Q: My 11.5 year old daughter was diagnosed with Complex I in 2000. Last year, she began to show signs of puberty and quickly declined.  This past April, as the seizures were out of control (50+/day) her mensturation began.  The combination of seizures, puberty, and mito disease was apparent when in June she went into respiratory arrest. The doctors recommended Depo Provera, not to stop the periods but to reduce the hormone levels. After reading more about Depo Provera, including risks associated with seizure disorder and phenytoin (which she is on), I am questioning this option.  Do you have any info?

A: I am sorry to hear about your daughter. The stress of puberty onset with the added energy demands and changes in hormones can really alter mitochondrial disease. Trying to manage seizures, puberty, and mitochondrial disease is really a rough road as you have described. There are some issues that need to be worked on. I try to maximize the changes that I can make before letting the endocrinologist weigh in on what is best for a particular young adult. First, is the matter of the enzyme inducing medications that we use for seizure control. They profoundly affect hormone levels as the seizure medications that induce the liver CYP system will increase the way hormones are metabolized as well as the fat soluble vitamins (especially vitamin D needed for bone mineralization). I find that in my practice, I stay away from these seizure medications (carbamazepine, Phenytoin, Phenobarbital, and some extent oxcarbazapine and topamax) and use one or more of the other medications that do not influence liver function. If I use Lamotrigine, I have to alter dosing as estrogen will reduce Lamotrigine levels.
The next step is to decide on what is acceptable with menses, meaning that it is going to happen so how to best manage the mitochondrial disease with the coming of monthly periods. Some patients are regular some are not. Regularity helps predict what you might do to intervene such as increase dietary intake just before menses. Irregularity seems to be the more common theme in my practice so we just do our best to enhance calorie intake.
As far as trying to manipulate hormone levels, I try and let the endocrinologist recommend what is best for the particular young adult. Many patients we just allow menses to occur and react to how the patient responds. Contraception is an issue with a few of my patients and that is another issue that the endocrinologist can be very helpful. There are other issues that I have had to deal with such as polycystic ovary syndrome (PCOS) and lamotrigine is the only medication that helps control her seizures. The endocrinologist is trying to use a specific medication for her and we are currently trying to manage her needs. In one young adult, her bone mineralization and bone age were abnormal (younger than age) so we stopped menses with hormone treatment for several years. So, it is complicated and these interventions need to be individualized and working together with an endocrinologist is so very helpful.
Specific recommendations are difficult to make as I do not know the full medical picture of your daughter, especially her hormonal status. You can alter the seizure medication and that might make things more manageable.

Answered by: Russ Saneto, DO, PhD

A: In regards to dysautonomia - some mito patients seem to have several symptoms where dysautonomia has been invoked as a possible etiology - but not proven by autonomic testing. The symptom that might be most linked to dysautonomia would be dysmotility since the gut is controlled by the autonomic nervous system.  The dilemma with this explanation is that the gut also has its own internal nervous system and some of the motility issues may be due to patches of abnormal motility due to a true cellular energy deficiency. The explanation for cardiac arrythmias may be similar - not due to abnormal signals from autonomic controls in the brain stem but rather aberrant electrical generation/conduction in energy-poor areas.
Other symptoms that have not been explained include:
1) Sensitivity to heat in that they 'wilt' in hot weather -> I do not think we know if there is an inability to regulate body temperature or sweat.  Dehydration may play a role in symptom exacerbation.
2) Blue lips/extremities -> typically not causing discomfort. I have not seen this but have had parents report it.  There are biopsy proven reports of neuropathy in mito patients - but I do not know if this would explain episodic color changes in the patients (especially with rapid resolution of the symptom).
3) Postural tachycardia or orthostatic/positional hypotension -> this is a common complaint in many individuals (some with abnormal autonomic testing on the tilt-table)  - not just mitochondrial patients and we do not know if this is more common in DNA or biopsy proven mito patients.

Answered by: Sumit Parikh, MD

A: The gastrointestinal (GI) tract is one of the organ systems that are most frequently affected in individuals with many different mitochondrial disorders. Generally, the problem involves motility, which means that the movement of food and its byproducts through the GI tract is abnormal. It is well appreciated that mitochondrial disease patients can suffer from constipation. However, many other mito patients suffer from diarrhea, while others alternate between constipation and diarrhea.
In many mito patients, special diets can be helpful with motility, while not so in others. However, as is generally the case in these complex disorders, there is no simple answer to your question. Some mito patients do better with small frequent feedings. Some mito patients do well with a degree of fat restriction (what is generally considered to be a "healthy diet"). Some mito patients cannot tolerate a lot of starch, and do better on whole grains and/or on higher protein diets (close to the "Paleolithic" diets sometimes advocated in children with autistic spectrum disorders). Your description of rice, corn and soy intolerance in your daughter suggests to me that this could be the case. Furthermore, some mito patients have intolerance to various foods; milk being possibly the most common.
Finally, carnitine supplementation often can contribute to diarrhea. Two suggestions to discuss with your physician are spreading out the carnitine into smaller amounts given more frequently, and/or decreasing the total dose given to a small degree.
Unfortunately, GI symptoms and diet in mito disorders are areas that are not well studied, and opinions are far more numerous than facts. What works in your child may be the best answer. [In addition, I personally believe that all mito patients should avoid fasting, unless carefully shown that this is not a problem.]

Answered by: Richard G. Boles, M.D.

A: First of all I would say that he may not have Alpers syndrome. Clinically the diagnosis of Alpers syndrome is established when there are intractable seizures, psychomotor delay and liver problems. I did not see that in your description. Has he been tested for elevation of his liver enzymes? Mutations in the POLG gene may be associated with other clinical presentations or syndromes besides Alpers syndrome. There are other conditions where children may present seizures, an unsteady gait (ataxia) and problems with constipation. We have now learned that mutations in this gene may not necessarily cause typical Alpers all the time. Does he have difficulties moving his eyes? I think it is very important to document that both you and his father are carriers for these mutations. If that is the case the chances of having affected children will be 25% for each pregnancy.

Answered by: Fernando Scaglia, M.D.

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

A: Most of the time in medicine, “common things occur commonly,” for example: a running nose, eye tearing, mild fever, with some achy muscles and feeling tired is usually a viral illness. This is what we are taught in our training and pretty much is what most of us find to be true in our practice. What mitochondrial disease can do is confuse the issue because many clinical events that occur can be the “common things”, mitochondrial related, or a combination of both. Ruling out the common things and treating by standard medical treatment is what most of use initially consider in our medical practice. That being said, most of us in the mitochondrial field always keep in the back of our mind that the set of symptoms may be impacted by a patient’s mitochondrial disease.
So, gasping for breath may mean anything from simple exercise to cardiac failure. One has to judge the circumstances surrounding the symptom, exam the patient, use clinical judgment (see above), and then formulate a plan to understand why the symptom is happening and if needed, how to treat it. Trying to evaluate a patient based solely on a symptom is usually not wise. Many patients with mitochondrial disease have what we call “air hunger” or periods of gasping for air for no apparent reason. Many patients have asthma and gasp for air due to asthma exacerbation. Some patients have cardiomyopathy, and due to poor cardiac function gasp for air (shortness of breath). The same would be for a rash. So, I would recommend seeing your physician and put the symptom into an overall clinical context for possible treatment.

Answered by: Russell P. Saneto, DO, PhD

A: Unfortunately, most of the supplements and herbs commonly advertised as being helpful for hot flashes and night sweats have been shown to be no better than placebo. If you have severe symptoms, you can always ask your physician whether you are a good candidate for the nonhormonal medication venlaxafine which has been shown to improve night sweats and hot flashes.

Answered by: Maria Yialamas, MD

A: Currently gallium is most commonly used in nuclear medicine as part of diagnostic testing - but not for treatment of any kind.  It is being studied for potential anti-inflammatory and antibiotic properties - but it is not the recommended therapy for any medical condition.
There is no known anecdotal or studied use of gallium for mitochondrial disease.  Thus I could not tell you if it is something that would help or harm an individual with mitochondrial disease and can not recommend a dosage.

Answered by: Sumit Parikh, MD

 A: Your concern is certainly understandable, given the recent publicity about a potential relationship between mitochondrial disease, autism, and vaccination. We are dealing with three "dots" here: two of them (mitochondrial dysfunction and autism) have definitely been connected: although probably only a minority of autistic children have an underlying mitochondrial disease, some (like, apparently, your son) certainly do. The third "dot" (vaccination) however has NOT been connected to either mitochondrial diseases or to autism. I doubt very much that vaccination triggered the autistic features in your child, which can be simply explained by his mitochondrial dysfunction. Children with mitochondrial diseases should be vaccinated to protect them from horrible infectious diseases!

Answered by: Salvatore DiMauro, MD

 A: I have not been able to find any information on the effects of the acai berry in mitochondrial patients.  Information on the berry itself indicates that it is an "anti-oxidant" but that the exact mechanism of its anti-oxidant abilities is unknown at this time.  Although anti-oxidants are thought to be beneficial in patients with mitochondrial disorders, they have not been proven to be effective.  They also do not appear to be harmful. Based on the information I have been able to find, I do not see any contra-indication to taking the Mona Vie supplement with any of the following:  carnitine, CoEnzyme Q10, riboflavin, or folate.

Answered by: Mary Kay Koenig, MD

 A: When we digest food or our body metabolizes its energy stores (fats and carbohydrates), we break down these molecules further through various metabolic pathways, typically by intermediate metabolism or beta oxidation. The products are then metabolized through the Citric Acid cycle (within the mitochondria) and energy stored in the form of ions (in this case an electron) are shuttled through the electron transport chain within the mitochondria. The end product is ATP (the energy compound). The metabolic products having the extra electron are in the form of two compounds, NADH and FADH2. A larger proportion of NADH is made by the breakdown of carbohydrates and a larger portion of FADH2 is made by beta oxidation of fat. NADH enters the electron transport via complex I and FADH2 enters via complex II. Now, the proportions are relative and both carbohydrates and fats make NADH and FADH2. So a patient with a complex I disorder may not be able to utilize as much NADH as a normal person would. Since complex II would be normal, utilization of FADH2 passing electrons into complex II would be going full speed ahead while complex I is compromised. Theoretically, then fats would be better utilized than carbohydrates in this scenario. Fact or fiction? I have many patients with complex I disorders that actually do better on carbohydrates than fats. So, likely there are other factors involved such as whether the abnormality affects the NADH binding site or at another site within the complex I molecule. I hope this explanation helps you a little.

Answered by: Russell P. Saneto, DO, PhD

 A: I am sorry to hear about your daughter. I know it is so difficult to watch you daughter have all these problems. Tremors are difficult to control, especially when they are due to mitochondrial disorders. It is very common to see neurological deficits during illness as this is a strong stressor to our systems and energy demands go up (fighting infection, keeping the body going, etc) the poor mitochondria are faced with added energy demands that in the face of a mitochondrial disease, compromises their function even to a greater extent. This is why many patients have their first symptoms during a viral illness. Over time as the mitochondrial disorder progresses, these same symptoms are enhanced and may, as seemingly with your daughter, become continuous. You are doing the correct things, at least in my opinion with the coenzyme Q10 and carnitor. Enhancing the carbohydrate level of the diet might help a little as well. I have not found the usual medications such as beta blockers or mysoline to be very helpful, but you might ask your physician about these drugs.
There are some practical points. With intention tremors, when using writing or coloring instruments, use the big fat ones. The glass should be half full and not completely full. At school, see if it is okay to use a helper (such as a computer) for class projects and long writing assignments. When doing a lot of hand work, then a weighted glove can be helpful (although should not be used continuously). Velcro is a heaven sent item and can be used in many situations where the tremor becomes an issue.

Answered by: Russell P. Saneto, DO, PhD

 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

 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

 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.

 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

 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

 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.

 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

 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

 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

 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

 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

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

 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 

 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

 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

 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

 mk 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

 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

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

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

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

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

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

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

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.  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.  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

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).

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

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 www.cvsaonline.org
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

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

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

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

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

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.  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).  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.  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

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

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

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. 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

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

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

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

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.

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

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.

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

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."

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.

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 s