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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

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Q:
I have a new diagnosis of Mito. My granddaughter was diagnosed 5 years ago at the age of 4 and my daughter diagnosed 2 years ago at the age of 30. I have diabetes, slow GI motility, neuropathy, muscle/nerve pain, sleep disorder, temperature intolerance, mental fog and now I am experiencing air hunger. I am currently on a Fentanyl patch 25 mcg every 48 hours, neurontin 2100mg/day and a lot of Aleve. The problem is that the pain is constant and my quality of life poor, and with this new onset of air hunger, I am frightened to add anything else to the mix. I take multiple vitamins and cofactors, so what else should I take? I am 52 and was very active up to 1 & 1/2 years ago. I was employed as an RN but now I can't remember simple things. I do not want to take any more meds that will tire me; could you recommend any other treatment?

A: The exact combination of supplements that work best in any one person is highly specific to the individual. It is best determined in colalboration with your metabolic physician. Please keep in mind that mitochondrial respiratory chain disease is usually, unfortunately, progressive. Even with optimal therapy, you may not find improvement through mito supplements. In this event, your physicians should focus on treating the symptoms that are most problematic as best they can.

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

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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

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Q:
I was diagnosed with a carnitine deficiency and mitochondrial defect based on medical history, a dramatic decline after taking sulfasalazine (an article I found notes that it inhibits acetylCoA acetyl transferase) and a "high normal" blood lactate (although my doctor said it was too high) followed by a dramatic rise after <6 minutes of mild exercise (walking). I am improving with supplements, but still have symptoms preventing me from working. My disability company is disputing my diagnosis. My physician (who is a mito specialist) felt that a muscle biopsy would not aid in my care or recovery. My question is, is a biopsy necessary for the diagnosis? Some of the past Mitodoc questions seem to advocate for it and others seem to point out the inconsistencies and problems with the biopsy and that it is not necessary.

A: I am sorry that you are unable to work, and hope that your improvement will continue so that you will be able to return to full function. Now to your question – not an easy one to answer. You are correct to point out what seems to be inconsistencies in responses to prior Mito Doc questions about muscle biopsy. I find, however, that there are some consistent themes in the Mito Doc responses, and these are important to understand how to apply the complex discussion of the “pros and cons” of muscle biopsy applies to any individual.
First, historically, muscle biopsy was the gold standard for diagnosis of most mitochondrial disorders. However, we are aware of instances in which muscle biopsy showed a decrease in mitochondrial oxidative phosphorylation that later was found to be the result of some other primary medical condition, or to be an artifact of sample collection, handling or testing. On the other side of the discussion, we are also aware that there are some instances in which muscle biopsy can fail to find evidence of mitochondrial disease in a person who we know must be affected, because we later find in that person clear evidence of mitochondrial disease by examination of his or her DNA. However, we shouldn’t forget that in the research that led up to discovery of the DNA causes of mitochondrial disease, most often it was evidence from muscle biopsy that was used to determine that any particular DNA alteration causes disease. And, since we do not yet know all the DNA changes that cause disease, muscle biopsy will continue to have an important role in the diagnosis of mitochondrial disease for some time to come. Biochemical testing – such as that you describe – has always been important, along with enzyme assay in tissues other than muscle. DNA testing is increasingly useful. But there is still a role for muscle biopsy. The art of the medicine includes deciding when muscle biopsy is needed and when it is possible to be certain of the diagnosis without muscle biopsy.
An equally important role of the muscle biopsy is to make certain that we do not miss other treatable conditions that can cause or contribute to health problems. For example, primary mitochondrial disease is only one of many inherited and acquired conditions that can be diagnosed by muscle biopsy. These other inherited and acquired conditions include many that can cause carnitine deficiency. And, of course we cannot forget that conditions that cause carnitine deficiency can cause mitochondrial dysfunction.
Coming back to your specific issue and question – in your description of the evidence for your diagnosis, you mention lactate levels and carnitine levels. Since you indicate that you are working with a mitochondrial specialist, I expect there are other pieces of information that you haven’t mentioned, and I appreciate that in this forum you try to keep your questions as short as possible. However, if you already have additional information that proves a diagnosis of primary mitochondrial disease and/or primary carnitine deficiency, then I expect that your mitochondrial specialist would have been able to explain this to the satisfaction of the disability insurance providers. So, it may be that for some reason you do not have such proof of primary diagnosis. Again, this is important because there are many conditions that can cause secondary alteration of carnitine levels and of the electron transport chain, and some of these have specific therapies. Finally, there are also a host of conditions that cause symptoms that can be identical to some of the myriad symptoms caused by mitochondrial disease – including hemochromatosis and some of the porphyrias, glycogen storage diseases and primary myopathies to name just a few. So (based of course only on the information you have shared as part of your important question) it could still be possible that you might have some condition that is causing a secondary mitochondrial dysfunction. Or that you could have more than one health problem – certainly something I’ve seen many times. Depending upon the specifics of your case, then, muscle biopsy or some other additional testing might be useful not only for the question of disability eligibility – it could be critical to be certain that you are not missing any important information that would help to assure correct and complete diagnosis. Only you and your own health care providers will be able to decide the risks and benefits of the decision to have – or to not have – a muscle biopsy. I hope this proves helpful in your discussion with you disability coverage providers and with your health care providers.

Answered by: Carol Greene, M.D.

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Q:
I am a 62 year old male. I have Complex 1 Mito. It seems the course of treatment for all types of Mitochondrial Disease is the same, COQ10, Levocarnitine and B-2. My question is how long would I take these before I see results and if there is no real improvement in my condition could I stop these after a while. Also, there are different forms of COQ10, (Ubiquinol and Ubidecarenone). Ubiquinol is suppose to be an active form of Q10 and is recomanded for people over 40. I don't know if this is true or just advertising. What form of COQ10 do most doctors recomand and is there a certain brand that is recomanded. I don't know if whats listed on the label on is actually in the bottle on the cheaper store bought brands. I have a question about levocarnitine. Is it safe to take this for a long period of time? Seisures is listed as one of the possible side effects with the information that comes with it.

A: As a doctor who cares for patients with mitochondrial disease, I ask myself these same questions with regards to supplements. Some doctors may recommend a standard "mito cocktail" to every patient, while others may be more specific about the supplements. There is no question that carnitine, coenzyme Q10 and B vitamins have a role in mitochondrial machinery; however, there is a question as to whether supplements will help an individual patient. I believe that a good time frame would be over several months of trying a supplement, and if there is no notable benefit, to consider stopping the supplement. However, what may be less understood is the potential benefit of continuing a supplement even if you do not feel like it is doing anything! I also like to keep an observer in the dark about the supplement: a physical therapist may notice a difference in performance, endurance, etc. and you can believe this observation without bias if they do not know!
In terms of coenzyme Q10, ubiquinol is the most bioavailable form, and the form that I recommend. Tischon has been manufacturing coenzyme Q10 and available for purchase on the website www.epic4health.com. I do blood tests to measure the coenzyme Q10 levels and aim for a level between 3-5 (higher than the reported normal range). I prescribe brand name L-Carnitor but have found that there is not the same variability in product quality with carnitine that there is with coQ10. Some insurance companies will reimburse for both of these supplements with a mito diagnosis. I have noticed that seizures are listed as a side effect of carnitine, but I have yet to see it increase seizures in any of my patients. I have noticed the side effects of a fishy odor, followed by GI cramps or diarrhea. B vitamins (B1, B2, B6, B12) can be found together in a "mega-B" vitamin and are commonly recommended, as are vitamins A and E. The list of supplements includes many others; however, it is important to remember that none of the supplements have been proven to treat mitochondrial disease in a clinical trial. A trial of supplements is best done in consultation with your doctor, and a nutritionist experienced in metabolic disorders, if available.

Answered by: Amy C. Goldstein, MD

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Q:
Is it important to get an ophthalmologist familiar with treating conditions related to mito disease or CPEO when getting cataract surgery and ptosis surgery for this condition? If so, how does one find such a doctor? If not, what should we look for in an ophthalmologist and what should they know before performing these surgeries? Also, does cataract surgery potentially cause an increase in ptosis or an increase in dry eyes in patients with CPEO?

A: I recommend finding an ophthalmologist specializing in neurologic disorders (neuro-ophthalmologist), if one familiar with metabolic-genetic diseases is not available in the area. A neuro-ophthalmologist typically works at most university-based hospitals and centers. To see if there is a specialist with a background in genetic and metabolic ophthalmology close to you, I recommend visiting the International Society for Genetic Eye Disease online at http://www.isgedr.org/. I would pose the remainder of your questions to an individual with this type of expertise.

Answered by: Sumit Parikh, MD

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Q:
Has anybody ever considered alopecia (areata, totalis, and universalis) a mitochondrial disease? I’ve looked for some medical articles but was unable to find any.

A: This is a very interesting and unique question. Mitochondrial diseases have been associated with changes in hair formation-texture-pattern in some patients - including alopecia, brittle hair, pili torti (kinky hair), hypertrichosis (excess hair), and madarosis (loss of eyelashes). We do not know if these findings are cause-and-effect or simply associations noted by astute clinicians. In addition to this, we know that the mitochondrially-mediated cell death plays a role in chemotherapy leading to hair loss, though specific details are still being researched.
As far as alopecia areata goes, there is no known connection yet to the mitochondria. However, a study in 2002 (J of Dermatologic Science) did find higher than normal levels of antioxidants in scalps of individuals with alopecia areata, along with an increase in reactive oxygen species (ROS). Coenzyme Q, and other supplements are partly used in mitochondrial disease to decrease the burden of ROS that may increase in these conditions. It is plausible that this same mechanism may benefit the individual with alopecia areata if ROS are truly increased in this disease. However, such a theory would not answer the question of whether or not alopecia areata and mitochondrial diseases are connected.

Answered by: Sumit Parikh, MD

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Q:
I have a diagnosis of CPEO with possibilities of Kearns Sayre Syndrome. Right now I only have eye movement issues. I recently had an incident where I was outside and went to run. I started to move; however both of my legs, especially my left, were reluctant to move and I almost fell. Is that possibly something to do with the Mito Disease?

A: Although chronic progressive external ophthalmoplegia (CPEO) means weakness of eye muscles, limb and oropharyngeal muscles are also affected in many patients with CPEO. Therefore, your difficulty moving your legs may be due to limb muscle weakness, which typically affects proximal (i.e. hip) more than distal (i.e. ankle) muscles. Alternatively, the difficulty moving your legs could be due to cerebellar ataxia (incoordination due to dysfunction of the lower posterior portion of the brain), which is a common feature of Kearns-Sayre syndrome. Both ataxia and limb muscle weakness could be present. A careful neurological examination by your internist or neurologist may be useful to pinpoint the cause of your trouble moving your legs.

Answered by: Michio Hirano, MD

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Q:
I have a mitochondrial depletion syndrome due to POLG1 mutation and have passed it on to both of my children, ages 6 years and 19 months. We all have different but similar issues with my 19 month old being the most medically involved and my 6 yr old the most developmentally involved. My son loves to play with friends both at school and at home now but as it gets warmer he is MELTING! It is so hard to tell him to come in and cool off rather than be a typical kid and just play...but I worry that he is going to stress his body too much in the heat. Any advice? This is the first year he has had this drive to fit in and doesn't want any restrictions! Thanks!

A: I am sorry to hear about your genetic condition. Mutations in POLG1 can be autosomal dominant or recessive depending on the mutation site. Is your mutation autosomal dominant or recessive? Mutations in the POLG1 gene produce very diverse and heterogeneous diseases, but most now place the types of disease into 3 broad categories; 1-progressive external ophthalmoloplegia, 2-Alpers, and 3- Ataxia and neuropathy. Depending on whether mutations are dominant or recessive, and where they are located within the gene, diseases can cross categories with similar symptoms One of the most difficult things to do as a parent is to allow your children to be as “normal” as possible yet realizing that they have a really profound disease, to limit them. Children need to “fit-in” as we all can see when we go to the mall. Your son needs to play with his friends. Yet, he needs boundaries because of his disorder. It is very common for patients with mitochondrial disease to have intolerance to heat. Many times children will self regulate and refrain from playing in the heat, but of course it sounds like your little guy is 100% boy and wants to be involved and play regardless. Somehow, you will have to explain to him (in ways that will make his particular personality understand) that it is okay to play, but when it gets really hot, he must not play too hard and may even have to find shade or a cool area during play and rest a bit. You might even have to be more proactive when it is really warm- play days at your house with drinks and treats. I am sorry I can’t be more helpful. Only you know your little guy and his personality.

Answered by: Russell Saneto, DO, PhD

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Q:
Among other symptoms, some of our daughter’s issues include temperature instability, hypotonia, dysphagia, developmental delay, unidentified genetic syndrome, gain in chrome 12q13.31 as well as I, positive labs for metabolic problems (SCAD a couple of times, muscle biopsy that showed possible mito or FOD, elevated organic an plasma, and then normal as well, No IgA, low IgG...etc). GI issues are her very worst problem. Is it possible to have many features of mito and an amazingly positive response to the mito cocktail if it isn’t mito disease? She is also doing better under the mito anesthesia protocol, no longer going into metabolic crisis.
I am quite confused. Is it possible she has undiagnosed mito as is currently thought, or could it be some metabolic issue, or do they fall under the same thing? How can SCAD show up and then not show up?
Also, would having a neuropathic motility disorder fall under mito? Would it make sense that there is a malabsorption problem if she is able to now gain and grow on a lower caloric intake? And why can't she get past taking in 890cc per day at 27 calories and she is almost 3? I'm just trying to understand what her secondary issue is.

A: These are indeed difficult but good questions to ask. Without all the details I cannot be definite in answers but:
1. Mitochondrial diseases are a form of metabolic disease- it specifically affects the metabolism /biochemical activity in the mitochondria
2. Yes I have seen those with secondary mito dysfunction respond to the supplements which are to increase mito enzyme activity and antioxidant effects
3. I am not sure what were the abnormalities to suggest SCAD but both urine organic acids and plasma actylcarnitine levels do fluctuate and can be normal and then abnormal depending on a variety of factors including the health of the person on the day, when/how much/what they have eaten etc.
4. There are a number of people with mito diseases who have dysmotility but there are also a number of other causes of dysmotility not only mito
5. I would suggest you discuss whether she has malabsorption with the GI doctor taking care of your daughter to better assess that question.
6. She will hopefully grow as long as she gets enough nutrition - calories etc. for her- this depends on a number of factors including her metabolism and level of activity etc. - this can be assessed by a dietitian- sometimes the children need a calorimetry test to better assess this.
7. Mom does not explain why she cannot tolerate more feed- is it the dysmotility/reflux? If so, that is quite common in many children with mito or other neurological problems... sometimes medications can help. I hope you get to all the answers you need.

Answered by: Annette Feigenbaum MD

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Q:
I have a 24 y/o son with GAll and complex lll deficiency he has been in crisis for a year now. He gets D10 frequently and his ammonia levels stabalize and he comes home. He is only stable for approx 48 hours then they rise again (198) this week and he re to hosp. How can we tell if high ammonia is from GAll or mito complex lll.

A: The disorder, GA II, is most certainly linked with hyperammonemia. And the levels of plasma ammonia are more likely to rise in the patient with GA II when the products of fatty acid and amino acid metabolism accumulate in mitochondria as chemical compounds which contain coenzyme A, such as glutaryl-coenzyme A. This usually occurs when the patient has fasted, has ingested too much dietary long-chain fat and/or protein or even just with severe stress. The mitochondrial respiratory chain defects like Complex III deficiency are not usually associated with hyperammonemia but it can happen. For example, it may appear in a patient with a Complex III defect when it involves the liver. Under these circumstances, it would be important to find out if the cells in the liver are very sick and undergoing deterioration. For example, it is possible that a respiratory chain defect in the liver may lead to liver failure or cirrhosis. Your physician will be monitoring this problem perhaps with the help of a gastroenterologist. Finally, it is possible that the rare occurrence of both GA II and Complex III deficiencies in liver may change the nature of hyperammonemia due to GA II deficiency, or, more simply, how it tends to appear and then stabilize. In other words, the ammonia might rise even in the absence of severe fasting, dietary lapses and stress. But the encouraging finding in your son is that carbohydrate administration as IV D10 seems to bring the levels back to normal. My suggestion is to work with your physician to try to control the hyperammonemia with dietary cornstarch or other nutrients to augment daily carbohydrate intake, at least as a first step.

Answered by: Gerard Berry, MD

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Q:
Do you happen to know if Mitochondrial Disease has been associated with Ohtahara Syndrome? The description of the disease has striking similarities. In doing a little research online, there are some who think there is a link.

A: Ohtahara syndrome is a rare epilepsy disorder that is among the epileptic encephalopathies, meaning that this disorder has a preferential age of onset (in this case, during the neonatal period), frequent minor seizures (in this case tonic spasms-up to 300 or so per day), severe and continuous EEG abnormality (in this case-suppression burst pattern), heterogenous etiologies (can be cortical dysplasia-thought to be to the most common cause but there has been a rare case of Leigh encephalopathy reported), co-morbidity of mental involvement with seizure intractability and severe psychomotor (cognitive and motor development) prognosis. Often what is seen is that the EEG pattern will evolve over time with the suppression burst pattern evolving into hypsarrhythmia (Infantile spasms EEG findings) and then into an EEG pattern of Lennox-Gaustaust syndrome-of slow spike and wave discharges. Another epileptologist and I reported a patient who did not have an EEG pattern evolution and still at 7 years of age, remained with a suppression burst pattern. This would be highly unusual as most Ohtahara patients have an evolving EEG pattern as noted above. The patient that I treat has remained refractory to any and all seizure medications as well as ketogenic diet. I actually did a muscle biopsy on this patient and the results were normal. The long term prognosis for these patients is extremely guarded with early demise the usual pattern. My opinion is that most Ohtahara syndrome patients do not have a mitochondrial disorder. However, since there have been previous reports (albeit rather limited, I think only 2) it is a possibility. There is a Ohtahara syndrome website and family blog on the internet.

Answered by: Russ Saneto, DO, PhD

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Q:
Is oral pyruvate supplementation effective in mito function restoration?

A: Likely not – for several reasons: 1) The amount of pyruvate that is tolerable is about 5 grams and this is equivalent to 5 grams of sugar (from an energy perspective) so the amount of potential energy is only 20 calories of energy. 2) Studies do not show any benefit during exercise – when the need for pyruvate is high. 3) DCA massively increases the amount of pyruvate getting to the mitochondria and even that does not have much of an effect (if any).

Answered by: Mark Tarnopolsky, MD

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Q:
Is there a risk to using lignans like flaxseed or black cohosh to boost estrogen naturally in premenopausal women with mito disease, because of theoretic cyanogenic potential?

A: Flaxseed oil is likely of no benefit – all the health benefits are from flax seed itself – flax oil is an omega 3 but it is not converted to the beneficial EPA and DHA in humans and does not increase estrogen, Black cohosh is not well studied – best to avoid it – estrogen in pre menopausal women goes up and down with the menstrual cycle – no need to manipulate it for health reasons.

Answered by: Mark Tarnopolsky, MD

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Q:
I was wondering if a child that has been diagnosed with Complex I, had the tests ran on her muscle biopsy showing that the inheritance was not maternal, is that test accurate? We were told that it was either autosomal recessive or sporadic. She now has a new baby brother who has great tone, eye contact, babbling (the new baby is doing developmental things that she never did). However, he does this weird thing with his mouth that she did. He sticks his tongue in and out at 5 months, which could be nothing but I was concerned. I guess my question is: if it is autosomal recessive, wouldn't the disease manifest itself similar to the first child’s involvement with symptoms such as low muscle tone, poor visual tracking, weak suck, no verbal babbling? Could the first test of showing that it was not maternal be incorrect?

A: Complex I deficiency is typically diagnosed based on muscle biopsy enzyme testing showing that the complex I enzyme is not functioning as expected. The degree of dysfunction (for example less than 20% of what is expected) is important to know to determine if the genetic cause is stemming from a gene that encodes a part of complex I. Complex I has 45 different subunits, each encoded by a different gene! 7 of these genes are actually in the mitochondrial DNA, and the other 38 are in the regular gene pool in the cell's nucleus. If the cause is an error in any one of those genes, than the person has a "primary" mitochondrial complex I deficiency, and it is reasonable to look for the genetic causes in both the nuclear and mitochondrial DNA. It is currently possible to thoroughly examine all of the mitochondrial DNA (mtDNA) - by whole mitochondrial genome sequencing (to detect single letter misspellings) and deletion testing (to detect large "gaps" in the mitochondrial DNA. If this is what was done in this patient's muscle sample in which the complex I deficiency was found and no "mtDNA errors" were found, then it is very likely the cause is in the nuclear DNA. Indeed, the muscle would be the most reliable tissue to make this determination in this child.
Mitochondrial depletion testing (to detect a decrease in the total amount of mitochondrial DNA) could also be performed, but if found, would indicate the causative genetic defect lies in the nuclear genes. However, it is also possible other nuclear genes (besides those coding for complex I subunits) could be the cause for this child's problems, and it may be worth re-evaluating the child with time by a mitochondrial specialist (either neurologist, geneticist, biochemical expert, etc) to see if it's possible to identify the specific genetic cause in this child. Identification of the underlying genetic cause and having the ability to test additional family members with concerning manifestations is the only way to gain certainty in this situation.
When the cause lies in the nuclear genes, autosomal recessive inheritance is the most common pattern in children with mitochondrial disease (although x-linked and autosomal dominant are also possible). Recessive inheritance implies two asymptomatic carrier parents together have a 1 in 4 chance with each pregnancy to have an affected child. While the presentation of the disease often is similar in affected siblings, depending on the specific gene, variations can be seen. However, the overwhelming likelihood (75%) is that the healthy-appearing child is truly unaffected. It should be recognized that "healthy" siblings themselves have a 2 in 3 chance of being asymptomatic carriers, which means they could "pass it on" in the event their future partner is also a carrier for a mutation in the same gene. This likelihood depends on what the actual genetic cause is and how common it is.

Answered by: Marni Falk, MD

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Q:
My daughter had a muscle biopsy that revealed the following: “Myopathy, with rare necrotic fibers; some fibers show mitochondrial proliferation (ragged blue fibers). Comments: This is an abnormal muscle biopsy which demonstrates mild necrotizing myopathy with no inflammation or fibrosis. Rare fibers with mitochondrial alteration in the form of mitochondrial proliferation are seen.” A frozen piece was then sent off to determine the type of Mito but it was normal. What does that mean? Is it common for the frozen piece to be normal?

A: The types of testing that can be performed on frozen compared to fresh muscle biopsy samples are different. In general, more detailed types of studies can be done on a fresh sample. If mitochondrial respiratory chain analysis was performed on the frozen specimen, it is not uncommon for results of such testing to be "normal", even in the presence of mitochondrial disease. If a definite abnormality is identified on respiratory chain analysis, this may lead to a more precise diagnosis. For example, specific DNA testing may yield an answer in such a case. Without knowing more about your daughter's clinical presentation and other test findings it is hard to comment further. However, it is always a good idea to be sure she is seen by a specialist who cares for children with mitochondrial disorders.

Answered by: Greg Enns, MD

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Q:
My son, who is 4, just had the Whole Mitochondrial Genome Analysis done. This is a very new blood test. How effective is it on finding a mito condition in a child? Would it also be more specific than the muscle biopsy? My 3 yr old son has mito complex 1 & 4. Would testing him with this new blood test give us more details? Also, what exactly will it tell us?

A: The mitochondrial DNA (mtDNA) genome analysis is a blood test that scans a person’s mtDNA for mutations (typos) that might lead to mitochondrial disease. This is the DNA that is inherited from mother-to-child and is involved in building/maintaining 10-15% of the mitochondrial structure. The vast majority of mitochondrial patients do not have problems in this portion of the DNA - but rather in nuclear (regular) DNA (inherited from mom and dad). Thus this test is only expected to be abnormal in a small number of mitochondrial patients (likely 10%).
Finding DNA mutations for any condition can help confirm a diagnosis. It may allow for some prognosis information to be provided - but since we are still learning about DNA and how various typos in DNA affect the body - our understanding of the problem is still limited.
DNA mutations can be of 3 different types:
1) Known to cause disease (pathogenic mutation)
2) Known to exist in the general population and be relatively harmless (polymorphism)
3) New mutations that have not been described before (novel mutation)
As we explore newer and newer portions of DNA, many of the typos we find are ones that have not been seen or described before. In that case, we have to wait for other patients to be identified with a similar DNA typo before we know for certain whether or not a mutation/typo is a disease-causing one or a common population variant. We might be able to use computer paradigms to help us predict whether a mutation/typo is harmful in some cases.
Currently, knowing where the problem is in DNA does not change management, medication choice or overall prognosis. Having a DNA mutation identified does allow for other family members to get tested and undergo genetic counseling. If a disease-causing mutation is identified, it does allow for one to have a 'gold-standard' diagnosis and not have to worry about missing another neurologic disease.

Answered by: Sumit Parikh, MD

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Q:
My 13 year old daughter and 52 year old wife have MELAS. The original Mito cocktail has a lot of pills. I was thinking of instead of twice a day dosing B-100 complex, folic acid 0.4mg, Vitamin C 500mg to reducing it to just once daily. We keep the Co Q10 and L-carntine at the current levels while increasing L-arginine BID to the per kg body weight max dose. Would this be appropriate?

A: There really is no right or wrong answer for the mito cocktail. Every mitochondrial doctor in the country has his or her own preferences. Commonalities among most physicians include recommending CoEnzyme Q10 and Levo-Carnitine. Personally, I also recommend Riboflavin and Folic Acid plus L-arginine for MELAS. I recommend taking vitamins 3 times a day (8AM, Noon, 4PM). I would suggest talking with your wife’s physicians about working out a regimen that makes sense for your family.

Answered by: Mary Kay Koenig, MD

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Q:
Our 15 yr old son was diagnosed with autism at age 9, then epilepsy at age 12, then mito & thyroid problems at age 13. Then it was discovered he had a chromosome disorder 10q22.2 at age 14. He's 5'5", 100lbs. He has frequent pain, weakness, fatigue, and is slow to process info. Our neurologist seems to think exercise & vitamins will delete the bad mito & he'll be fine. He rarely orders blood tests, EEG, etc. Am I overreacting or do we need to pursue another doctor?

A: I am sorry to hear about your son. I am assuming that the chromosome disorder was detected by gene array analysis. If so, then the 10q22.2 lesion could either be a deletion or duplication region in chromosome 10, short arm (q) at position 22.2. If this is a deletion, there would be missing chromosomal material at this location. There are essential genes that are deleted and this deficit can induce disease. There is one particular gene in this chromosomal region, urokinase-type plasminogen activator that is associated with disease (Alzheimer disease). So we know that genes in this region are very important. Whether this gene is altered in your son isn't known as you do not mention it. But certainly, he would have this region missing. Now, if this region is duplicated, which gene array analysis might also detect, than there is too much genetic information and may lead to imbalance of gene expression. Either way, there is either too much or too little genetic information. One would suspect that this is likely involved in your son's disease.
I am not sure what type of mitochondrial disease that your son has, but it would seem most likely, that the above gene problem is, at least in part, associated with your son's clinical problems. Having too many gene products (duplication) or too little gene products (deletion) is not something that physicians can manipulate easily. So, even though exercise and vitamins may help to optimize mitochondrial function, it would be my opinion that complete resolution of mitochondrial function is unlikely.
Ordering tests are often based on change in disease. So, for instance if seizures types change or medications begin to fail, we think about getting medication serum levels to see if this has changed. We may decide to get an EEG to see if long term seizures have altered electrical findings. If there is a change in clinical presentation, for instance a new imbalance (ataxia) or dramatic decrease in vision, we might order testing to see what may be responsible for the change. However, if there has been no change in a patient, we might not order any testing as we know the results of previous testing.
Not knowing exactly what is going on with your son, it is impossible to tell you if other testing should be performed.

Answered by: Russ Saneto, DO, PhD

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Q:
I have a twice confirmed positive muscle biopsy for complex II/III. Recently mtDNA tests were done that showed a new variant, there was a novel mutation at 7269G>A (V456M). There were also two secondary mutations in 4216 and 4917 both LHON. Could you explain the significance of these findings and any knowledge of these? I also have three affected kids with positive labs, elevated alanine and pyruvate and other amino/organic acids and mito disease symptoms. My geneticist said they only have a probable mito disease as they have no muscle biopsy to prove mito. Since I do as their mother, isn t one positive muscle biopsy and my DNA testing enough? Thank you.

A: All test results are best interpreted for you by your metabolic physician as he/she is in the best position to correlate them to your symptoms. In general, these mutation results would be consistent with your reduced muscle enzyme activity and a mitochondrial myopathy. Since these mutations are found on your mitochondrial chromosome and would have been passed on to your children, they too are at risk to develop symptoms. If they have already developed symptoms they should be treated for mitochondrial myopathy. Under these circumstances, there is no reason to biopsy them.

Answered by: Jerry Vockley, MD, PhD

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