by: Bruce Cohen, MD

Q: My son's ENT doctor asked me if there is some possibility that my son's chronic sinusitis, rhinitis and polypoid disease could be related to his metabolic problem? He already has had three sinus surgeries in the past two and one-half years. His official diagnosis is maglignant hyperthermia with mitochondrial defect - defect unknown.

A: I am not aware of any connection, except that gastroesophageal reflux disease (GERD) is very common in mitochondrial disease, and GERD can inflame the nasal passages causing at least some of those problems.
Answered by: Richard G. Boles, MD

Q: My son received a diagnosis of GA2 in June of 2002. He had abnormal acylcarnitine profiles and skin fibroblast testing that had suggested GA2. His concrete diagnosis came from an Enzyme Analysis test.

The result showed a defect in the ETF-QO enzyme. Upon retesting the enzymes to confirm the results, it tested normal. Now, based on what we were told about skin fibroblast testing, I don't see how this takes away from our son's diagnosis. We were told that it depends on the condition of the skin cells and so on when tested.

Now, we are back to "probable GA2". Does this really alter the results of his diagnosis? Would it be worth retesting the skin again?
How many different results can you get from a skin biopsy?

A: I am not an expert on GAII and had to discuss this question with several colleagues before responding. It is very difficult to give a clear answer to a question like this without having direct experience of the assays, knowing their details and which lab performed them. My impression is thus that the diagnostic certainty is probable rather than definite. Your physician may be able to give you more feedback about whether he or she thinks it is very very close to definite or not.

My experience of fibroblast enzyme assays is that there are rare occasions where repeat assays give discrepant results. There are at least 3 possible reasons for this:

(1) Sometimes there is a real biological explanation. I have had three examples of first hand experience with this. Some of the mitochondrial respiratory chain enzyme deficiencies can tend to normalise with prolonged culture due to a change in the amount of healthy and disease mitochondrial genomes. Similarly in some girls with X-linked disorders like pyruvate dehydrogenase deficiency, one area of skin really may express more of the disease gene than the healthy gene. The other example we noticed recently was a cell line that had lost one of the two copies of a particular chromosome, which could potentially have an effect on some enzyme activities. Those first two examples are not relevant to GAII, and the third example is probably very rare. However it is conceivable that other mechanisms could cause this, eg as fibroblasts go through more rounds of cell division (get older), the pattern of enzymes they express can change. This is usually only noted at very low or very high numbers of divisions.

(2) Occasionally there may be a technical problem with the equipment or a reagent but all diagnostic labs take a lot of effort to avoid and detect such technical problems.

(3) Diagnostic labs also try very hard to avoid any mistakes such as using the wrong cell line or forgetting to add something, but it is impossible to completely avoid human error, so very occasionally this can cause discrepant results.

With all these explanations, I think it is more likely that the normal result is going to be the "wrong" one, but can't be 100% certain. That is apparently also what was conveyed to you about being more likely to get a false negative result than a false positive one.

In terms of retesting the same skin biopsy or a new one, this is something that would have to be discussed by your referring doctor with the testing center. It depends on a number of things, including how close to definite the diagnosis is, whether further testing will affect the treatment of your son or the genetic advice that has been given and of course cost and whether it would be covered by insurance.
Answered by: David R. Thorburn, PhD

Q: How is testing for MERRF performed? If the mutation is present and the patient is asymptomatic will the test still be positive? Can the offspring of a woman with MERRF syndrome have symptoms which do not fit the classical MERRF diagnosis?

A: MERFF testing is done by DNA analysis, so it would most likely be done in blood, but could be done in any tissue from which genomic DNA can be obtained. A patient can be asymptomatic and be positive for the mutation both.

Although I am not completely certain, based upon the heterogeneity we see in metabolic disease, I would venture to say yes, the offspring of a woman with MERRF can have symptoms which do not fit the classical MERRF diagnosis.
Answered by: K. Michael Gibson, PhD, FACMG

Q: I have been diagnosed with Mitochondrial Cytopathy for eight years. On a visit to my neurologist, who is trying to learn about mitochondrial disorders, he noticed that, when doing sensation tests on my forehead, that there was a difference as soon as he crossed the midline. I have had this since I was little. Could this be part of the mitochondrial disorder, as I know of two other people with mito that this occurs in. My neurologist feels that this shouldn't be happening as he hasn't seen it before.

A: Is it possible that you had a history of herpes zoster as a child, or trauma to that side of the face? This could account for the sensory difference you describe. I am not aware of this as being a common finding in mitochondrial cytopathies.
Answered by: Andrea Gropman, MD, FAAP

Q: My husband has a mito disease but we don't know which one. He was on oxygen in Pa at 2 liters constantly but we move to Virginia and the Veterans hospital here says you have to be at least 88% oxygen and he reads 92%.

The problem is since the oxygen has been discontiued he is so tired. He did so much better when he had the oxygen, and I'm looking for any information about mito and the need for oxygen so he can get oxygen again, but I need to prove it to the Salem Vets Hospital in Salem, Virginia. is there any thing written about this by a mito doctor?

A: The response to your question is being tainted by my "political" views.

Here is the fact: In the USA any doctor can write a prescription for oxygen. However, insurance companies will not pay for it unless certain conditions are met. One of those conditions is that the oxygen level in the blood, as determined by a Pulse oximeter (the thing that you wear on your finger) shows that the oxygen level is below some number. I am not up-to-date on the number this year, but I assume it is 88, as you said in your note.

I would suggest that you ask your doctor if there are any other tests that can be done that would justify the need for oxygen.

Here is my political opinion: In order to save money, the government and the insurance industry have taken the reason "it makes that patient feel better" out of the list of reasons that they should pay for the oxygen. There is a good reason for trying to have some control over the use of oxygen. It does cost a lot of money and it should not be prescribed unless there is a good reason. And I admit that oxygen probably has been overprescribed in the past. So your husband cannot get his oxygen paid for because of the "bad prescribing behavior" of others in the past.
Answered by: Bruce Cohen, MD

Q: I am facing the prospect of having a colonscopy in the near future and as a result of severe GI dysmotility the Drs. are wanting to do a 3-5 day prep. Should any particular precautions be taken during this time given that I have some components of autonomic dysfunction, particularly severe hypoglycemic events? I am fearful of a metabolic crash during this timeframe, but my GI doc seems unconcerned.

A: An intolerance to fasting is seen in many individuals with mitochondrial disease. Although not all mitochondrial patients are sensitive to fasting, it is difficult to predict which ones are and which ones are not. Fasting intolerance can be relatively mild and reversible, such as headache, vomiting or fatigue, or severe and potentially irreversible, such as heart muscle weakness (cardiomyopathy), stroke or sudden death. Hypoglycemia may or may not be present during fasting-induced symptoms. As surgery and other medical procedures are (in general) major stressors that increases energy demand, it is especially important to avoid fasting around the time of procedures. Thus, I strongly recommend that all medical procedures be performed in the absence of fasting in all individuals with proven or suspected mitochondrial disease.

In the majority of cases, fasting and fasting-induced complications can be avoided simply by the placement of an iv in the early morning with the delivery of D10 (10% sugar solution) at a standard (maintenance) rate. The D10 should run during the anesthesia induction, procedure, and afterwards until the patient is able to tolerate a meal. Usually, this does not necessitate an additional night in the hospital beyond that customarily required for that procedure, and outpatient surgery is often appropriate. Individuals requiring continuous or frequent drip feedings, with severe disease, or receiving complicated procedures are potential exceptions.

In your individual case, a history of hypoglycemia (obviously) likely indicates fasting intolerance. The dysautonomic/dysmotility manifestations may also be a sign of fasting intolerance, in my experience. Three to five days is a long time, and if you are unable to take in adequate calories by mouth in any form (i.e. liquids) during that time, then you should discuss iv alimentation (feeding) with your physicians.
Answered by: Richard G. Boles, MD

Q: I am a 44 year old woman and have recently been diagnosed with
Mitochondrial myopathy, with a heteroplasmic mutation (A10750G) in the ND4L gene.

Is it wise to "save" energy by using a wheelchair, or to continue though my body hurts a lot and gets tired sooner, without the wheelchair? Is it possible for a patient with mitochondrial disease to "build up" their condition? Would it be helpful to go swimming or other sports in the hope that I can push my pain limit further and feel fatigue later? and also is fatigue always the first symptom of in mito disease?

A: That is an interesting question. In general, patients with wasting conditions who can participate in a proper exercise program gain muscle protein mass, strength and endurance, and, in some cases, are more capable of performing the activities of daily living. Both resistance and endurance exercise training have been shown to have positive effects in patients with mitochondrial disease, although several questions remain to be answered. Lastly, a good diet, including adequate vitamin intake and the avoidance of obesity are important. Since fasting increases demand on mitochondria, regular meals is recommended. Excessive exertion should be avoided. What level of physical activity you should engage in depends on how severely your muscle is affected, but for those able to exercise, this will improve well being and in some cases lead to improved muscle function.

Answered by: Andrea Gropman, MD, FAAP

Q: Is an elevated alanine level of greater than 750 indicitive of mito?
Can alanine be significantly elevated in a patient that does not have mitochondrial disease, and can valporic acid alter alanine levels?

A: Valproic acid may lead to elevations in the glycine level. An elevated alanine may be seen in mitochondrial disorders, particularly those associated with abnormalities in pyruvate dehydrogenase and complex one. An elevated alanine alone is not always indicative of a mitochondrial disorder, however.

Answered by: Andrea Gropman, MD, FAAP

Q: I am about five weeks pregnant and a carrier of the t-c 8993 Mitochondrial DNA mutation with 81% mutant mitochondria. I have one mildly affected daughter with 87% mutant mitochondria and one totally unaffected son, negative for the mutation. I have a CVS procedure scheduled in December and was wondering if this test will give me some idea as to the presence of the mutation and to the extent of the percentage of mutant mitochondria. I have read conflicting information on prenatal genetic testing and was curious if this test or possibly an amniocentesis would be helpful.

A: There is no definitive answer to the questions that this patient is asking, but there are some general guidelines for the T8993C and T8993G mutations which seem to be useful. First of all in mothers with a high percentage of heteroplasmy, the chances of producing a child who will always be asymptomatic with a low heteroplasmy are lower than in mothers with low heteroplasmy. Results obtained prenatally either by CVS or amniocyte analysis have some predictive value although the correlates are not absolute. So a result with low heteroplasmy in prenatal samples will have good indications for the fetus, higher values may be harder to interpret.
Answered by: Brian H. Robinson, PhD

Q: My son has mito complex 3, he is 26 and has had chest pain for over 4 years. Echo proved normal and all tests have shown no problems. It was decided he probably have esophageal dismotility and was prescribed Prilosec and Carafate for over a year with no improvement and chest pain has become worse. Could there be any other explanation for chest pain and what type of specialist should he see next? He also recently sporadically developed purple splotches on his ankles and feet. Could this be related?

A: Your son's physicians were correct in first considering gastroespheageal reflux disease (GERD) (because it is common) and heart disease (because it can be severe, even if it is not a common cause of chest pain). However, as you suggest, there are many other potential causes of chest pain, including those that are more common in individuals with mitochondrial disease.

Muscle pain is not uncommon in mitochondrial disease, and the legs (and arms) are the most common locations. However, I have seen cases in which pain mostly resided in the chest, side or back. I believe that often this is a neurovascular abnormality, as in many of these cases intermittent/transient changes in skin color (red, white or blue/purple), temperature (hot or cold) or size (mild swelling) can be seen. Again, these changes typically occur in the limbs, but not always. Many cases also have migraine, abdominal pain, and/or cyclic vomiting. If this is what the problem is, than treatment with amitriptyline (Elavil) or cyproheptadine (Periactin) might be helpful, and you should discuss this with your son and his physician.

The chest pain may not be related to mitochondrial disease; inflammation of the rib/cartilage joint (costochronditis) is the most common cause of chest pain in young adults. GERD is very common and often quite difficult to treat, and still may be the culprit here. There are also many rarer causes of chest pain.

If the purple blotches do not move or fade, even when putting pressure on them with your fingers (no blanching), then this is a problem with blood clotting or blood vessel rupturing. The chest pain could be due to the same process, and may be serious.
Answered by: Richard G. Boles, MD

Q: I am a 43 year old woman and have recently been diagnosed with
Mitochondrial myopathy, with a heteroplasmic mutation (A10750G) in the ND4L gene.

In the blood of my late mother, they also found the same mutation but she had no complaints. Is it possible one can have the mutation but not the symptoms? If one is a carrier of the mutation but yet ill, will some day in your life the symptoms start, or can you be a carrier without any symptoms?

I have 3 daughters, who do have lot’s of health problems so I wonder if it is advisable to have my daughters checked for the same illness I have, so that maybe the doctors will understand their complaints more?

A: Mitochondrial DNA mutations are passed down from the mother to their children. You are heteroplasmic which means you have some mutated mitochondrial DNA and some normal mitochondrial DNA. Your Mother had the mutation also and when your egg was formed, it is likely that a higher percentage of the abnormal DNA was passed on to you. The amount of DNA passed on is highly variable and therefore, symptoms can range from none at all to severe. In addition, as each new cell is formed with the many mitochondria, each cell has a different amount of normal versus abnormal mitochondria and this explains why some people have more muscle symptoms, some more heart, some more brain or other areas. Therefore, one can assume that your daughters have received some copies of the mutation but to what degree it is present in each tissue type is likely impossible to predict. Certainly, their health problems need to be considered as possibly due to mitochondrial DNA problems. I would strongly recommend that your daughters receive genetic counselling.

Also, mitochondrial DNA abnormalities tend to get worse with age and often the heteroplasmy for the abnormal DNA goes on to homoplasmy.

Hope this is clearer for you. I would strongly advise further counseling for you and your family until you are very clear about these points and about recurrence risks and signs and symptoms of mitochondrial disease.
Answered by: Susan Winter, MD

Q: Our first daughter was diagnosed in 1997 with mitochondrial disease,
deficiencies in complexes I-IV. Are there any new prenatal tests
available now?

A: The availability of prenatal tests for families with mitochondrial disease has improved dramatically since 1997. At that time, prenatal testing for any of the mitochondrial DNA mutations was widely regarded as unacceptably risky, no major nuclear genes causing mitochondrial "OXPHOS" diseases had been identified, and only a handful of centers anywhere in the world would offer prenatal diagnosis by enzyme testing. There is now a consensus in the mitochondrial field that mitochondrial DNA prenatal diagnosis can be attempted in some families (a consensus statement on this topic was published as Poulton and Turnbull, 2000, Neuromuscular Disorders 10:460-2). Also, more than 20 nuclear genes have now been shown to cause mitochondrial OXPHOS disease. However, despite this progress, at present it is still only a minority of families that have access to such tests.

This situation is starting to change quite rapidly though, and more and more families will have a range of reproductive options becoming available in the next few years. For those interested in a detailed scientific review of this topic, see Thorburn & Dahl, 2001, American Journal of Medical
Genetics 106(1), 102-114.

Unfortunately, in this question about a family with a child having deficiencies in complexes I-IV, there is probably no current prenatal test available. In all such situations, it is best to discuss the possible options with a physician who has particular expertise in mitochondrial diseases and is familiar with the detailed laboratory investigations on the affected patient. For those interested I will explain a little about reproductive options in general. In order to do this it is easiest to think of three different groups of families with mitochondrial disorders:

(i) Firstly, the most satisfactory range of options is for those families where the patient has had a disease-causing mutation identified in a nuclear gene. There are now six nuclear genes shown to cause Complex I deficiency, four causing Complex IV deficiency, one causing Complex II deficiency and one causing Complex III deficiency. There are also six nuclear genes shown to cause disease by affecting the amount or size of mitochondrial DNA, and another six that cause disease by affecting mitochondrial energy generation in various other ways. Some of these affect the activity of more than one of the mitochondrial OXPHOS complexes. More genes will be identified in the next few years. Families with nuclear gene mutations can usually be offered reliable prenatal diagnosis by DNA testing of amniotic fluid or chorionic villus (CVS) during pregnancy. Other preventative options such as donor sperm IVF or even pre-implantation genetic diagnosis (embryo biopsy) may be available.

(ii) The second group of families is those with a known disease-causing mutation in mitochondrial DNA. The most obvious and reliable method to prevent a recurrence of mitochondrial DNA disease is the use of donor oocytes accompanied by IVF using the partner’s sperm. It would be highly inadvisable to use a maternal relative as the oocyte donor, and availability of donor oocytes and costs are a problem in most countries. It is possible to test amniotic fluid or chorionic villus during pregnancy for mitochondrial DNA mutations but most specialists have been very wary of this approach until recently. One major concern was that it was uncertain if the amount of mutant mitochondrial DNA present in these samples at 10 to 18 weeks of pregnancy would be the same as that present in brain and other tissues at birth. More recent research suggests that for most mitochondrial DNA mutations this is not likely to be a problem. However, there is still a major concern about converting the measurement into a prediction of whether or not the child will be affected by mitochondrial disease. For some mutations, such as the 8993 mutations associated with NARP and Leigh disease, there are quite good data. Thus there is a general consensus that such testing can be offered to families where the mother has less than 50% of the 8993 mutation in her blood. However, for most other mtDNA mutations, this remains a problem and prediction could only really be based on an “educated guess” based on published family data. Any couples considering mitochondrial DNA prenatal testing thus need to be given good advice about the various types of uncertainty associated with such testing.

Preimplantation genetic diagnosis is another possible option for families with mitochondrial DNA disease. It is a form of IVF in which embryos are grown up to the 8-cell stage, and one or two cells can then be removed and tested. Unaffected embryos can be transferred in order to establish a pregnancy. This technique is being used increasingly for prevention of other genetic diseases and has a number of features that mean it is likely to become more widely used for families with mitochondrial DNA mutations.

(iii) The third group of families are those in whom no mutation has been identified and where the diagnosis is based on finding a deficiency of one or more of the OXPHOS enzyme complexes. The genetic basis and risk of having an affected child are usually uncertain, except for specific examples where the enzyme deficiency, clinical presentation or family history implies the type of inheritance. In some cases, it may be possible to offer prenatal diagnosis by measuring enzyme activity in amniocytes or chorionic villus during pregnancy. This can usually only be done if the enzyme deficiency has been shown to be present in skin fibroblasts of the affected child. There are several limitations to this type of testing, however, and in general normal enzyme activity does not provide an absolute guarantee of a healthy outcome. These limitations mean that enzyme-based prenatal testing is less reliable than direct gene testing and it is only available from only a very limited number of international centers.
Answered by: David R. Thorburn, PhD

Q: Is there any link between rheumatoid arthritis and mitochondrial disease? Is it possible to have both, one making the other worse and less likely to respond to treatment? My daughter has been diagnosed with complex IV deficiency, and my mother, who has never been tested for mitochondrial disease, has rheumatoid that has not responded to treatment. She also has severe sweating, and temperature instability. Should my mother be tested?

A: The short answer is that there does not appear to be any substantial relationship between rheumatoid arthritis and mitochondrial disease. Both of these conditions are apparently common, so it would not be surprising if some patients suffering from one of these diseases later develops symptoms of the other. Since any stressful situation that increases energy demand can make mitochondrial disease symptoms worse, it is reasonable that significant flares of arthritis might exacerbate mitochondrial disease. However, this is only a theory and there are no studies or articles in the medical literature on this topic.

Regarding testing, the presence of arthritis does not mean that mitochondrial disease is not present, and a medical evaluation should be considered. However, in the absence of a proven mutation in your family, "testing" is not so easy in mildly affected family members, and likely is not feasible by current methods.

One last point: some individuals with mitochondrial disease suffer from muscle pains, particularly in the arms and legs, which can be misinterpreted as "arthritis". Mitochondrial patients with dysautonomia seem to be at high risk for suffering from these muscle pains. Severe sweating and temperature instability are signs of dysautonomia.
Answered by: Richard G. Boles, MD

Q: By any chance could Valproic acid (Depakote) cause abnormal urine organic acids and abnormal plasma amino acids?

My daughter was diagnosed with probable mito based on abnormal urine and plasma acids, along with intermittent elevations of lactate. All but one was drawn with a tourniquet (the one drawn without tourniquet was 0.8). Her muscle biopsy was ok and she has been on Valproic acid for 3 years. Could Valproic acid cause her abnormal labs? Could her lab results be false abnormal? Could the long use of Valproic acid give us a false diagnosis of mito disease?

A: The administration of depakote may lead to elevations of glycine in the plasma amino acids. In addition, since valproic acid is a fatty acid, it undergoes metabolism in the liver by the mmechanisms that promote fatty acid degradation of dietary fatty acids. Since many patients with mitochondrial disorders exhibit abnormalities of fatty acid metabolism, it is not uncommon to see unusual breakdown products present in the urine organic acids. A plasma acylcarnitine level may help sort this out. Also the prandial state (i.e. whether the paitent is fasted or non fasted) can affect some of the amino acids (i.e. taurine is often elevated after a meal). So without knowing specifically which organic acids were detected, or which amino acids were abnormal, I cannot be more specific.

If the labs can be repeated off depakote, that may help clarify (this may not be an option). Also, a muscle biopsy may be useful if the diagnosis of a mitochondrial disorder is being proposed.
Answered by: Andrea Gropman, MD, FAAP

Q: When a patient with mitochondrial disease sleeps excessively, where do you draw the line between allowing them to sleep/rest or pushing to maintain some level of activity. What about trying caffeine?

A: This is a very difficult question for which there is no correct answer. Perhaps here, culture and belief are more relevant than medicine and science. The determination to "be as normal as possible" and to exceed one's previous limits is a powerful force that I have seen people with mitochondrial disease use to overcome many obstacles. The price is a lot of willpower, discomfort, and the many "mito-bumps" on the road to this goal. However, such determination is difficult to continually impose on another person (like a child), and the best that one can do is to live those same values and hope that your child adopts them.

Having said this, in mitochondrial disease there are some medical issues here. Some form of exercise, or at least an active life, is important in maintaining the current level of strength and stamina, as well as possibly to improve them. As everyone knows, obesity and inactivity will reduce anyone's "energy level". In mito patients, they are a double-hit with the disease. Exercise should be fairly frequent (such as at least twice a week), and to push the individual to the point of fatigue. Excessive exercise, especially in the presence of cramps or in hot weather, can precipitate a dangerous metabolic decompensation and should be avoided. The problem lies in determining "the point of fatigue". Distinguishing true metabolic fatigue from simple laziness is not always easy.

Another possibility that should be given serious consideration is that of a "chemical" depression. In my experience, depression is very common in mitochondrial disease and can look a lot like fatigue and laziness. I have found that depression in mitochondrial disease responds to the same antidepressant medications as those that are generally prescribed. Some signs of depression are a lack of pleasure in activities previously enjoyed and/or a change in sleeping or eating habits. If you think that you or your child may possibly be depressed, please discuss this with your physician. Depression can be very serious, often is progressive, and is treatable.

Regarding caffeine, I frequently suggest this treatment for dysautonomic symptoms such as migraine, cyclic vomiting and arm/leg pain. Caffeine appears to be safe in patients with mitochondrial disease. It does not "cure" the underlying cause, but if you think that it helps I see no problem with using it, except that the fatigue likely will come back when the caffeine wears off. However, caffeine is not an appropriate substitute for exercise or antidepressants.
Answered by: Richard G. Boles, MD

Q: Is there any link between a diagnosis of Pyruvate Defienciency with Leigh's Disease and violent and disruptive behaviour?

Our 17 year old daughter has been diagnosed with Pyruvate Deficiency and Leigh's Disease. Over the last 4 years we have noticed an increase in violent and disruptive behavior. Pshyciatric examinations by doctors say that there is no link and that she has behavioural problems and so cannot be treated.

A: I am suprised by the response by the physician implying that she cannot be treated. Adolescence is a particularly rough time for children with developmental disabilities. Even children with no previous behavior problems may suddenly have uncharacteristic behaviors. I have seen this in children with migration disorders, chromosome disorders and metabolic diseases including mitochondrial disorders. Violent or disruptive behavior can be a manifestation of worsening of the underlying disorder, a sensory problem (ie the child cannot see or hear very well) or can be a manifestation of comorbid psychopathology (ie bipolar disease, depression, etc). Some children with Leigh disease have behavior problems, others do not. The problems are not specific to Leigh disorders. The approach should be as follows:

1. What is the timing of the behavior changes, do they have a pattern? Any changes in the family or social activities that may be contributory-ie new baby, divorce, new school, etc?

2. Assess whether the changes in behavior could reflect worsening metabolic control or sensory deprivation-check lactate, pyruvate, amino and organic acid levels, vision, hearing, consider EEG to rule out seizures and MRI to rule out disease progression.

3. If there is no evidence of metabolic derangement or disease worsening one could consider a short course of medication. However, this can be a double edged sword in children with mitochondrial disorders who can be very sensitive to medications. If seizures are present, or there is an abnormal EEG, one might consider using an anticonvulsant such as tegretol to try to modulate the behavior. Other meds that might help include risperodol, but caution has to be used in this population. The benefit of treatment effect has to outweigh any possible harmful side effects.
Answered by: Andrea Gropman, MD, FAAP

Q: My two year old son has been diagnosed with a Complex IV defeciency. He is highly affected,profound global dev. delay, hypotonia, gastric reflux with fundoplication, stridor,dysphagia, entirely g-tube fed. He cannot sit unassisted, is non verbal and is considered medically fragile by health care proffesionals. I understand to give a prognosis is difficult, but I was wondering if there have been any studies or statistics generated as to life expectancy of such children.

A: I do not know of any statistics for survival in mitochondrial disorders. There are statistics for kids with cerebral palsy and articles written on that which might shed some light on this question.
Answered by: Susan Winter, MD

Q: Which anticonvulsant has had the best dual affect for seizure control and movement disorder control?

I have a child who is on Tetrabenazine ( it has been a miracle drug for her dystonia with no side effects), Artane, Klonopin and Baclofen for her dystonia and spasticity with good sucess. She takes Neurotin for seizures which also helps her complex movement disorder. Since last year we have had to more than triple her Neurotin to manage her seizures and we are at the maximum now. There has been no significant weight gain that would require the increase dose so we are investigating why she is needing more. We are considering adding an additional medication with the thoughts of changing medications altogether rather than dealing with two meds. My daughter has a diagnosis of Leigh's Syndrome with no identified mutation.

A: There is no one best answer to your question. The movement disorders as a group are difficult to treat and some patients do not respond to any medication. You may wish to share this information with your doctor regarding my personal experience with my patients. As far as I know, no one has written a paper comparing any of the medications I have mentioned.

My first choice is generally Lamictal. It is difficult to use because it takes "forever" to get enough of this medication in the system to do any good. Going slow with the dose increases is the key to preventing a terrible skin rash. It could take 2-3 months to taper up the dose to see a therapeutic benefit. If you get impatient and try to increase the dose too quickly, a life-threatening rash could occur. Lamictal is neuro-protective, and excellent anti-seizure medication and helpful with many myoclonic movements (myoclonus is a sudden jerk) that so many of my patient 's have.

I have found Gabitril to be very helpful with pain and cramping, and sometimes relaxes the dystonic (dystonia is a slow twisting movement) component of some movements. It is a good anticonvulsant but not really used first-line as a single agent anticonvulsant. I have had a number of patients that have had great success as an add-on anticonvulsant. If dystonia and seizures are the two target symptoms in your child this may be the best choice. I tend to start with a night time dose of 2 mg in the young child and work up if tolerated.

Keppra is an excellent anticonvulsant for partial seizures and is also helpful for some types of dystonia and chorea (chorea are rapid movements involving different muscle groups each going in random directions). In about 10% of my patients, Keppra causes irritability and meanness. (90% have no problem).

The old time drugs Mysoline and Dilantin have been used to treat movement disorders for years but I do not use them because of sedation (Mysoline) and drug-drug interactions (both). Both are excellent anticonvulsants.

I do not have any practice using Topamax for movements, but it is an excellent anticonvulsant as well. I have not found Tegretol/Carbatrol/Trileptal helpful for movements. Depakote can cause a tremor, and I would also avoid this mediation in any person with a mitochondrial disorder (although I have had many patients do well with this medication and do not stop it if they have tolerated it.)

It is trial and error, sometimes called the "art of medicine" and not the "science of medicine".
Answered by: Bruce Cohen, MD

Q: Is there a higher incidence of eosiniphilic gastroenteritus in people with mitochondrial disorders? If so, why?

A: I personally, have not seen an increased incidence of this with mitochondrial disorders, but no one is really looking for it. Doctors are becoming increasing familiar with this entity and it is getting diagnosed more frequently. It is possible that a patient with mito could also have this. I think we have alot more to learn about the GI manifestations of mitochondrial disease, but at this point I am not aware of an increased incidence of this in the mito patients.
Answered by: Andrea Gropman, MD, FAAP

Q: If a child has a diagnosed oxphos disoder, what specialty type physician would be the best to oversee this child's case?

A: To my thinking, management of the care of a patient with an oxphos disorder has to be multifaceted, and can not be a solo opportunity. The PCP must be actively involved, as should be the attending neurologist and the metabolic specialist (who will have a close liaison with the biochemical genetics laboratory). The latter individuals provide the key biochemical interpretations that benefit both PCP AND the neurologist involved.
Answered by: K. Michael Gibson, PhD, FACMG

Q: Is high COX activity (greater than three times normal), high succinate dehydrogenase and citrate synthase (two and three times normal) in muscle biopsy along with other mildly elevated respiratory complexes and mitochondrial proliferation indicative of a mitochondrial problem?

A: It all depends upon a whole lot of things. The numbers of the assays you report are related to another enzyme that is [normally ]thought to be independent of primary mitochondrial disease at least of the respiratory chain. As you report them they do not indicate any primary difficulty in mitochondrial respiratory function indeed they seem to indicate that everything was working exceptionally well! For example, the results seem to indicate that the muscle was in a state of excellent training so that the activities were all above normal!
Answered by: Neil Buist, MD

Q: Is sudden onset of muscle pain, along with burning sensation in the arm and leg muscles consistent with mitochondrial myopathy? What can be done to reduce the muscle pain?

A: In medical school there is the saying, "If you are walking in Central Park and hear hoofbeats, don't think of Zebras." For those that are not familiar with Central Park in New York, there are plenty of horse and buggy rides, but only one Zebra in the zoo. In other words, common diseases occur commonly.

Pain is the most common reason a person will see a doctor for an urgent problem. Pain is a symptom with hundreds of causes. If pain is the only symptom then it is unlikely to be due to a mitochondrial disease. If one forgets that viruses can cause muscle pain (by destroying a fraction of the muscle tissue and elevating the enzyme CK) then you could end up spending a year and tens of thousands of dollars investigating a simple problem that went away with the virus.

On the other hand, if the diagnosis is confirmed as mitochondrial, pain happens to be a common symptom. The pain could be from the nerves (neuropathy) or the muscle (myopathy). Nerve pain tends to be a burning type of pain, usually along the soles of the feet, but can have other distributions. Unless you have experienced nerve pain, you cannot imagine how bad it can be. Muscle cramps are also painful; this it the type of pain you get with a Charlie Horse. Muscle pain is also thought to be due to an accumulation of metabolic toxins.

Each person's pain is a separate issue and treatment is beyond the scope of any simple discussion. Identifying the cause of the pain is the most important point. For those with mitochondrial diseases I use Carnitor and Neurontin for most pain, and Gabitril for cramping pain. None of these are typical pain medicines. I find that ibuprofen is not that helpful and that narcotics are not helpful (and addicting).
Answered by: Bruce Cohen, MD

Q: How does mitochondrial disease affect the brain, and cognitive
function? How common is it to see a child with mitochondrial disease that is quite bright?

A: As all cells and organs require energy, mitochondrial disease can affect almost any part of the body. However, because of their very high energy requirements, nerve and muscle, and especially brain, are affected more often than other parts of the body. Mitochondrial disease can affect any part of the brain, resulting in many possible problems that can occur in any combination, including mental retardation, learning disabilities, autistic features, depression, attention deficit, seizures, loss of balance (ataxia), floppy muscles (hypotonia), tremor, and many others.

Many physicians have the opinion that all individuals with mitochondrial disease are mentally retarded. Many are, but many are not. The truth is that any level of intelligence is possible ranging from gifted to profoundly mentally retarded. Personally, I have evaluated several individuals with mitochondrial disease that are "bright"; usually they suffer overall from mild to moderate disease.
Answered by: Richard G. Boles, MD

Q: My two year old son has been diagnosed with a Complex IV defeciency via muscle biopsy. Are there further tests which can help to determine whether or not the defect is maternally inherited or inherited via nuclear DNA? We have had five children in total, one of which died at three days of age (hydrops fetalis cause undetermined). I would like to know what impact this disease may have on our other three children who are healthy at this time. If there are more tests available could you please indicate what these tests may be and where they are performed. C.H.

A: In most young children with Complex IV deficiency, the disease is caused by mutations in nuclear genes, although there are likely to be some exceptions with mutations in mitochondrial DNA genes. To date four different nuclear genes have been shown to cause Complex IV deficiency and it is likely that several more such genes will be identified in the next few years. Of the four genes identified so far, mutations in the SURF1 gene are probably the most common cause of Complex IV deficient Leigh disease. Mutations in the SCO2 gene have been found in a number of different families, typically in association with severe heart disease and encephalopathy. Mutations in the SCO1 and COX10 genes have each been identified only in single families so it is unclear if they have cause a characteristic set of symptoms.

It should be possible to arrange further testing for Complex IV mutations, but this will depend on a number of factors. These issues need to be discussed with a physician who has expertise in mitochondrial disorders, who should also be able to give advice about whether other family members may be at risk. For example, apart from the clinical symptoms and family history, it would be important to know the details of the muscle biopsy results, preferably for Complex IV assessed both by enzyme studies and by enzyme histochemical staining. Depending on these results, it may be feasible to test for SURF1, SCO2 or mitochondrial DNA mutations at a limited number of specialist reference laboratories.
Answered by: David R. Thorburn, PhD

Q: I have identical twins, 5 years old, who have been diagnosed with Complex I. Their liver function tests show elevated SPOT/SPGT but liver biopsy proved normal. How often should the SPOT/SPGT be tested? What are other signs of liver failure/disease? J.C.

A: This is a difficult question to answer - I think they should probably be checked on a regular basis so it can be seen whether they are going up or down -sometimes elevation in liver enzymes can happen with disease or with drug treatment etc. Again it would depend on how the enzymes were as to how regularly I would have them checked - once every two to three months if they are only mildly elevated.
In liver failure other functions of the liver start to fail - jaundice
can develop, clotting problems, general malaise etc.
Answered by: Douglass M. Turnbull, MD, PhD

Q: Can Mitochondrial Cytopathy be aggrivated by Chiropractic treatment?
or can Mitochondrial Cytopahy effect chirpractic results? J.P.

A: I would not imagine that most mitochondrial symptoms would be aggravate by chiropractic treatment. However, mitochondrial disorders are highly variable and although I assume that chiropractic treatment includes manipulation and massage; there may be other treatments I am not aware of. Likewise, chiropractic treatments may result in improvement of some symptoms of mitochondrial disorders, such as pain or stiffness. Unfortunately, the field of chiropractic medicine is still a "black box" to most of us allopathic doctors (MDs) and osteopathic doctors (DOs). I have had patients with pain, headaches, backaches and so forth benefit from chiropractic treatment. Many chiropractic doctors focus on nutrition and exercise, which is very reasonable as long as it does not involve therapies such as chelation. (However, many mito doctors are criticized for using supplements such as carnitine and CoQ10). Like any medical care, you need to choose your doctor with care. If a patient wishes to use chiropractic treatments, I do pick up the phone and speak with the other doctor to make sure we are on the same page.
Answered by: Bruce Cohen, MD

Q: Our 5 year old daughter was diagnosed with Leigh's Disease after two "episodes" at 15 months and 2.5 years of age. The episode consisted of loss of motor skills during and after an illness with high fever. The last "episode" required hospitalization in the ICU with ventilator support. MRI scans indicated basal ganglia damage and later blood testing revealed the mtDNA 8993T-C mutation. After 2 years she has recovered 80% of her motor skills, appears as a normal child, has been illness free, and has not had another "episode".

All that we read about Leigh disease paints a very grim prognosis. We realize that no one has a crystal ball, but can we hope that preventing the onset of illnesses will impede the progression of the disease? Is there any data on the longevity of Leigh disease patients? Perhaps statistical information indicating percentages of patients surviving 1,2,5,10.. years?

It was mentioned during one of the UMDF symposiums to avoid illnesses at all costs. Would the exclusion from the school environment in order to avoid highly contagious areas, be a reasonable cost? (ie. school service provided at home) We are looking for a second opinion, since our local neurologist does not support our belief of limiting exposure to high risk environments. R.W.

A: Let me start with the good news. As you probably know, the T-to-C mutation at nucleotide 8993 is probably the "mildest" of all causes of Leigh syndrome, certainly much less "malignant" than the T-to-G mutation at the same nucleotide. We have seen children and young adults with this mutation manifesting variously severe, but not fatal, neurological symptoms (Santorelli et al, Pediatr Res 1996;39:914-917). Nobody has statistical information on percentages of survival, but, as I mentioned above, survival is much more common with this mutation than with others.

Regarding the degree of protection, my personal inclination would be NOT to isolate the child in a "bubble", but simply to be vigilant about intercurrent infections.
Answered by: Salvatore DiMauro, MD

Q: My 2 year old son, has a complex I dx. He also has myoclonic seizures daily that have not responded successfully to medication or the ketogenic diet (8 months). We have tried many different meds (zonegran, ACTH, phenabarb, lamictal, tegretal, topomax, klonopin, neurontin, felbatol, keppra) and now his neuro wants to try Depakote.

I know that it is not "mito" friendly, but what exactly does that
mean? Is this a theoretical conclusion, or is this an observed pattern? What have been some of the complications with other mito patients?

A: There is a great deal of debate about the use of valproate in those with mitochondrial disease. This was discussed in a lively debate at the 2000 UMDF meeting in Cleveland. The transcript of this is available on audio tape through the UMDF office. Comments ranged from "I would never place a mitochondrial patient on valproate" to "Mitochondrial diseases are hundreds of different unique diseases and some patients can be safely treated."

Conflicitng thoughts by experts include the following:

1) Many patients come to diagnosis of a mitochondrial disease because they develop life-threatening complications (liver failure requiring liver transplant) when they are treated with this medication.

2) The fatal/life threatening hepatotoxicity is similar to other mitochondrial processes

3) Many patients with mitochondrial diseases are on Depakote and have no problems.

My own personal practice includes a number of patients on Depakote (valproate) without a problem and a handful that have suffered near- fatal events. I personally do not think a child will respond to valproate if he or she has not resonded to all those other treatments. Furthermore, the risk seems to be clearly increased in young children previously treated with inducing anticonvulsants (ask your doctor which are and are not inducing drugs), and those on more than one anticonvulsant. It is not clear if close monitoring of liver function can really prevent the liver problem.....the issue if stopping the medicine if liver problems arise is one of "too little too late."

The final decision is between you and your doctor. This is obviously not a satisfying answer, but I cannot get closer to the truth aside from presenting the facts as they are known.
Answered by: Bruce Cohen, MD

Q: My son was diagnosed with an unknown leukodystrophy in 1989, and in 1997 with mitochondrial complex III deficiency. His feet & legs began swelling in 1996 and this was treated with spironolactone & furosemide. The swelling continued until his legs were so huge he could no longer stand, and he was constantly in pain. He also began having chest pains at that time. I found a specialist in 2000 who diagnosed lymphedema and recommended lymphedema therapy. Is lymphedema a complication of mitochondrial disease? G.E.

A: In my personal experience, localized swelling and/or pain are common in children and adults with mitochondrial disease. Changes in color and/or temperature of the skin can also occur. Usually the arms and/or legs are involved, but the face and/or torso (including the chest) can also be affected. Like other "mito symptoms", the problem usually comes and goes, often triggered by stress (fasting, fever, illness, exercise, sunburn, etc.). Most often the problem is less severe than what you describe, but it can be severe in some cases. Usually, there is a maternal inheritance pattern.

I believe that these changes are manifestations of dysautonomia (abnormal regulation of the automatic part of the nervous system), as they usually occur in individuals with at least one other sign of dysautonomia (migraine, vomiting episodes, reflux, severe constipation, racing heart rates, hyperventilation, changes in body temperature, etc.). Avoidance (as much as possible) of any triggers is important. Also, the simple treatment regiment of ibuprofen (Advil, Motrin), caffeine, sugar and fluid (the latter 3 are found together in colas and Mountain Dew) is helpful in some. Amitriptyline
(Elavil) or cyproheptadine (Periactin) are usually helpful. However, like any medication, there are potential side effects so please discuss this with your doctor(s) before trying anything.

Lymphedema is a descriptive term; many different diseases can cause it, and thus this "diagnosis" was not made in error. In regards to the diuretic medications your son was given, my advise is to continue them if they are helping, but watch carefully for dehydration, as this can cause metabolic decompensation and serious illness in individuals with mitochondrial disease.
Answered by: Richard G. Boles, MD

Q: Recently my dermatologist prescribed a lotion for my dry skin called Lac-Hydrin 12%. Every time I put this cream on my skin I experience muscle pain and aches. When I looked at the ingredients I noticed that it contains lactic acid. Is this a normal occurance for mitochodrial patients? Y.B.

A: No. Lactic acid, even when given into the blood stream, does not cause pain. The pain everyone feels with vigorous exercise is not due to the lactic acid. There is something else in the cream that causes pain.
Answered by: Bruce Cohen, MD

Q: We have a 7 year old granddaughter who has been diagnosised with Mito, with ragged red fibers. She is mobile with only clinical symptoms of muscle weakness. Is there any information on the product called Ambrotose obtained from Mannateck Company in Texas? V.W.

A: Ambrotose and other similar products have not been studied in a systematic fashion in mitochondrial diseases. Aside from Coenzyme Q10, creatine monophosphate levo-carnitine and dichloroacetate, there is very little information about any vitamin or supplement aside from case reports. For the above mentioned supplements, there is very little data, and that data is not entirely convincing, but the studies were not designed to answer the question if the supplement will help over the long term.

I have had a few patients try Ambrotose and they swear by it. Others have tried it and not continued because it did not help. I do not see where it could pose any harm either but that does not mean I said it was safe. As will all decisions you must discuss this with your child's doctor.
Answered by: Bruce Cohen, MD

Q: Could BIH (benign intracranial hypertension) or any of the following symptoms be related to Mitochondrial Myopathy?

blurred vision
aura around the outside of the eye
along with a progressive tunnel effect

A: Episodes of blurred and/or distorted vision (including the "tunnel effect") are common in migraine. Headache does not need to be present. Migraine is very common in a wide variety of mitochondrial disorders. I am not aware of any association between intracranial hypertension and mitochondrial myopathy/disease.
Answered by: Richard G. Boles, MD

Q: Is not sleeping common in mitochondrial disease?

A: Sleeping problems are very common in infants, children and adults with Mitochondrial diseases. I do not believe there is any study in the Literature that addresses this issue. In Angelman syndrome, which shares many characteristics with mitochondrial disease (lactic acidosis, low ETC activity in those that have been biopsied, microcephaly, seizures, developmental delays and autistic features)lack of sleep is part of the illness. The comments below reflect my impressions.

I would divide the problem into two categories:

1) difficulty falling asleep
2) difficulty staying asleep

I believe some brain disorders result in abnormal cycling of the sleep wake cycle. I am not an expert in sleep and cannot provide the details. There are three centers in the brainstem that mediate wakefullness, REM sleep (dream) and non-REM sleep. The balanced interactions of these centers mediate normal sleep patterns and if one or more are not functioning, there there could be sleep onset problems or sleep maintance problems. Medications are used for these problems but are not very effective. Melatonin is sometimes helpful. There are no magic potions.

Hunger (either the sensation of hunger as we know it, or metabolic hunger can interfere with sleep). This is why a bedtime snack is helpful in some.

Pain is also a cause of sleep problems. I use Neurontin for body, muscle and nerve pain in my patients, with some benefit.

Depression can cause sleep problems.

Sleep apnea, either central (the brain is not driving the ventilation process) or obstructive (due to weak throat muscles or obesity) can cause difficulty with sleep onset or repeated awakening.
Answered by: Bruce Cohen, MD

Q: Our son is 2 1/2 years old and was diagnosed with complex IV defeciency via muscle biopsy. He has low tone, 100%g tube fed, gastric reflux, stridor, global developmental delays, heat intolerance, excessive sweating and seems to have crisis about evey six months or so which require hospitalization and IV fluids though all his blood electrolytes and blood gases are normal. With this past hospitalization they noticed elevated blood pressure which has continued since he has been home. They average around 125/65-70 he is 2 years 7 months and 93 cm in length. He also started having a red blothcy rash in his chest, neck and face area when overheated or stressed. As well, he vomits 2-3 times a day which started about one year ago and does not seem to repond to changes in rate, volume diet or mediction. His cardiac and renal function are fine. Could these symptoms be related to autonomic dysfunction, and if so are there any treatments you might be able to suggest? CMH

A: In my experience, dysfunction of the autonomic nervous system (dysautonomia) is not uncommon in patients with mitochondrial disease. Findings in your child which likely are related to dysautonomia are gastrointestinal dysmotility (including reflux), heat intolerance, excessive sweating, hypertension and a red blotchy rash. Episodic deterioration can be caused by many factors, including dysautonomic crises. Vomiting a little each day is likely secondary to reflux.

Treatment for dysautonomia is complicated and requires evaluation and follow-up by a knowledgeable specialist. Sometimes, frequent high carbohydrate feedings can help(but it sounds like this has been tried and did not help your child). Medical treatment, especially amitriptyline (Elavil) is usually effective for some of the symptoms of dysautonomia, but is not always appropriate in every patient. If used, EKGs should be checked before and after starting treatment for the possibility of a prolonged QTc or other rhythm disturbance.
Answered by: Richard G. Boles, MD

Q: My pediatric neurologist requested that I ask about the use of Clonazepam and Tetrabenazine for choreoathetoid movements in mitochondrial patients. C.H.

A: Some children (and adults) with mitochondrial cytopathy develop abnormal movements. This is due to damage in the motor control centers within the deep parts of the brain, which are also the parts that require the greatest amount of energy to function normally.

The names used to describe the movements are difficult to pronounce and the nature of one type of movement often blends into the nature of another type of movement. Chorea are movements that are caused by rapid contraction of a muscle group across a joint, and have a jerking quality. They tend not to be large amplitude movements and not flailing movements either. (You have to see them to understand them). Dystonia is an abnormal sustained posture. These two movements are often seen in combination and are classified as choreoathetosis or choreoathetoid movements.

Other common movements we can see in mitochondrial patients include tics (twitches of the face, neck), tremors (fine shaking -shivering movements), myoclonus (lighting fast jerks) and hemiballism (large scale trashing type movements).

There is a long list of medications that can be used to decrease these movements. There is no one best medication, and what works in one person may not work in another. All medications have side effects.

The first question is whether or not treatment is needed. If the movements are mild and/or do not interfere with function, I tend not to treat.

The use of muscle relaxants (Valium, Clonazepam, Baclofen and so forth) can be helpful, but these tend to be sedating. I use these only when the movements are severe and do not respond to other medications. They are safe medications, but sedating. I do not use tetrabenazine, because of side effects and lack of effectiveness in the patients I have seen. Some of the newer anticonvulsants (Lamictal, Keppra, Gabitril and Topamax) have reduced these movements in some of my patients, so I tend to start with those medications. Each doctor has their favorites....medications that they feel comfortable with and seem to work for their patients.

Many neurologists and almost all other doctors do not treat movement is a small part of neurology. If this is the case it is worth seeing a movement disorder specialist. All big medical centers have one of these subspecialist neurologists. They usually see only adults but will often do a one time consult to help the pediatric neurologist out with a difficult clinical situation.

One important factor to keep in mind is to have a goal with a medication. Plan the dose escalation (start at a low dose and work your way up to the maximum tolerated dose), and if the movement does not improve, get off that medication and try another. Keeping people on these medication for months does no good. This means that you may need to tell your doctor that you want another visit in a month (instead of 3-6 months), so as to assess the improvement or lack of improvement and plan the next move.
Answered by: Bruce Cohen, MD

Q: I have adult onset mitochondrial problems, which have not yet been Clarified as to which metabolic pathways are involved. Meanwhile, I Ffind that cold exposure as well as physical activity can lead to considerable weakness, incoordination and pain in my legs and feet. I no longer know how far I can go in a day and how to determine the significance of pain, which is the first of the symptoms that develop as the day goes on. While I want to be as active as possible, I do not want to cause tissue or nerve damage. Could anyone suggest guidelines to help a patient determine when to continue or curtail activity? C.C.

A: Mitochondrial disease can be thought of as like an electrical power crisis: the lights tend to "brown-out" at times of peak energy demand, for example during extreme weather conditions when everyone is running the heater or air conditioner. Similarly, in mitochondrial disease the body's cells suffer from low available power at times of peak energy demand, for example during hot and cold weather, exercise, fever, illness in general and stress. Weakness and pain are typical symptoms when muscle is low on energy. Incoordination may be secondary to muscle weakness or low energy in the nerves.

I wish that I could answer your question regarding activity guidelines, but I cannot. In fact, no one can, except perhaps yourself. When you are experiencing significant pain or weakness, that is the time to stop. The amount of allowable activity varies substantially among patients, and, as you have found out, there is tremendous variability from time to time even in the same patient.

In some patients, rhabdomyolysis (muscle breakdown) can occur with exercise. Other potential triggers for rhabdomyolysis include illness, fever, fasting, alcohol and stress. Rhabdomyolysis should be suspected when the urine becomes "Coca Cola colored". If present, medical attention should be immediately sought and hydration (by mouth or iv) given to avoid possible kidney damage.

Please do not take this response to mean that exercise is dangerous and should be avoided. Many "mito" specialist strongly believe the opposite: that exercise is necessary and can improve muscle strength and endurance, as well as general well being in patients with mitochondrial disease. The best advice is moderation: don't over do it or under do it. Exercise frequently and up to your individual tolerance (which will vary from time to time), and stop once symptoms become significant.
Answered by: Richard G. Boles, MD

Q: I recently read an article about the adverse effects of Co Enzyme Q on worms. The article was about a study that indicated that worms that were given Co Enzyme Q had shorter life spans. What are the implications of this study for mito patients? JB

A: I also read the article and thought about its potential implications for humans. First, of course, one has to keep in mind that extrapolating data obtained in worms to the human situation is dangerous. Second, my intuitive reaction is that, in nature, too little and too much of a good thing may be detrimental. Clearly, patients with primary CoQ10 deficiency are severely affected and benefit from CoQ10 supplementation. Do we give them too much CoQ10? We are studying this question, in an attempt to establish the minimum dose of CoQ10 needed to reach a maxumum level in blood. However, it is also clear from our own experience with CoQ10-deficient patients and ALS patients, and from the experience of the Huntington Study Group (published in the latest issue of Neurology) that high doses of CoQ10 are well tolerated by patients.
Answered by: Salvatore DiMauro, MD

Q: I understand that a lactate:pyruvate ratio greater than 20 might suggest that an individual has an OxPhos disorder. Can you tell me why? Also would this ratio apply to urine lactate and pyruvate, blood samples, cerebral spinal fluid, or all three? A.J.

A: You may want to get out your textbook of metabolic pathways here. There is no easy way to explain this. However, if you follow the dotted lines, it all makes very good sense. Here we go.

The ratio of lactate to pyruvate reflects the ratio of NAD+ to NADH.

Glucose is converted to pyruvate, which enters the citric acid cycle, where high energy NADH is generated. The electron transport system accepts the high energy NADH and as it is converted back to NAD+ electrons are pumped across the inner mitochondrial membrane. The charge created by this electric potential will be used to generate the high energy usable form of energy (ATP) from ADP.

If the electron transport chain is not working, the NADH cannot be converted to NAD+ (and energy, ATP, is not produced).

By converting the normal intermediate chemical pyruvate into lactate (which has no role inside the human body), the body is able to convert all the extra NADH that is accumulating to NAD+. Why is this important? Because one step in glycolysis (the set of reactions where glucose is converted to pyruvate) just so happens to make a little ATP by converting NADH to NAD+. Remember that glycolysis does not require oxygen either. Therefore, the body has developed a way, by converting pyruvate to lactate, to regenerate a compound (NAD+) that can then be used to tweak out a little more ATP when the electron transport chain is not working or when there is not enough oxygen around. The body has no use for lactate, but this is a compensatory mechanism to get the unusable NADH back to NAD+ which in turns helps generate a little more ATP. In doing so, however, more pyruvate is made, resulting in the lactic acidosis situation getting worse.

What happens inside the body during a mitochondrial crisis or oxygen deprivation is that the ratio of lactate to pyruvate rises. The ratio of 20:1 is what is in the literature. This would apply to CSF as well. I would not use this on urine however.

A few key points however:

1. MOST medical centers do not run pyruvate correctly. Unless the blood is instantly deproteinized, it is not the gold standard method of doing the test.

2. IF the lactate is not elevated, do not bother looking at the ratio. It is not important. In other words, the only time an elevated lactate/pyruvate ratio is important is when the lactate is high.
Answered by: Bruce Cohen, MD

Q: I recently read an article about the adverse effects of Co Enzyme Q on worms. The article was about a study that indicated that worms that were given Co Enzyme Q had shorter life spans. What are the implications of this study for mito patients? JB

A: I find this very interesting and it raises a few points:

1. Very few things in life and medicine are free of costs and risks. Vitamin A is essential for life but too much (25,000 IU a day in some people can cause liver and eye damage. Vitamin B6, in small overdoses (500 mg a day) can cause nerve damage in humans. There is now data to suggest that in a primitive life form, excess CoQ10 shortens life.

2. One must caution about using animal data when making decisions about human health and disease. For example, scientists have been able to cure the most malignant form of brain cancer in lab rats for over 20 years, but have made no headway in humans. Furthermore, harmless foods like chocolate can be poisonous to dogs but is harmless (some claim lifesaving) to humans. There may be factors in worms that just do not translate to human physiology.

3. The worms did not have a mitochondrial disease.

4. Despite the cost and inconvenience, most of my patients that start on CoQ10 stay with it because it serves some benefit, which is difficult to measure, or because they (and their doctor) believe that "it makes sense" to stick with a treatment for a group of illnesses without a cure.

5. On rare occasion, I do see a child or adult with an adverse reaction to CoQ10. This has included anxiety, hyperactive and maladaptive behavior, and recently a dramatic increase in seizures (although other supplements were added at the same time). We do not have an explanation for this.

6. The authors of the study do a good job in explaining the pitfalls in this study. Antioxidant drugs can become oxidant drugs under certain conditions, as this study probably demonstrates. Our grandmothers all taught us that "too much of a good thing......"

This study does bring us to always question whether or not Coenzyme Q10, or any supplement, is helpful in any one person. Most physicians in the field believe a trial of Coenzyme Q10 is indicated in those with a mitochondrial cytopathy, but we all want to know if it makes sense to continue this supplement in a person that does not show some form of improvement. I do not think Coenzyme Q10 levels are the answer to the question either, although there may be a value in knowing what a person' CoQ10 level is before and after treatment. The results of this study will not influence the way I practice medicine. Having recently reviewed the literature for a chapter written by Dr. Gold and myself in Dr. Shoffner's monograph on Mitochondrial Diseases, the data suggest that coenzyme Q10 and levocarnitine are worth a trial in any patient with a mitochondrial cytopathy.
Answered by: Bruce Cohen, MD

Q: My son has been diagnosed with mitochondrial disease. In the Winter 2000 UMDF newsletter article "Mitochondrial Disease in Perspective Symptoms, Diagnosis and Hope for the Future", I read that idebenone may penetrate the nervous symptom more easily. My doctor is willing to prescribe it, but is unsure of dosage. My son weighs 23 lbs. and is 3 years old. Where can we find more information? D.W.

A: Idebenone is a molecule similar to Coenzyme Q10. It is currently not available in the USA, although I have heard of some being able to get it easily from oversea sources. I do not know how to get a hold of this product.

The reported advantage is that it passes into the brain better than coenzyme Q10. I have spoken with one European expert that uses a Idebenone and feels that it works as well or better than Coenzyme Q10, but this was based on limited experience and outside of the context of an actual study. I have also talked to and have heard that their was no improvement or worsening on this. For this reason, I have not recommended this supplement in any of my patients.

There have been a number of case reports indicating improvements in strength, visual acuity, intellect and other neurologic features. However, these seem to be all case reports. Doctors do not write case reports on failed therapies. Idebenone may be very helpful in cardiomyopathy associated with mitochondrial disorders and it is being studied for a very specific indication in Friedreich Ataxia (a disease that causes mitochondrial dysfunction). The doses I have found in the literature vary between 100-200 mg a day for older children and adults but I was not able to find the dose (in time to answer this email) that they are using in the FA study. I would ask your doctor to investigate the FA study through the NIH if you wish to pursue this treatment.
Answered by: Bruce Cohen, MD

Q: If a post mortem is performed on a child with? Leigh's or Inborn error of metabolism. What specimens should be collected and how should they be stored to confirm this diagnosis and also to be able to test for the exact defect causing Leigh's? J.M.

A: In case of autopsies from patients with possible Leigh syndrome (or any other metabolic disorder), we routinely ask the pathologist to freeze portions of the following tissues: skeletal muscle, cardiac muscle, liver, brain, and kidney (about 1 gram amounts for each tissue). We use these tissues for biochemical and, when warranted, molecular analyses.

Answered by: Salvatore DiMauro, MD

Q: Would you be able to tell me a bit about type 1 fibre predominance. My son had a biopsy and it showed he had irregular size muscles fibres is it the same thing? What does this mean?


A: No, it is not necessarily the same thing. Hope the summary below helps. It is a good question but a little complicated.

Type I fiber predominance refers to an increase in number of Type I fibers above the predicted level for a given muscle. For example, the ratio of Type I (OXPHOS dependent) to Type II (glycolytic)fibers is about 1:2 (Superficial triceps, biceps, vastus lateralis. The finding is not specific for a certain disorder and can be seen in many different conditions including myotonic dystrophy, various types of congenital myopathy, in muscle from the legs of children with club feet, mitochondrial disorders, etc.As you can see, this finding does not predict the presence of a specific disorder. The Type I fibers are generally smaller than the Type II fibers.

Answered by: John Shoffner, MD

Q: Is it possible to have very high lactic acid upon exertion, without having a mitochondrial disorder? If so, what would be some other causes? And is Lactic acid testing a normal procedure to check for mitochondrial disorders? Y.B.

A: Yes, lactic acid can be very high on anaerobic exercise or in a young child screaming. this is why it is essential to only measure lactic acid levels under basal conditions or under a carefully controlled exercise test. Lactic acid measurements in blood and the spinal fluid are commonly used to help with the diagnosis of mitochondrial diseases especially in children, but only measured under carefully controlled conditions.
Answered by: Douglass M. Turnbull, MD, PhD

Q: What are the possible side effects of CoQ10 enzyme? Is there a reason why you would need a blood test for Vit. E prior to taking CoQ10. K.S.


A: Coenzyme Q10 is not an enzyme, but a naturally occurring component of the respiratory chain. In our experience (and according to available literature), there are no side effects even with high doses (800 mg/day) of CoQ10. I do not see any reason to test for vitamin E.
Answered by: Salvatore DiMauro, MD

Q: With new onset of Central sleep apnea at the prepuberty point, would you explain it as progression or possible temporary stress on the body? Once central sleep apnea is diagnosed, can it be stable and not cause any significant health risks or can you expect once it has started to continue and get worse?

A: There are a number of causes of sleep apnea, and the answer to your question depends on the exact cause. Sleep apnea is not common in mitochondrial disorders but I have seen it occur. Sleep apnea is rare and the causes can be broken down into two large groups: obstructive sleep apnea and central sleep apnea. I will offer a simplistic viewpoint of the issues you have raised.

The common obstructive causes are obesity, large tonsils, weak muscles in the throat. These are easy to diagnose and although the treatment is not easy, it is generally effective. I have one mitochondrial patient that is overweight and has weak throat muscles. His sleep was interrupted one hundred times a night because of the apnea that occurred as a result of these problems. By sleeping with a device called a BiPAP, which "forces" pressurized air into his nose continuously, he can sleep without the obstruction and repeated awakening. His mind is clearer and his headaches have resolved. There are also surgical treatments to obstructive sleep apnea.

Central causes of sleep apnea involve a defect in the regulation of breathing during sleep. The part of the brainstem that controls breathing and other functions of the sleep-wake cycle can be affected by defective mitochondrial function. If this is the case, the problem can become more severe over time. At the most severe end of the spectrum, death can result. The use of assistive breathing devises, the so called "iron-lungs" are often the necessary treatment. Iron lungs do not exist anymore, but there are two devices that function the same. One is made out of canvas and the other looks a bit like a hard plastic turtle shell. The person sleeps inside the device, which is attached to a pump that assists breathing by placing negative pressures on the chest wall (so the lungs inflate). Seizures and chest wall muscle weakness can also cause apparent sleep apnea.

If sleep apnea is a consideration, the person should undergo a sleep study in a comprehensive laboratory, using pulmonary and Ear-Nose-Throat consultants as well as neurologists, to come up with a plan of treatment.

The bottom line is that new onset sleep apnea can be part of a mitochondrial cytopathy. The treatment depends on the cause. As with any new sign of the disease, it is impossible to make predictions.
Answered by: Bruce Cohen, MD

Q: After 8+ years of doctors, hospitals, tests, etc., my 9 year-old son has a confirmed diagnosis of a complex I defect. What would make a doctor choose to test some complexes and not others? He was not tested for complex III or complex IV.

A: This is a difficult question without seeing the test report. It is possible that there were not enough mitochondria isolated for complete enzymological testing. A complete report would be needed in order to evaluate what kind of complexities existed during the evaluation.
Answered by: John Shoffner, MD

Q: I was diagnosed with a mitochondrial myopathy 4 years ago on the basis of symptomology (including, stroke like episodes, cardiac dysfunction, lactic acidosis, loss of muscle strength, etc) and a muscle biopsy which showed reduced Complex I function, and abnormalities in the shape/size of the mitochondria. My 4 year old son has many health issues (including, autonomic dysfunction, immune suppression, GI issues, respitory issues, language delays, etc). Our doctors are presently refusing to test for mitochondrial disease, as his symptoms mostly differ from mine, thus they believe he cannot have my mitochondrial disease. We have also been told that because his developmental milestones ar on track then he cannot have mito. Are they right? Should I be pursuing this further? What should we be doing? I feel it is important to know if he has mito so that we can treat him accordingly (e.g. mito cocktail, etc).

A: Among the large group known as "mitochondrial disorders", mutations of mitochondrial DNA (mtDNA) are inherited from mother to child. Among mtDNA mutations, it is the rule that every family member is affected in very different ways. This is true not only in terms of disease severity, but also regarding symptoms, organ systems involved and the age of onset. I have personally treated individuals with mtDNA mutations who suffer from each of the problems that you list for you and your child, including mothers with myopathy whose child(ren) have dysautonomia. In addition, many if not most children and adults affected with mtDNA mutations have normal intelligence/development.

If your family had "mtDNA analysis" performed which was negative, that in no means rules out a maternally-inherited mtDNA mutation. Commercially-available testing only identifies a small minority of known mutations. Many more mutations are found upon very tedious and expensive research investigations, but even then there are families with obvious maternal inheritance of which the mutation cannot be presently identified. Therefore, mitochondrial disease remains a possibility and you should pursue this further. The UMDF can help to steer you to the appropriate expert(s)closest to you.
Answered by: Richard G. Boles, MD

Q: Do you feel that there is any hope for the kids (or adults) with mitochondrial disease to benefit from stem cell research? Our doctor said that it would be such a long time before anything came from the research but it seems they are making such strides. How could a family find out which scientists are working on projects that may benefit their child? A.P.

A: Stem cell research will have important consequences for all neurological conditions. There are many hurdles to cross before this form of therapy will be available for any of these conditions and therefore your doctor is correct. I know of a number of groups who are trying to use stem cells to prevent the transmission of the disease and for the muscle complications. I know of no groups that are currently working on Neuronal stem cells to treat the neurological condition but there are many groups working in this area to treat Parknison's disease and Alzheimer's disease.
Answered by: Douglass M. Turnbull, MD, PhD

Q: Can you please explain causes and symptoms of complex migrane with auras. I get symptoms without pain, then other times a headache will come on with no warning at all. Is this all part of the mito? L.H.

A: Despite the fact that migraine is very common (it is seen in 10% of all people), its causes are not well known and are the matter of much scientific debate. Many, but not all, migraine sufferers will occasionally or always experience an aura before the headache and nausea appear. Aura can also occur without pain - this is still migraine. The aura is best defined as a sensory disturbance, and can involve any sense. Some examples are flashes of light, hearing everything as if in an echo chamber and an unusual taste.

Patients with "mitochondrial disease" often complain of migraine. Frequently, so do their matrilineal (maternal) relatives. In these family members, migraine can occur even in the absence of other problems. Since migraine is so common overall, it is difficult to know for sure that it is related to mitochondrial disease/dysfunction in any given individual. My theory is that anyone can get migraine for a variety of reasons, and some degree of mitochondrial dysfunction increases the probability.

However, whether due to mitochondrial dysfunction in whole, part, or not at all, migraine responds to many of the same treatments, in my experience. In "mito" families, fasting avoidance with frequent complex carbohydrate snacks is often helpful.

Answered by: Richard G. Boles, MD

Q: Recently I have undergone a pulmonary stress test with blood gases, and found out that after 5 minutes of exertion I excrete quite a bit of lactic acid. Is it possible to NOT have a mitochondrial disease--but some other type of illness with lactic acid problems? Can sedentary people have this type of lactic acid problem? What kinds of health problems can lactic acid cause on my muscles and/or organs? Y.B.

A: A high lactic acid response is non-specific and will depend on a number of factors including fitness, drugs that are being taken, heart conditions and mitochondrial disease - to name just a few. Lactic acid rarely causes any specific problems and is usually metabolised in the liver.
Answered by: Douglass M. Turnbull, MD, PhD

Q: My 6 year old son has a probable mito encephalomyopathy,late last year year he developed stroke like episodes. just this last month he has started myoclonic jerks. i know nothing about thesejerks can you please help me they are scarry. J.O.

A: Myoclonus (also referred to as a myoclonic jerk) is a sudden single rapid movement caused by rapid contraction of a muscle group, usually across a joint, such as an elbow joint. The movement looks like what can be described simply as "a jerk".

Myoclonus should be evaluated in the context of the rest of the person's problems. If it is keeping company with other bad symptoms, the chance that is represents something "bad" is pretty high.

Myoclonus can affect a limb, a part of a limb, the trunk or the neck. It also can affect facial muscles or the throat (known as bulbar myoclonus). Myoclonus can be seen in healthy people. We all have some of these movements, on occasion, when we fall asleep. This "sleep onset myoclonus" is not really a disease. It can become a problem if severe, and if it persists during sleep, it is a sign of problems. There is also a harmless form of myoclonus in babies, but the only way to tell this apart from seizures is to do an EEG.

Myoclonus is a descriptive term and never implies a cause. This is an important concept for myoclonus and other terms used in medicine. For example, you may ask a doctor the following question: "Why do I have a cough?" The answer would include the following possibilities: simple cold, pneumonia, asthma, emphysema, lung cancer. The word "cough" is the descriptive term and the job of the doctor is to determine the diagnosis.

Myoclonus can be caused by a lack of oxygen (the main cause of bulbar myoclonus). It is also seen in many destructive diseases of the brain and spinal cord. There are at least 75 known diseases that have myoclonus as a prominent feature. I have listed just a few, and as you can see, many of these are mitochondrial based illnesses. Why? Probably because the damage to the brain and spinal cord cells that occurs when the body is deprived of oxygen is the same damage as done when the body is deprived of energy. Remember: We breath oxygen so that complex IV can do its job. Taking away oxygen from the body is the same as stopping complex IV from working properly. (Complex IV pumps an hydrogen ion across the inner mitochondrial membrane and turns oxygen into water.)


The bottom line is that myoclonus affects many people with mitochondrial diseases. Although there are a number of medications that have been used to stop or lessen myoclonus, I have not found the standard treatments to be helpful in my patients. I have had limited benefit from Lamictal and Keppra (two medications that are usually used to prevent seizures, and are "safe" to use in those with mitochondrial problems.)


Answered by: Bruce Cohen, MD

Q: In your experience, how do girls going through puberty tolerate it. If you could speak to Leigh's Disease more specifically I would appreciate it. Are there worseing of symptoms, progression etc.? L.S.

A: I have not found more mitochondrial problems related to the years of puberty than any other particular timespan in a person's life. Children with Leigh disease can deteriorate at any time and I have not observed this point in a person's life to be more metabolically unstable than other times.

Having answered part of the question, I will bring up a few more points:

The issues surrounding puberty needs to be considered separately for those children that are bed bound because of their illness and those that are functioning normally (and everyone in between these extremes).

However, the growth that occurs during puberty can cause other problems to occur. Scoliosis, or curvature of the spine, often becomes much worse in any person with a muscle disease, during growth phases. This affects children that are not mobile, such as those that are not able to walk or sit independently. Scoliosis can lead to pulmonary problems, such as aspiration and pneumonia, which can be fatal.

Puberty is a time for exploration and problems such as alcohol and smoking come up for all kids. These two substances can worsen mitochondrial problems. Lack of sleep can trigger migraines, seizures and fatigue.

There are management issues that crop up as well for those those young women that are bed bound; hygiene issues surrounding the menses are difficult to handle. I have had two patients that have undergone hysterectomy as a measure to handle this problem. The use of birth control pills for the purpose of managing heavy periods can be considered in those without strokes or complicated migraines. I advise against birth control pills as a routine form of contraception, because of the concern over strokes, although I know of no literature to show it is more dangerous in person's with mitochondrial problems. (For those women that are already on them when I do their evaluation, I do not have them stop unless there are problems).

A little off the topic: for the affected (mitochondrial) women entering menopause, I advocate estrogen replacement as long as they have discussed all the aspects with their doctors.
Answered by: Bruce Cohen, MD

Q: My 9 year-old son has a confirmed diagnosis of a complex I defect. What actually causes the pain he suffers on a daily basis? Sometimes he cannot walk other times he needs the use of crutches in order to walk, sometimes the pain in his head is so bad he screams. His joints can be heard "cracking", which then become painful for him. No two days are the same for him. We never know what type of day he'll have until he gets up in the morning. Lately, it's been one bad day after the next. What seems like a "good day" quickly turns into a day of struggle after struggle for him. C.C.

A: There are a number of pain syndromes that can occur in people with mitochondrial diseases. These syndromes include, but are not limited to, mitraine-type headaches, muscle pain, nerve pain (neuropathic pain), abdominal pain from poor gastric motility and fatigue, which can be perceived as a painful condition. Within the muscle pain group, there are a number of different subtypes of pain as well; such as pain from cramps, pain from inflammation, and the pain that is not well understood, but assoicated with muscle weakness.

The daily flucuation in symptoms and symptom severity is not uncommon, and can be related to factors such as lack of sleep, diet, concurrent viral infections, temperature and so forth.

There is no one treatment for pain; your doctor needs to determine what type of pain your child is experiencing and perscribe the best therapy for that type of pain.

Many of the treatments for pain in mito diseases have been discussed in a recent article by Dr. Gold and myself in a recent issue of Seminars in Neurology. This should be in a medical library within the next month or so. Your doctor has the ability to get this information. You can read another article online, at (and follow the links to the July 2001 issue).

There are some general pointers that you and your doctor may wish to think about.

1) Maintaining activity, despite the pain, is important. Lying in bed tends to make most pain worse.

2) Hydration with fluids (water, Gatoraid-like drinks) often helps with muscle pain.

3) Stying out of high heat and humidity conditions is critical for many patients.
Answered by: Bruce Cohen, MD

Q: I have a 5 year old daughter who has been diagnosed with a mitochondrial myopathy (the specific type is not yet known). Her doctor feels that she should have an ERG to check her retinas as she has been having problems with her sight or her coordination (she cannot reach the pencil she is trying to grab, for example). My question is whether this would be a test that would be able to benefit her--would they be able to correct or slow the progression of this problem assuming it is the degeneration of the retinas. A.P.

A: 1. It sounds like your family really needs to sit down and discuss a number of clinical and diagnostic issues in detail.
2. The first issue that is apparent from your question is that it is important for your family to know whether a test that is being recommended is for diagnostic or for therapeutic purposes. The ERG test is a diagnostic procedure that is capable of characterizing rod and cone function in the retina.
3. It is difficult to take the response much further without more
detailed understanding of the clinical situation, the criteria for diagnosis of a mitochondrial disease, etc.
Answered by: John Shoffner, MD

Q: I have a question regarding snoring. Our son is 8 years old and has Leigh's. Over the past few years he has developed snoring which seems to be getting worse as time goes by. Is this common? We know that it is not really a good thing for anyone to snore and were a little worried that his snoring is so loud and frequent. P.C.

A: Hypotonia (decreased muscle tone, often part of mitochondrial disease) of the muscles comprising the airway can result in narrowing of the airway during sleep. If this interferes with breathing it is called "obstructive sleep apnea", and can present as excessive snoring, especially if the patient is awakened multiple times during the night. In some cases, there is a decreased amount of oxygen available for the body and serious complications can result. In addition, Leigh disease can involve brain stem function and cause apnea by other mechanisms. Thus, although snoring is common and usually benign, excessive snoring should not be ignored but should be evaluated by a physician, especially an Ear, Nose and Throat (ENT) specialist. Various treatments are appropriate in some cases.
Answered by: Richard G. Boles, MD

Q: Is it possible to have two different results in two different muscle bioposies? (one taken in bicep and the other in the muscle under the armpit?) Y.B.

A: You really need more details to answer this correctly. However, different muscles may express defects differently. Certainly, respiration enzyme activities can vary depending on the muscle used for analysis. This is one of the reasons it is important to biopsy the same muscle when making comparisons between data and between patients.
Answered by: John Shoffner, MD

Q: In a patient with mitochondrial disease, does giving extra calories, in the form of glucose, extra tube feeds or uncooked cornstarch have any effect on decompensation due to illness? Can it prevent decompensation if started at the first sign of illness, before any noticeable decompensation? D.L.

A: If by "mitochondrial disease", we refer, as it is now customary, to disorders due to defects of the mitochondrial respiratory chain, then unfortunately provision of extra calories does not help because the problem is not in the metabolism of foodstuff (glycogen, lipids), but in the generation of energy from their terminal product, acetylcarnitine. However, many patients with mitochondrial diseases have gastrointestinal problems, making adequate nutrition difficult. In these patients, nasogastric feeding or percutaneous endoscopic gastrostomy (PEG) may be of great benefit.
Responder: Salvatore DiMauro MD

There is no single answer to this question.

The stomach and small intestine break food down into fats, carbohydrates (sugars) and amino acids (protein). In a healthy person, any food eaten that is needed immediately is stored in the liver as glycogen (a complex form of sugar) or as fat. Protein cannot be stored and is converted into sugar and urea. The urea is excreted in the urine. The liver can store enough sugar to run the body for about 12 hours. The ability to store fat is enormous. During times of starvation, whether this is voluntary or due to an inability to eat because of illness, we live off our stored sugars and fats. In the healthy person, the ability to survive starvation depends on how much fat is stored, and given a supply of water, people can live for months. The fat can be mobilized and quickly converted into fatty acids and ketones, which can run the body. During periods of fasting the blood sugar levels can drop to very low levels, but the body can still survive as long as it can produce and use those fatty acids and ketones.

In many mitochondrial patients there is an inability to store or access any stored sugar, and an inability to convert fat into ketones, or an inability to use the fatty acids and ketones. Because there is a relative block in metabolism, the ability to process (the speed at which food can be turned into energy) calories is reduced. During an illness, giving supplemental sugar is usually necessary. This can be given as food, a beverage (Gatoraid for example), or as an IV. Cornstarch is a complex carbohydrate, which is slowly digested and releases the sugar over 6-8 hours.

In a healthy child, starvation during a one or two day illness rarely causes any problems. In a child with a mitochondrial disease, where the caloric reserves are low and the ability to compensate for any stress is reduced, the risk of energy failure with resultant serious effects is heightened. This is a relative risk, and some patients are more susceptible to problems than other patients. Early fluids and sugar is helpful as a general rule. In children with fatty acid oxidation disorders, such as medium chain acylCoA dehydrogenase deficiency, each illness needs to be treated as a crisis. These children must have IV fluids and glucose. I tell parents "do not pass GO, do not collect $200,,,,,go to the ER with the first sniffle." In other children, everything can be handled at home. The protocol for this problem should be discussed with your physician beforehand.

In some circumstances, early sugar is not helpful and the viral illness itself causes the decompensation.
Answered by: Bruce Cohen, MD

Q: Can heat/cold intolerance be a part of mitochondrial disorder, along with inflamed muscle's, and enlarged lymph nodes? Y.B.

A: Although no scientific study has been published on the matter of temperature intolerance in people with mitochondrial cytopathies, it is a common feature of many affected adults and children. Most "healthy" people feel exhausted when the temperature (or the heat index, which is a measure of how the body senses heat and humidity) rises above a certain point. However, some with mitochondrial cytopathies have a much lower tolerance to what most would consider only a mild discomfort. Symptoms can include excessive fatigue, weakness, irritability (especially in the young child) or fever. I have had one patient develop a life-treatening crisis (it took her months to recover) when she was left resting under a shade tree on a hot day. It is critial to note that this child was properly clothed and a hundred people that attended the picnic were all fine, but this child, who was in the shade, got very ill. The normal process of sweating is the body's way of cooling itself, and one mechanism of this intolerance is the inability to sweat normally, which occurs in some people with mitochondrial diseases. If this is the situation, heat stroke can occur at temperatures that are considered "safe" for otherwise healthy people. However, even in those with a normal ability to sweat, heat intolerance is a common symptom. There is no "safe" temperature, and what can be safe in one person may not be in another. Tips for dealing with the summer months include avoidance of outside activities on hot and humid days, avoid direct sunlight, drink plenty of fluids (even healthy people should consume extra fluids on warm days), and of course, use proper sun screen. This does not mean the people cannot be outside. Swimming pools usually are a wonderful source of relaxation and exercise, and most pools are cool enough to be safe, even on the warmest and most humid summer days. Common sense should prevail: if the person is exhausted or irritable, they should be taken inside to a cool enviornment and their temperature taken. If there is a fever or other worrisome signs, they should be evaluated by medical personnel. Remember, skin temperature does not correlate with body temperature. The skin will be cool in the worst cases of heat stroke. Keep a thermometer handy at home and use it. I recommend the old fashion mercury thermometer. It is accurate and inexpensive. If the child is too young for an oral temperature, you can take a rectal temperature or axillary (arm pit) temperature. The fancy ear thermometers are not reliable. Certain medications, such as antihistamines or stomach relaxants can inhibit sweating as well.

Overdressing in the winter months ,especially infants that are not able to complain, can also be dangerous. Some parents dress their infants in layers of clothes and coats, preparing the child for freezing temperatures, and put them in the car where the temperature will be 60 or 70 degrees after the heater warms the car. This can lead to heat build up.

In hot weather or with excessive exercise, some people, including both healthy individuals and those with metabolic illnesses, are subject to a serious condition known as rhabdomyolosis, which is destruction of muscle tissue. The by-product of this process is myoglobin, which can clog up the kidneys and permanently damage them. Muscle cramping and aching, along with brownish (Coke-colored) urine is the feature of this illness. People that are dehydrated or that take certain antibiotics, can also have dark urine. However, if there is a question of this, go to the hospital for treatment.

Children and adults with muscle disease or inability to move normally are subject to rapid cooling in cold environments. The most fragile people are those that are not able to express themselves. Most children and adults that are able to move about normally or near normally can tolerate 32 degree days with no wind if dressed properly for a reasonable period of time. Children that are in active play will tolerate these cool temperature better than those that are sitting in the bleachers watching a football game. I do not have any recommendations about what exact temperature, wind chill, or heat index is safe. This will vary between people. Common sense should rule and this will take a bit of trial and error. The goal is for the person to have as much activity as they can tolerate.

Enlarged lymph nodes are usually a part of an infectious illness, and are not directly related to a mitochondrial disease.

Please remember that the UMDF is in the early stages of a 5.5 million dollar campaign to raise money for research into mitochondrial diseases. We need to count on ourselves to raise this money. If you have a fundraising project in mind, please contact the national office at

For those that want to read about adult topics, please click on the first link, and for a video of a recent talk to the Ohio Chapter of the UMDF, click on the second link.

Answered by: Bruce Cohen, MD

Q: What is the difference between a mitochondrial disease and a metabolic disease? E.H.

A: The mitochondrial disorders/diseases are all metabolic disorders/diseases. But, there are many other kinds of metabolic disease that do not involve the mitochondria.

Answered by: Richard G. Boles, MD

Q: We have a 2 1/2 year old son who is currently undiagnosed. He has had a progression of symptoms from the time he was around 6-8 months of age. He has developmental delay, repetitive vomiting and diarrhea (often leading to dehydration and in cycles approx. 4-6 weeks apart), ataxia (worsening), low muscle tone (worsening), abnormal EEG's worsening), possible cardiac involvement (enlarged heart just noted last month), abnormal EMG studies, seizures (began at 15 months and are not controlled with meds), bouts of excessive irritability (screams for hours as if in pain and needs to be medicated to stop it), has previously had intestinal inflammation (originally diagnosed as Crohn's at 8 months of age, now thought to be a by product of ? disease). He has had a fairly extensive workup including a muscle biopsy that was negative for mitochondrial disease. It only showed type I fibre predominance. He is currently supplemented by G tube feeds, although, feeding and swallowing is becoming more difficult for him.

Our questions are:
1) What tests, other that a muscle biopsy, could help us determine if this is a mitochondrial disease? (some of his docs still feel strongly that it could be even with negative muscle biopsy)
2) Is there any harm in trying the mito supplements in an undiagnosed child? A.B.

A: Your child's medical problems are very similar to several children that I have evaluated, and you are correct in considering mitochondrial disease as a possibility in your child. In particular, the cyclic episodes of vomiting got my attention since my own research involves cyclic vomiting syndrome and its link with mitochondria. Among children with mitochondrial cyclic vomiting, diarrhea, gut inflammation, ataxia, developmental delay and seizures are not uncommon. Cardiomyopathy is uncommon in these children, but not very rare. (For more information see my recent article in Mitochondrial News (Spring 2001), and the website of the Cyclic Vomiting Syndrome Association USA/Canada

Regarding diagnosis, I have found that muscle biopsy results are often borderline, non-specific, and occasionally even "negative" in these children. In my opinion, the most important diagnostic test is urine organic acids obtained early during a severe or typical vomiting episode. Children with mitochondrial cyclic vomiting excrete Kreb cycle intermediates and ketones, and occasionally ethylmalonate, glutarate, lactate and other "mito markers" at this time. Organic acids are usually normal if obtained at other times. A carefully obtained pedigree is also helpful. In most (but not all cases), siblings, the mother, and occasionally other maternal relatives have a history of intermittent and usually mild disease manifestations, which can include migraine, seizures, dysautonomia, depression, hypothyroidism, "hypoglycemia", gut dysmotility (reflux disease, severe constipation, etc.), exercise intolerance, muscle pain, and peripheral neuropathy.

The bouts of excessive irritability are common, and are likely migraine-related. The good news is that they are treatable in most cases. You will want to discuss this with your child's doctors before changing any of your treatment regiments. In my own patients what often helps in prevention is frequent snacking of high carbohydrate foods and the avoidance of stress (fasting, dehydration, over-exertion, environmental temperature extremes, etc.). Caffeine (15-30 mg, about one half to one cola drink) and ibuprofen (Motrin, Advil, 10 mg/kg/dose) often helps during pain crises. In some cases, the use of medications to prevent crises is appropriate. I have the most experience with low dose amitriptyline, which can help to reduce the frequency and intensity of vomiting and pain episodes alike. I see no harm in trying the usual "mito supplements", but in my experience, the above measures are usually more successful.

Answered by: Richard G. Boles, MD

Q: What is the definition of coma? How is a coma differentiated from sleeping for several days unable to be awakened or being awakened only after INTENSE stimulation? D.L.

A: Coma is a state of awareness beyond sleep. When you are sleeping you can be woken up. In a coma - you are not returned to consciousness by physical stimuli. This is the difference.

Answered by: Douglass M. Turnbull, MD, PhD

Q: Our daughter passed away at the age of 22 months. Her diagnosis was Leigh's disease, however no mitochondrial defect was detected through genetic testing. Her symtoms included seizures, global development delays, muscle weekness, abnormal MRI, mild elevated lactate etc. Symptoms began at 6 months. We have a son who is 21 months old with no apparent symptoms. Is it possibe for our son to develop symptoms at a later age than our daughter? L.T.

A: Without knowing the biochemical or genetic defect that caused Leigh Syndrome in your daughter, it is impossible to give you an absolutely certain answer. However, if we assume that the syndrome in your daughter was due to a mutation in nuclear DNA rather than in mitochondrial DNA (a reasonable assumption), and assuming, as I do, that both you and your maternal relatives are in good health (further decreasing the chance of a mitochondrial DNA mutation), then it is reasonable to conclude that your son should remain in good health, because the clinical presentations of nuclear gene mutations tend to "breed true" in the same family. In other words, affected children tend to have similar clinical presentations and age at onset. If frozen tissues or cultured fibroblasts from your daughter are still available, it would be important to try and define the genetic defect, so that sound genetic counseling might be available to you.
Answered by: Salvatore DiMauro, MD

Q: I know that iron supplements can cause free radicals to "Poke holes" in the mitochondria. Does this occur only when there is too much iron in the system? Does it happen if iron is being given to treat anemia? I also wanted to know, if the iron is causing free radicals to "poke holes" in the mitochondria, are there any signs (outward or biochemical?) Will there always be signs of deterioration? D.L.

A: From the time we were children, our parents urged us to eat food rich in iron, because "it is good for you." Iron is an essential nutrient and is required for the normal functioning of red blood cells, which carry oxygen throughout our body. However, iron can exists in different states inside our bodies, and one of these states can cause iron to act as a free radical and thereby cause damage to membranes and the DNA. Iron toxicity is a well-known mechanism for mitochondrial injury. The formation of free radicals with iron is likely due to both the general handling of iron and when iron is in present in excess. The usual handling of iron as it is stored within the cell produces a constant but small amount of oxidative radical production (Fenton reaction). One cannot avoid this and the level is small and in the otherwise healthy person, iron causes little in the way of cell or mitochondrial damage. When iron is in excess, the radical production is enhanced and a larger amount of radicals are formed to produce as you indicate, the subsequent "holes in the membrane". Storage of iron also occurs over time and too much iron over time will have a similar effect.

The use of iron supplementation in a person with or without a mitochondrial cytopathy should be done only if there is a reason, such as an iron deficient anemia. We have safely given high doses of IV iron to two children with mitochondrial diseases, with beneficial effects and no toxicity. In these two cases, thier bodies could not absorb iron. Otherwise, our diets should replace the needed iron and extra supplementations should likely be avoided. We see no reason to avoid dietary iron. We think that people with mitochondrial cytopathies should avoid iron supplements, and look for vitamins without added iron.
Responder: Russ Saneto, MD
Answered by: Bruce Cohen, MD

Q: Can a child with Leigh's disease, also develop Luft's Disease? Has this
ever happened? D.L.

A: Although there are only two reported cases in the literature of Luft syndrome, the biochemical features of this disorder are probably more common. The original description was of a young adult woman with hypermetabolism caused by uncoupling of oxidation and phosphorylation: meaning that food is burned, but instead of being turned into energy in the form of ATP, it is turned into heat. In normal circumstances, protons are pumped across the inner mitochondrial membrane, by complexes I, III and IV, from the matrix of the mitochondria into the innner membrane space. These protons then pass back into the matrix thru complex V, which functions as a motor that will add a phosphate onto ADP to form ATP. If there is any disruption in the integrity of the inner mitochondrial membrane, the protons can leak back into the matrix without passing through complex V, resulting in generation of heat but no generation of ATP. This is the same phenomena as if you put your car into "neutral" and press on the accelerator: the car engine will burn gasoline and will heat up but the car will not move.

Electron Transport Chain Activity, which is the typical testing done by most mitochondrial labs, cannot test for Luft syndrome. The test known as polarography can. The problem with polarography is that it requires a large number of fresh mitochondria and is a long and cumbersome test.

I am not sure if a child with Leigh syndrome has ever developed Luft syndrome. It is important to remember that all "syndromes" are descriptions of illnesses, with no attention addressed to the biochemical or genetic causes. It is certainly possible that a child with the features of Leigh syndrome could develop a hypermetabolic state as described by Dr. Luft. There are no specific treatments for Luft disease, and is probably more resistant to the typical therapies than most disorders of energy production.
Answered by: Bruce Cohen, MD

Q: I have a son who is 12, diagnosed with mito in 1993. I also have a 14 year old daughter with signs and symptoms of fibromyalgia. There was a lecture at the conference last june in cleveland that mentioned some people who had been diagnosed with fibromyalgia but then rediagnosed with a mito disorder. Since we are considering taking our daughter somewhere else to be evaluated, do you think there is a connection to mito?

A: The daughter should be assessed by someone with the knowledge that the brother has mitochondrial disease. It would be sensible if it was the same physician who looks after the affected child.
Answered by: Douglass M. Turnbull, MD, PhD

Q: My 21 month old son has been suspected of having a mitochondrial disorder for over a year (we are still in the process of diagnosis). Last week he experienced extreme high temperatures for 4 days. One day his temperature was 105.1. This week his temperature is lower than normal. A pediatrician saw him last week and found no reason for these extreme temperatures. He said this could be an indication of the disorder -- that the temperature "gauge" in his brain is now malfunctioning. Could this be true, and if so why does this happen? And, is this common to mitochondrial disorder patients?

A: Body temperature control is very complex, with many factors contributing to high and low temperatures, including infection, hormonal disorders, brain disorders, auto-immune diseases, tumor, drug reactions, etc. Body temperature is controlled by the autonomic nervous system, and in some individuals an abnormality in this system ('dysautonomia') can result in frequent high and low body temperatures. Other signs of dysautonomia can occur in the same individuals, and sometimes include changes in heart rate, breathing rate, blood pressure, sweating, skin color/temperature, and digestion.

Dysautonomia has been described in a few case reports in children with suspected mitochondrial disease. In my personal experience, dysautonomia is not rare in children and adults with probable mitochondria-related disease, especially those with maternal inheritance. Disease manifestations tend to be intermittent, as is the case with dysautonomias in general. Specific findings in some individuals include migraine-like headache, abdominal pain, racing heart rate, apnea, hyperventilation, fainting, severe reflux, cyclic vomiting or diarrhea, delayed gastric emptying, chronic constipation, blotchy skin rashes, pain, swelling, color or temperature changes in an extremity, and abnormal body temperature control (both high and low temperatures).

Since fever can be a sign of a serious illness, caution is prudent, especially in a child who appears to be ill. However, in some children diagnosed with dysautonomia who otherwise appear to be healthy, body temperature variations (up or down) that last only minutes to an hour can be ignored. However, first it is important that a knowledgeable physician establish the diagnosis of a dysautonomia and rule out other causes of an abnormal body temperature.

In rare cases, very high body temperatures (about 106 and higher) can cause brain damage. This rare situation usually occurs in children with significant brain/neurological disease. An MRI of the brain might be indicated.
Answered by: Richard G. Boles, MD

Q: When muscle is taken for a muscle biopsy, I know that when the new muscle grows to fill the hole it usually does not have any diseased mitochondria in it. Is the same true when a piece of skin is taken for a skin biopsy? B.F.

A: Although this question has not been addressed experimentally, my guess would be that this is not t

rue for regenerating skin cells: in other words, I would expect regenerating skin cells to harbor approximately as many mutated mtDNAs as the original skin.


by: Salvatore DiMauro, MD

Q: If skeletal muscle and cardiac muscle are becoming weaker due to
progression of the disease, wouldn't that raise lactate and pyruvate? D.L.

A: Elevated lactic acid (also referred to as lactate) levels in the blood are a well known "hallmark" feature of mitochondrial diseeases, however there is not a direct correlation between clinical symptoms (how sick a person is with their mitochondrial disease) and the actual level of blood lactic acid. Lactic acid will also increase in those without a mitochondrial disease in the face of serious illness, lack of oxygen or shock.

In terms of those with mitochondiral diseases, there are a number of explainations why there may not be a correlation between lactic acid levels and seriousness or worsening of the illness. Remember that mitochondrial diseases can affect the different organs to a greater or lesser extent. The liver is responsible for the majority of lactic acid production in the body, and in those with severe brain disease and no liver disease, the lactic acid level may not be elevated at all. When the kidney is functioning normally, the kidney tends to "hold on to the lactic acid" and keep it in the blood (and not let it escape into the urine). If the kidney is affected by the mitochondrial disease, the lactic acid will pour into the urine and result in normal levels or low levels in the blood. Infants tend to run higher lactic acid levels than older children and adults. The bottom line is that clinicians in the mitochondrial field have accepted that lactic acid levels alone do not correlate well with the clinical behavior or disease state of most, but not all, people with mitochondrial cytopathies. There are exceptions to this statement.

Pyruvate is the normal product of glucose metabolism that is the chemical interface between glycolosis (the first steps in metabolism) and the citric acid cycle (the so-called second phase). If pyruvate cannot be properly used, due to a disorder in pyruvate dehydrogenase, the citric acid cycle or the electron transport chain, then it will build up in concentration and get turned into lactate. The "reason" for this is when pyruvate gets turned into lactate, a little more energy can be produced through glycolosis, the first phase of metabolism. In those with electron transport chain disorders the lactate is elevated far more than the pyruvate is, and the increase in the normal ratio of lactate levels and pyruvate levels tells the doctor to suspect an electron transport chain disorder.

Regardless, until we have a better biochemical bait, we use lactic acid levels as only one method to help us screen for those with the illness and use them as monitors of the disease.
Answered by: Bruce Cohen, MD

Q: In San Diego there was a reference to Cystic Fibrosis being a common misdiagnosis for mito disease. Our adopted daughter has a half sister (common birth Mom) with CF. Our child has Complex 1 and a leukodystrophy. We were wondering what the atypical signs/symptoms might be with CF to indicate that the half sister should be checked for a mito disease. Thanks.

A: Cystic Fibrosis is a common genetic disorder that is inherited in an autosomal fashion. The gene frequency of CF is one in 27 persons, meaning that about one in 700 (27 x 27 = 727) couples are at a one in four risk of having a child with CF. Although the late manifestations of CF are generally lung disease, the most common early manifestations of CF in infancy include failure to thrive, diarrhea and frequent infections. These early symptoms are similar to what many children with mitochondrial disease show. Unless the doctor thinks of CF, it is often missed early on because it cannot be diagnosed by any commonly ordered blood test. CF can be tested for by an easy and painless test called a sweat chloride test.

Because CF is such a common disease, there are going to be persons with mitochondrial diseases that also have CF, or have siblings with CF. As far as I am aware there is no genetic or biochemical link between CF and mitochondrial diseases.

Unless there is a mitochondrial gene defect found, in which case testing is straightforward, screening family members without symptoms of mitochondrial diseases is prone to error and not generally recommended.

Answered by: Bruce Cohen, MD

Q: Can you tell me if there is any information on Mitochondrial disease and relationship to hearing loss?

I have a female patient with binaural sensori-neural hearing loss. Looks more low frequency than high frequency in configuration. Much like one might see in a patient with mild Menieres disease.

I have been unable to find any information on this? I would like to know as we are treating her. It would help to know indices for prognosis and rehabilitation.

She is currently @30 years of age. Her symptoms are progressive and severely episodic. But the hearing loss seems stable over the years. Mild to moderate.

Any leads or direction would be appreciated.

A: The hearing loss is usually high frequency at first, so if what you are seeing in this patient is low frequency, it could be due to another cause. I do not recall seeing any patients with just low frequency.

The hearing loss in mito patients is unpredictable, and in some patients seems to occur stepwise. I have seen patient's go deaf over 10 + years and others in a few months. Obviously, some drugs (gentamicin for example) can cause the hearing to go fast.

I know this is not a lot of info, but it is about the best there is.

Answered by: Bruce Cohen, MD