OUR MOST CURRENT - PDF document

1 OUR MOST CURRENT “ ASK THE MITO DOC â
OUR MOST CURRENT “ ASK THE MITO DOC ” QUESTIONS Q . Do you have any studies or information about the use of Botox in patients with mitochondrial diseases? A. I would OigOly douNP POMP POere’s Mny sucO sPudy. NonePOeless, BoPox injecPions musP be considered in the injections would best know whether a patient would be at higher risk for complications due to their general medical condition or not. Fran Kendall, M.D. Q . l disease and we are awaiting testing. I am not diabetic, but I am having odd blood sugar symptoms. If I do not get up in the middle of the night and have a snack, I awake the next morning feeling like my fasting blood sugar is very very low, but according to the glucose meter, it is not improve and I do not feel right until shortly after my 3rd meal of the day no matter what I eat. I feel like my body isn't using the food I eat prop erly and I eat more that I should to compensate, yet I am not overweight. My A1C has dropped over the past couple of years from an average of 5.5 to 5.0. I have heard mito and fasting A. Before we can relate your s ymptoms to mitochondrial disease, you need to have confirmation of the diagnosis. Your testing shows that your symptoms are not related to fasting or feeding. Once your d iagnostic testing is complete, then planning further evaluation and designing a treatment can be addressed. Gerard Vockley, MD serum carnitine. How long do I have to stop su pplementing with carnitine for the blood test to be valid? A. We would hold the carnitine for at least a few weeks if measuring it in blood; 4 - 8 weeks if measuring it in muscle Sumit Parikh, MD Q. I want information regarding the effects birth control h as on people with mitochondrial disease . A. I don’P OMve Mny specific resources POMP Mddresses POMP issue in pMrPiculMr NuP I suspect it depends on the type of birth control. Of course, some may have absolutely none like the use of condoms whereas others could potentially impact an individual. AgMin, iP depends on NirPO conProl Mnd POe pMPienP’s underlying disorder Mnd proNlem seP but many women with mitochondrial disease specifically take birth control to help regulate their cycles and prevent some of the autonomic dysfunction and fatigue they geP wiPO POeir monPOly menses. IP’s M discussion POey sOould OMve in POe conPexP of POeir problems with their OB/GYN. Fran Kendall, M.D. Q. I s adenosine monophosphate deaminase 1 deficiency a mitochondrial disease? A . IP’s complicMPed. Some people POink iP’s M diseMse Mnd some don’P. IP’s noP reMlly M mito disorder, though it does affect energy metabolism. I assume it was diagnosed by a neurologist. If he is having symptoms, he should probably have a full metabolic ev aluation. Here is some info

2 rmation about it. http://omim.org/entr
rmation about it. http://omim.org/entry/6 15511?search=Adenosine%20Monophosphate%20Deaminase% 201%20Deficiency&highlight=monophosphate%201%20deficiency%20adenosine%20d eaminase%20%22adenosine%20monophosphate%20deaminase%201%20deficiency% 22 Gerard Vockley, MD Que stions from 2018 Q. I saw a patient in Travel clinic with Mitochondrial type I an IV deficiency; any concerns for malaria prophylaxis with malarone or traveler's diarrhea meds to include loperamide andazithromycin; any other concerns for this patient traveling to Zambia for 1 week? A. No outright concerns unless they have not tolerated the medications before Sumit Parikh,MD Q . I have MIDD (3243a - �g mutation) and my hearing loss is progressing. Can anything be done to slow progression or revers e it? Any research trials I should be aware of? Thank you! A. Unfortunately, no, there is nothing to prevent the progressive hearing loss. In regards to clinical treatment trials, the enrollment criteria and details of the existing trials are variable. My recommendation would be to look for any possible trials for which you might be eligible at clinicaltrials.gov and to update yourself on the status through po stings on the UMDF website . F ran Kendall , MD Q. I have p tosis but am having problems focusing on my kindle...almost a loss of vision on the perimeter. I do wear glasses and have mito with neuropathy. Please help. A. Thank you for your question, and I am sorry to hear that your vision loss is affecting your a bility to focus and use your Kindle. One of life's pleasures is a good book! Many mito disorders can affect the eye in a multitude of ways. I would advise that you find a good Neuro - ophthalmologist to help evaluate you and see what might be treatable, such as use of prisms in eye wear. It sounds like you might have CPEO (chronic progressive external ophthalmoplegia). Some of the eye issues we encounter include: corneal exposure from facial weakness or ptosis repair, limitations of extraocular motility with diplopia, convergence insufficiency with double vision, optic neuropathy with central visual loss, retinal degeneration with peripheral visual field loss and night blindness or with central visual loss (maculopathy), and cortical vision loss from stroke - l ike episodes. Hopefully we will continue to have new medications in clinical trials and eventually approved for mitochondrial disease to stop progression and possible reverse some symptoms. Speak to your primary mito doctor to see if they recommend any a dditional treatments or supplements at this time. If you do not have one, the UMDF can help locate someone for you to see. Amy Goldstein , MD Q. Do I risk muscle damage if I continue exercising during rhabdo

3 mylosis and atp problems ? A. If a p
mylosis and atp problems ? A. If a person is actively having muscle breakdown (rhabdomyolysis) - they should not be exercising at that time and wait until their muscles recover. Exercise levels may need to be adjusted until the muscles have fully healed. This is true for muscle breakdown due to mitoc hondrial disease or other genetic causes. Sumit Parikh , MD Q. My 10 year old niece suffers from Very long - chain acyl - CoA dehydrogenase deficiency; VLCADD. The past six months she has had constant diarrhea and throwing up. She has been taken to the ho spital and tested in different ways but there is still no solid understanding as to why this is happening. Next they will probe her stomach from both ends. Her mother keeps her on a very low f a t diet, administers regular doses of MCT oil. She also gives her coconut oil and she drinks orange juice. Recently, I had heard that coconut oil used regularly and especially in a low caloric diet can cause problems with the body ingesting carbs and almost acts like a lard in the body. Can you direct me t o any information to better understand this? Also, am I correct that iP’s best to maintain an alkaline system and to limit the intake of acids such as orange juice? As you know it is such a complex condition but I appreciate any guidance, information, su ggestions you have. A . There is not a general tendency for patients with VLCADD to have GI issues including vomiPing, so POe pOysiciMns Mre correcP Po look for oPOer cMuses. You don’P sMy how much MCT oil the child is on. In excess, MCT oil can cause dia rrhea, but usually noP vomiPing. TOe primMry componenP of coconuP oil is MFT oil, so pMPienPs sOouldn’P Ne on both as the fat intake is too high. There is no need to avoid orange juice. I recommend reviewing diet with an experienced metabolic dietitian. Jerry Vockley, M.D., Ph.D. Q. How safe is Plaquenil for Mito patients? A. With the exception of medications such as Metformin, generally the decision to utilize a medication or not is based on the severity of the problem one is attempting to treat and whether or not the medication at hand is the only medication to treat that significant problem. Having said that, have the patient discuss the use of any biological such as PlMquenil wiPO POeir PreMPing pOysiciMn Po dePermine if iP’s use is definiPely indicated in the management of their comorbid disease. Fran Kendall, M.D. Q. I have mitochondrial deficiency which has left me with great a deal of neuropathic and myopathic pain. With the opiate situation it has been recommended that I take buprenorphine for the pain, which is debilitating. I know that Buprenorphine has an adverse effect .on liver mi tochondria...but is

4 it safe to take if liver enzymes are c
it safe to take if liver enzymes are closely monitored ? A. The general answer is that buprenorphine and other narcotics are not outright contraindicated in mitochondrial disease or dysfunction in most cases. Unless the patient's physic ian feels otherwise there is no need for special monitoring of the liver just because of mitochondrial disease. As an aside - we usually do not recommend routine narcotic use for any of our patients - including for neuropathic or myopathic pain. Sumit P arikh , MD Q. My daughter has started her cycle about 3 months ago and has dysautonomia with her mito...she is having some significant swelling (pitted edema) daily that seems to be even worse around her cycle time. She also has hypotension so lasiks ar e not an option. Her cardiologist says she is "mimicking heart failure" but her cardiac labs and echo are normal...any advice? She also has lots of discoloration (turning blue) in her arms, hands, legs, and feet. Walking when her swelling is this bad is pa inful for her... A. This is not uncommon in Mito: Is her albumin normal? Is she a candidate for IV albumin infusion? FMn sOe see M “lympOedemM” experP or cenPer? Wear compression hose or use SCD (compression devices)? Amy Goldstein, MD Q. Hi, I am 34 years old and it looks that me and my son both have mitochondri al disease. Unfortunately we li ve in Poland and doctors don't know anything about it. I cannot stop blaming myself because I was perfectly healthy all of my life . Before pregnancy , I didn 't eat prop erly, changed my job and worked all Day and night and overstressed so horrible. When I got pregnant I felt that s ome th ing is not right with me. When my son was born he ha d the same symptoms as me when I got pregnant and later on, because my symptoms hasn't improves till now. My sons are also worse. And my question is it possible that I destroy my mt dna because of those horrible stress, lack of nutrition , not sleeping enough etc. ? I read that mtdna is ver y weak and mutate very often during the life especially if they don't get it what they need. My whole f amily is perfectly healthy and I also was till the pregnancy and now we - me and my 4 year son are so exhausted. My son spends most of his time lying on t he couch because he is too tired. I was also overstressed during my pregnancy. Could I have destroy ed my mtdna during my life an d then passed to my son? A. T he simple answer is - yes they likely did not do anything to cause primary genetic mtDNA disease - but the true answer is not as straightforward. We now know that any and all lifetime exposures - from cigarette smoke/nicotine or obesity or diabetes to more dramatic thin

5 gs like cancer/chemotherapy lead to very
gs like cancer/chemotherapy lead to very relevant DNA changes including mtDNA... an d these changes affect children and grandchildren if conception occurs after the exposure. Sumit Parikh,MD Qu estions From 2015 - 2017 T o see additional questions, visit the UMDF C o nnect Newsletter archives here. pleased to offer answers to some of those questions as taken from Ask the Mito Doc SM at www.umdf.org. Please note that infor mation contained in Ask the Mito Doc SM is for informational and educational upon as professional advice, whether medical or otherwise . Q: My Great Plains Labs report shows that I have Mitochondria dysfunction. What do you think about that blood test? A: The Great Plains Laboratory is not a traditional/commercial lab. Their interpretations do not align with how mitochondrial and metabolic physicians interpret metabolic test results. We do not know what to do with these results. For many patients with the se abnormalities on the Great Plains testing - nothing concrete is seen on traditional tests. Sumit Parikh, MD Q: Inheritance question : My mother in law has Chronic Progressive External Opthalmoplegia(CPEO). No genetic testing was ever done for her two boy s (one being my husband). Could my husband be a - my main question - could he therefore pass it on to his offspring? A: CPEO is often a sporadic disorder caused by mtDNA deletions. However, there are also autosomal dominant fo rms of the disease. You need to determine the genetic etiology for your mother - - law and once that is known, you can address the possible recurrence risk for your husband and subsequently your children. Fran D. Kendall, MD Q : My daughter has Complex IV / Leigh’s blood work and nothing showed out of her norm so doctors are stunned because they are not familiar with the illness. A: No. But, hair loss can be reflective of multiple other issues to include poor nutrition and general poor health . Fran D. Kendall, MD Q : My currently 2.3 year old has hypotonia. We did genetic testing and received a result of: Variant of unknown significance in the MT - TV M.1647 T A (otherwise known as Leigh’s). While she has lost a lot of her mobility, she is stable. She is currently on a mito cocktail of Levocarnitine, Leucovrin, Ubiquinol, Biotin and a 7.5 mg of Liquid B - Complex by Natures Answer. I am concerned that the B - Complex I am using contains PABA. I am consideri ng switching her to a more natural product such as Buried Treasure Brand Liquid B Complete or the Tropical Oasis Liquid B Complex, but neither have been reviewed by the FDA and I don’t know if these supplements are legitimate. I would appreciate your advic e on a suitable solution and dosage for my little one. After reading many of t

6 he posts I have also seen creatine, alph
he posts I have also seen creatine, alpha - lipoid acts, and magnesium 400 - 800 mg and I’d like to know your thoughts about adding these supplements to the current cocktail. Thank you. A : In regards to supplement or vitamin therapies for mitochondrial disease - we do not have evidence to show that any of these are effective. However, they are generally low risk and can sometimes make a difference in our patients - and so they are tr ied - sometimes one - at - a - time or sometimes as a combination or “cocktail.” Depending on the physician you see - each one may have their own preferences. Alpha lipoic acid, creatine, CoQ10 as ubiquinol, carnitine, leucovorin and B - complex vitamins are some of the most popularly used supplements. L - Arginine is tried if there is a history or risk of strokes. The list of things that could be tried is long. The truth is that these may not help so it may not be worth continuing them endlessly. If there are no b enefits noted after 3 - 6 months - it may be worth streamlining the vitamins given to a crucial 2 or 3. We hope that future research provides us with better guidance on which supplements may work better for specific patients . Sumit Parikh, MD Q : My 6 year o ld daughter is diagnosed with PDHD E1. Her caregiver was just told she has mononucleosis. I know this can last for up to six weeks. What precautions should I take with her caring for my daughter? Do I need to suspend her until it has completely cleared, or for a shorter period of time? Is there extra risk for someone with mitochondrial disease when contracting mono? What should I watch out for? A: Mononucleosis is spread from person to person by direct contact through saliva. As such, coming into close conta ct with somebody with the disease makes you at risk for contracting the infection. While good handwashing and use of gloves and mask would reduce the transmission possibility, to be completely safe, you may wish to find another caregiver until the infectio n has resolved. Although some patients with a host of mitochondrial diseases do have low immunoglobulin levels making them more prone to infection, the primary risk for infection contraction in mitochondrial disease patients is the metabolic instability th at occurs when they get sick. I would recommend that you speak to your caregiver, and your local providers to determine your best option for managing the situation. Fran D. Kendall, MD Q : I have epilepsy, cardiac, endocrine, muscular and gastric issues. My daughter has asthma gastric issues cvs severe abdominal and regular migraines we are both the second child the other people in our family have been fairly healthy we know she has a mito disease just not sure which one.

7 Is it possible that we can be a swin gi
Is it possible that we can be a swin ging door so to speak where I got some symptoms and she have separate symptoms but basically have the same disease? A : Yes , clinical symptoms can vary between mother and daughter who have the same mutation. This is most often seen in mtDNA related diseases. There is something that is called heteroplasmy where the percentage of mutation can vary from one child to the next or from mother to her offsprings. This is less so in disease caused by nuclear DNA mutations, but still symptoms can vary in generations de pending on the which chromosomes the defect lies in, e.g. X - chromosome. Other nuclear mutations are most often not seen in one generation and then the next generation unless the other parent has the same mutation - pretty rare. I would suggest getting testi ng, as there are some pretty interesting medications being used in clinical trials for certain disease. Russell Saneto, DO, PhD Q: I have had tests for mitochondrial disease and on my genome everything was positive and I thought that was the end of the c oncern of having a form of mitochondrial disease. A more in depth testing has come back showing evidence of cox deficient fibers and they are now checking for s specific mutation that my uncle was diagnosed with which I believe will take months before I kn ow any more. Having cox deficient fibers showing in a test. Does that mean I have a mitochondrial condition? Or can it show up in perfectly healthy individuals as well? Thank you for your time. A: Without knowing the specifics of your case (or your age) - I can try and provide some general information. I am presuming that you mean your “genome testing” came back normal when you say that it was “positive.” I would be curious to know what DNA test you had - as there is no one mitochondrial DNA test and even i f all available DNA testing in blood is completed - we are only able to confirm a mitochondrial disease diagnosis in patients where we are highly suspicious of one about half of the time. The muscle biopsy is often sent for a variety of tests - some where we look at the muscle under a microscope - but additional tests of how mitochondria are working (biochemical tests) and how the mitochondrial DNA looks (Genetic tests) are also routinely performed. You mention “COX - deficient fibers.” In this situation - the mitochondria look different under the microscope. This finding can be seen in mitochondrial disease, as a part of normal aging and in other genetic and muscle/ nerve disorders - so it is a non - specific finding by itself. This piece of information would be used by your physician along with other test findings to help decide the likelihood of your having a primary mitochondrial disorder.

8 Sumit Parikh, MD Q: My daughter
Sumit Parikh, MD Q: My daughter is 8 years old, and was diagnosed with CUD when she was about 3 months. She has been ta king L - Carnitine since she was 4 months old. Lately she has had symptoms of extreme hunger. She even goes so far as to sneak food in her room, eat it and hide the evidence. She has also been having stomach pain, and burps that smell like rotten eggs, and a t times nausea, vomiting, and diarrhea. Do you think that any of these sym ptoms have to do with her CUD? A: These are not symptoms of CUD per se. However, the odor and GI and some of the GI symptoms may be due to carnitine. Excess appetite could be a symp tom of low blood sugar, but it would unusual with good metabolic control. You should contact your metabolic physician for an appointment. Jerry Vockley, MD, PhD Q :What are the prospects for genetic therapy using CRISPR/Cas9 gene editing technology to treat mitochondrial disease? It seems that mitochondrial diseases that are the result of a single autosomal genetic mutations (e.g., those involving mitochondrial aminoacyl - tRNA synthetases) are well suited to CRISPR and that CRISPR technology is on the cusp of moving from the realm of academic research to the realm of practical treatment. A: CRISPR/Cas9 (more generally known as gene editing) technology is indeed a promising prospect for correcting genetic disorders, including those causing mito disease. In fact, the UMDF is already sponsoring a research project to explore gene editing of the mitochondrial chromosome. While exciting, it must be kept in mind that any clinical use is still likely years away. Jerry Vockley, MD, PhD Q: I am 48 and have LHON plus . I hav e been having horrible GI issues as well as many other issues for six months, still trying to get resolved. Fever, chills, weight loss, extreme abdominal and back pain, malnutrition, black stools, nausea, heartburn, and more. My palliative nurse found thru sh yesterday. I’m worried about an infection throughout my entire body now but can’t get my doctor to respond. Any advice I can print and pass on for urgently testing and treating an infection such as thrush that could be candida in the blood stream? Thank you. A: A systemic fungal infection is very serious and can certainly be deadly so it is unlikely that this is causative for this patient’s issues. She definitely needs to seek assistance from her local doctor. Fran D. Kendall, MD Q: Through genetic testing using a sample of a muscle biopsy taken 4 years prior, I have been told I have a large single 12kb mitochondrial deletion with a heteroplasmy level . My assumption is since my symptoms have progressed significantly since the muscle biopsy, my heteroplasmy level has increased over time. I am an ad

9 ult whose main symptoms include muscle f
ult whose main symptoms include muscle fatigue/weakness throughout body and muscle fasciculations which have progressed with time, light headedness/mental fatigue as well as focus issues/blurry vision occasionally in one eye primarily. Exercise appears to lower my baseline (creating what seems to be more significant fatigue and weakness which never gets better). My questions are as follows: I was curious if any of the medicine being tested in current pharmaceutical trials (Stealth Biotherapeutics, Reata Pharmaceuticals, etc.) could be beneficial to someone who has such a large single dele tion (i.e., with having so much genetic material deleted in a percentage of mitochondria, is it still theoretically/physically possible to still somehow receive benefit from these medications being tested)? ?Are there any treatments recommended for adults with large single mito dna deletions? I am taking supplements (CoQ10 - 300mg morning and 300mg at night, Creatine 5 grams/day, Vitamin E 400 IU/day, Vitamin C 500 mg/day, Vitamin B2 100 mg/day, Vitamin D3 2000 IU/day, Alpha lipoic acid 300 mg morning and 3 00mg night) which don’t seem to help. I have tried light exercise which seems to permanently lower my baseline after engaging, which I notice a few days later after engagement. ? Is muscle fasciculation, typical with those having large single deletion in m itochondria? Any research of large single mitochondrial dna deletions that I should follow? Any doctors in US that specialize in adult patients with large single deletion in mitochondria? Thanks very much. I would greatly appreciate all or any subset of th ese questions answered. Please let me know if you need any additional information. A: I am sorry to hear about your medical condit ion. Currently, as far as I know, the only clinical trial looking at mitochondrial myopathy is the study by REATA. The Stealth study has closed but what we hear, they will be having a Phase III study on their medication opening soon. You can always check c linicaltrials.gov and look for mitochondrial disease studies. Since your heteroplasmy is so low, likely the normal mtDNA present should be working and providing enough energy. There are no studies showing any vitamin therapy to be universally helpful (Coch ran Report). Certainly, in any particular patient the vitamins may give some help. Muscle fasciculation is rare in mitochondrial disease and mostly only seen in young children with mtDNA depletion syndromes. Muscle fasciculations are often seen in other ty pes of myopathies, especially ALS. But there are benign forms seen in viral illness. At your age, I would follow the mtDNA induced CPEO literature as single deletion disorders expressed during adult age ranges are usually related to CPEO. I do not know of any physician special

10 izing in large mtDNA deletions.” Rus
izing in large mtDNA deletions.” Russell Saneto, DO, PhD Q: Recent labs (OAT) support that my 7 year old autistic son has at least some degree of mitochondrial dysfunction (high succinic, methylglutaric, and ketone and fatty acid oxi dation). He responded well to Levocarnitine (990 mg twice per day), which also improved GI motility even though it continues to be a problem. He also takes 200 mg of ubiquinol per day and 1 gram of vitamin C twice per day with good results. He continues to struggle with hypotonia related issues: he has extreme difficulty pedaling a bike with training wheels, becomes exhausted after biking a few feet, unable to bike up slight inclines, unable to balance, etc. Per his doctor’s recommendation, I recently began supplementing him with 1000 mg of kre - alkalyn twice per day. I have noticed some improvement with his speech with this and it also seems to have a calming effect. However, the improvements last for 2 hours maximum. I believe that he would benefit from a m uch higher dose eventually. My big concern is that the creatine supplementation has made him physically weaker and exhausted. Any idea of why this could be? A: I am sorry to hear about your son. There are no universal treatments that are beneficial for all patients with mitochondrial disease. This is unfortunate and many of us are trying our best to uncover best treatments for this disorder. In a recent review article, in a very well respected journal The Cochrane Collaboration, a review of the literature wa s performed on creatine and its use in muscle dystrophies and metabolic myopathies (which would include mitochondrial myopathies). The authors looked at all studies investigating the effects of creatine on muscle performance. There was no significant effec t on metabolic myopathies. So, although in some patients a beneficial effect might be seen, overall there is no significant effect on the majority of patients. So, what you are noticing with your son sounds very much like there is little benefit and maybe even a loss of muscle performance. This would be congruent with what the review study in the Cochrane Collaboration reported. I am sorry. Russell Saneto, DO, PhD Q: My 6 year old son has been diagnosed with respiratory chain enzyme complex IV deficiency . We are in Dublin, Ireland and we are going to attend a neurologist soon. Is this particularly rare and if so should I push to be seen abroad (US/ UK) where bigger numbers are treated. I am a cancer nurse and can find very little info on this particular de ficiency. Thank you. A: I am sorry to hear about your son. It is somewhat difficult to answer your question just based on complex IV deficiency. As an isolated electron transport chain complex, complex IV is not the most common defect we

11 see. However, if t he genetic etiology
see. However, if t he genetic etiology of the complex IV defect is known, then it might be very helpful. For instance, if the deficiency is due to mutations in the SURF1 gene (this gene helps the assembly of complex IV), then this is one of the most common nuclear mutations causing Leigh syndrome. However, there are multiple other genes, both genes from the nucleus and mitochondrial DNA that can alter complex IV activity and give rise to disease. As a group, complex IV disorders are very heterogeneous in their clinical presen tation and possible course. Knowing the possible genetic etiology of your son’s complex IV might be helpful in knowing the next best steps. There are large mitochondrial centers in the UK, Newcastle and Cambridge come to mind. These larger Institutions may know of possible clinical trials that might benefit your son in your region, so I would keep a look out for possible treatment trials. In the US there is an internet site, https://clinicaltrials.gov that list the current trials in the US. Although many ge nes that are involved in complex IV are known, there are likely genes that remain unknown. I do hope for the best for your son. Russell Saneto, DO, PhD Q: My 33 year old daughter abruptly lost most of her vision simultaneously in both eyes 5 years ago. MS was ruled out, NMO was feasible, and then she was found to have the LHON 11778 mutation, heteroplasmy. However, her neurologist suggested NMO was the root cause because of small spinal lesions and neuro - symptoms though blood NMO antibody was negative. Thr ee years ago she suddenly started having severe headaches and a year ago abruptly presented with episodic muscle knots and severe pain, urinary retention, muscle weakness, exercise intolerance, unexplained weight loss, tachycardia, neuropathy, and worsenin g vision. MS and NMO have been discarded and MRIs actually show fewer lesions. LHON plus is thought to be the cause. Pain level and incapacity can be severe, especially during ‘episodes’. Tizanidine and Lyrica help some but she needs better management. Is it worth testing for other mito disorders? What should she be tested for in order to determine an appropriate mito cocktail? She’s taking idebenone and Ubiquinol but hasn’t seen a marked improvement. She’s seen two mito docs but this is so rare both have n ot seen a case and are uncertain. A: The core neurological features are extremely likely to be due to the LHON mutation. MS - like features are more common in women likely because women have a higher propensity for auto - immunity. In fact, we have seen sever al people with true proven mitochondrial mutations (such as this case) with positive NMO antibodies and oligoclonal bands; consequently, it is likely that the mitochondrial disorder pred

12 isposes to auto - immunity (We know that
isposes to auto - immunity (We know that mitochondrial damage can activa te the inflammasome). I would not be looking for other genetic disorders for the LHON is the likely culprit and explains most of this. Pain medications are many and need to be carefully managed by a neurologist with expertise in pain or another pain speci alist. Mitochondrial medications for LHON are coeqnyme Q10 + alpha lipoic acid + vitamin E + creatine monohydrate - we also add VITALUX for LHON patients. I would also consider acute MS/LHON if there are sudden acute flare ups of the neurolog ical deficits (not pain but urinary retention, stroke - like episodes, etc.) and ima ging abnormalities that change. Mark Tarnopolsky, MD, PhD, FRCP(C) Q: My niece (sister’s daughter) was diagnosed by muscle biopsy with Mitoch ondrial Disease, she was 18 months at diagnosis and over a year behind developmentally. Since then she has improved remarkably and caught up to all milestones for her age. Other than being quite petite and less athletic than her sister, she has no symptoms . Her neurologist believes it is a mild to moderate case and my sister has decided not to pursue any more genetic testing which would reveal what specific type of Mito she has. I am 39 and after repeated miscarriages am pursuing IVF in the hopes of startin g a family. My doctor feels strongly I should be tested for Mito before IVF. I went to see a genetic counselor, but they had little to offer since I do not know what type my niece has. I scheduled an appointment at Stanford some time ago to investigate Mit o, but unfortunately the wait is quite long and my appointment is not until the end of the year. I do not want to hold up IVF any longer due to my advancing age (it took 4 months just to get the IVF process started), but I am at a loss for what to do next. My questions are 1) what are the chances that I am a carrier? 2) What type of testing would you recommend I do, and can my fertility doctor order these labs? 3) If I do turn out to be a carrier, what are my options during IVF to minimize risk? A: Based on the information you provided, it is possible that your niece does not have a mitochondrial disorder or has a reversible form that can sometimes occur. Without knowing what caused her issues at a genetic level - there is no testing that would be recommended for you - especially if you are otherwise well and asymptomatic. Without knowing the genetic cause of her disorder - we cannot offer specific information as to whether you are a carrier. Meeting with a genetic counselor could help go over some of this inf ormation in more detail and they may be able to offer you a little more. Sumit Parikh, MD Q : Here is the link from Michael J. Fox Foundation. Is there a link be

13 tween CVS with Mito? Mito problems…al
tween CVS with Mito? Mito problems…all together? My daughter has CVS with possible Mito. (Our in s. wouldn’t pay for test). My youngest daughter has Hypothyroidism, and I have Parkinson with CVS characteristic. My mom (still living) has Parkinson with the same characteristic. Are they all connected? A: At one time it was felt that CVS was a definite m itochondrial disease; however, in most cases there is at most a higher risk for CVS amongst certain types of mitochondrial DNA variants. Given the strong family history it would be worth getting the mom with PD and CVS tested with a muscle biopsy and mtDN A sequencing just to make sure that there is no rare mtDNA variant counting for this cluster of medical issues . Mark Tarnopolsky, MD, PhD, FRCP(C) Q: It is suspected that I have Mitochondrial Disease and was looking into the mtSEEK and nucSEEK testing, howe ver, I was told that these tests are 50% likely to find something that will change management and improve care. Are there tests besides the mtSEEK and nucSEEK that provide more definitive answers for Mitochondrial Disease? A: For suspected mitochondrial dis ease, most of the commercially available genetic tests have at best a 50% yield (likely to find something). It is much less likely that a positive gene test will also change management and improve care. We do not have specific therapies based on gene mutat ion for the majority of the mitochondrial disorders; gene therapy is just now in clinical trials for disorders such as LHON . Sumit Parikh, MD Q: I have a levo carnitine deficiency along with B12 and CoQ10 deficiency since Christmas of 2015 . I have had sponta neous compartment syndrome in both arms 5 times to the point I almost lost my arms.is there a correlation between the two? A: Carnitine deficiency, if secondary to a fatty acid oxidation disorder, could lead to increased muscle breakdown and sometimes comp artment syndrome. Carnitine deficiency can also occur due to nutritional issues. In that case it is less likely to be a cause of your symptoms. It would be worth determining why you have carnitine deficiency. Vitamin B12 deficiency and CoQ10 deficiencies, if not dietary, can also be due to select metabolic diseases, though they are less likely to cause muscle breakdown or compartment syndrome. Sumit Parikh, MD Q: My granddaughter has Leigh’s Disease . She had no breathing problems until she had surgery fo r a g tube. During that surgery she was administered propofol and ringers lactate; of which, I have read are absolute no no’s. Since then, she has not been able to breathe on her own. After surgery she coded and had metabolic acidosis. I am convinced that all of this is connected. Please let me know your thoughts. A:

14 I am sorry to hear about your granddau
I am sorry to hear about your granddaughter. Leigh syndrome is complex and very difficult to treat due to multiple reasons, one of which is the many different ways to get the disease. There are likely over 70 different genes that can causes Leigh syndrome, which suggests that each patient can be somewhat different from each other depending on the reason for the disease. This also means that likely the response to various medications can be diffe rent as well. Before we understood that Propofol could impact mitochondrial function, we used it for muscle biopsies and other procedures and there were only some patients with mitochondrial disease to have problems post anesthesia. Still, in parts of the country and world, Propofol is still used for sedation in patients with mitochondrial disease. Whether using it to place a G - tube caused your granddaughters problems after surgery is difficult to know without knowing more about the etiology of the disease and other clinical factors at the time of the surgery. In addition, the stress of surgery could have also placed your granddaughter at risk for worsening disease, which is really hard to factor in how much of this stressor might have played into the worsen ing of her disease. Unfortunately, there is no way to tell you for sure how much using Propofol and Lactated Ringers contributed to her worsening. I am sorry that your granddaughter has had such an outcome. Russell Saneto, DO, PhD Q: Could you please confi rm that “oxidative myopathy” falls under a mitochondrial myopathy? A 61 year old family member, with a history of fibromyalgia, RA, migraines, mitral valve prolapse (with MV repair and replacement 11 years apart) and cold - induced asthma recently had a rig ht heart catheterization/ stress test to assess for pulmonary hypertension. The diagnosis was oxidative myopathy. Who specializes in this disease...Neuromuscular? Rheumatology? Endocrinology? A: I don’t know what this term means, but it certainly doesn’t d iagnose mitochondrial disease. I think it’s likely to be a non - specific term that reflects muscle deconditioning. Sounds like a cardiologist is the first stop. If that’s who did the testing in the first place, then I’d try a neurologist who specializes in neuromuscular disorders. Jerry Vockley, M.D., Ph.D. Q: I have a 16 year old son with mitochondrial myopathy . He is diagnosed with hyper nasality, his palate is not functioning properly, and he is becoming very difficult to understand and always sounds nasa l. Doctor is recommending surgery to build up his palate. He uses a bipap at night. I am not finding any information on successes or failures with this type of surgery. Does anybody know if the results from this surgery are long lasting or only temporary s olu

15 tion? This surgeon has only done about 1
tion? This surgeon has only done about 10 of this type of surgery and none on patient with mitochondrial myopathy. Any insights would be most welcome, as I am not hugely in favor of surgery, but my son is desperate for some relief. Thanks A: The response to surgery is more likely dependent on the surgeon’s experience, how your son has tolerated anesthesia and surgery in the past and the type of mitochondrial disease. Mitochondrial myopathy is not a diagnosis - is the genetic cause known? This information may help us better understand what the response to surgery might be. You may also want to consider a 2nd opinion from another surgeon to see if you receive a similar recommendation. Sumit Parikh, MD Q: Hello, I have been really sick for about 16 months now and it has finally been narrowed down to autonomic neuropathy and some clotting disorder. Both believed to be autoimmune in nature but not definitive (I am currently going through chemo therapy to suppress my immune system). I recently had my COQ10 levels checked and they were rather low (.30 mg/L) is this indicative of a mitochondrial disease causing my issues or can low COQ10 occur due to other factors not related to mitochondrial disea se? Thank you very very much for your time! Sincerely. A: I am sorry to hear about your clinical problems. Your question about COQ10 levels. Can you tell us how these were checked - serum levels or intracellular leukocyte levels. There is some difference of opinion about what CoQ10 levels might reflect. Here is my view: If levels were taken from the former then likely just nutritional intake and likely not related to a CoQ10 synthesis problem. If the CoQ10 were related to an intracellular leukocyte level, the n this might be related to a CoQ10 synthesis problem, and therefore the possibility of a mitochondrial disorder related to the CoQ10 level. One needs to investigate this latter finding in more depth to really prove it is a primary CoQ10 synthesis disorder. For instance, gene testing or muscle levels of CoQ10. I think that supplementation with CoQ10 might be used in either case and would advise to talk with your mitochondrial specialist. Russ Saneto, DO, PhD Q: My son is 13 and disabled. In 2013, we received his diagnosis of Phelan McDermid Syndrome via Whole Exome Sequencing. He has a mutation on his SHANK3 gene. During his sequencing, it was also discovered that he has 2 mutations on 2 Mito DNA genes. He is Homoplasmic for a m.644� AG variant of unknown sign ificance in the MT - TF gene. He is also heteroplasmic for a m.3198 A�T variant of unknown significance in the MT - RNR2 gene. The heteroplasmy is approximately 23%. Due to finding his other mutation on his SHANK3 gene, we stopped investigating i

16 f the Mito mut ations were part of his
f the Mito mut ations were part of his problems/disability. Currently, he is experiencing extreme fatigue that has become debilitating. Fatigue is not a symptom of his other syndrome and I’m wondering how I can determine if his mito mutations are causing additional probl ems for him (or are benign) and what/how possibly to help him with his fatigue. Thank you for your assistance. A: Sorry to hear about your son’s fatigue. When we see such a symptom, we would want to ensure that treatable sources of fatigue such as iron or v itamin D deficiency, thyroid dysfunction and sleep disorders including obstructive sleep apnea are evaluated for. In regards to the mitochondrial DNA variants, you should meet with a genetic counselor to discuss these and consider maternal testing. If the homoplasmic variant is present in you, it is more likely to be benign. The heteroplasmic variant may require further investigation and study, especially if only found in Samuel. I would recommend following up on these. Sumit Parikh, MD Q: I present with multiple symptoms of Mitochondrial Disease. EMG and muscle biopsy indicate the disease may be present. A genetic blood test was done, 2 of them specific for the eyes because that was the first real problem I was having, sporadic vision issues...my neurolog ist said the test came back negative. Could I still have this condition? Main complaints muscle soreness and very weak after 4 - 5 hours of being awake. My doctor said nothing she can do for me. Your thoughts please and thanks. I just want some direction so I can feel better. A: Sorry to hear about your health problems. From the limited information that you’ve provided, you may have mitochondrial disease or dysfunction but you may not have it either since no definitive diagnosis was made. The most reliable di agnosis would be by DNA testing because it’s the most specific and the least one to be affected by artifact (like muscle biopsy) or biochemical markers and symptoms which are usually nonspecific, i.e. they can be seen in other diseases, not necessarily mit ochondrial. Or you could have mitochondrial dysfunction secondary to something else. If you have time and desire, read my latest article (attached) which is a bit detailed but you’ll get an idea. You probably had a limited genetic testing (mito DNA and/or nuclear mito genes). What you’ve described as 2 variants “specific for eyes” may be benign and I’d need to see which specific ones but they likely don’t explain everything so unlikely to be definitive diagnosis. You can have Whole Exome Sequencing (WES) wh ich tests the entire DNA (20,000 genes) which could give you an answer (see the booklet giving a good description of this test). In my practice, autoimmune diseases can present with mi

17 to symptoms, so see a rheumatologist. A
to symptoms, so see a rheumatologist. Another problem could be food alle rgies which you may not be aware of so see an allergist. You should check your blood sugar when you feel weak and plasma cortisol because some people may have adrenal insufficiency. You probably had your thyroid checked already. You can try ubiquinol for e nergy at this link (best brand for the best price): http://www.amazon.com/ActiveQ - Softgels - Ubiquinolantioxidant - Coenzyme/dp/B00E0O618C - take 1 gel twice a day, if you don’t feel any benefit, go up to 3 a day and even 4. There are many other vitamins to ch oose from as my paper describes. You should ensure that you have a regular caloric intake with avoidance of fasting - 3 major meals a day (don’t skip breakfast, clichés like it’s most the important meal of the day are usually accurate) and healthy snacks i n between so that you don’t go beyond 3 hours of fasting. I’ve attached the list of healthy snacks (good for both kids and adults). Try organic cornstarch before bedtime - 1 - 2 tbsp. in water or soft snack like yogurt. This would allow you to get energy fro m a complex carbohydrate at night (which slowly releases glucose which gives you ATP) when you typically fast and undergo catabolism which is better to stay away from whether you have mito or not. Dmitriy M. Niyazov, M.D. Q: Are sulfonylureas safe to use with complex I and complex III deficiency mito? My hgb A1c is 5.8 and my average blood sugar level is 99. I still get hypoglycemic. I have a new doctor in the mix and she wants me to take one of these and I feel uncomfortable about this as I feel my sugar is controlled. A: In general sulfonylureas are not contraindicated in mitochondrial disease. Some mitochondrial patients have had trouble tolerating Metformin, which is in a different class of diabetes drugs. In regards to whether or not you need this med icine for your diabetes, I would have to defer to an endocrinologist. You may want to ask her to explain her reasoning as to why she wants you to try this medicine if your numbers are as good as you noted. - Sumit Parikh, M.D. Q: Are there any laboratories in the United S tates that can do pre - implantation genetic diagnosis for maternally inherited Leigh’s syndrome if I do invitro fertilization??? If so, how do I contact them??? I’ve already lost my baby to this disease. Please help me. A: Pre - implantation d iagnosis is available for known autosomal recessive and autosomal dominant genetic mutations. However, because of problems with heteroplasmy in maternally inherited mutations, evaluating laboratories are unable to determine with a high degree of accuracy w hether or not the cells tested for the presence of a maternally inherited mutation are ref

18 lective of the overall status of mutati
lective of the overall status of mutation load in the fetus. More simply stated, the laboratories are not sure if the cells of the fetus evaluated accurately reflect the status of the new baby meaning is it affected or not? As such, I am unaware of any preimplantation diagnostic centers that will screen for maternally inherited mtDNA mutations. - Fran D. Kendall, MD Q: My maternal 1st cousin ( Complex IV Mito with Limb G irdle Dystrophy per exome sequencing) and I were just diagnosed in March 2013 after a lifetime of symptoms. What do you think are the chances of gene or stem cell therapy for me in my lifetime? A: I think the chances of seeing gene or stem cell therapy in our lifetime is extremely high. There are already several clinical trials dealing with gene therapy, including targeting diseased mitochondrial DNA by several researchers at the U of Miami http://med.miami.edu/news/clinical - trial - uses - gene - therapy - to - targe tmutations - in - mitochon . And work by Carlos Moraes, Univ of Miami http://biomed.miami.edu/?p=493&pid=309&m=facultyph&mid=2&item=128 . Also, there are active trials in the UK with mitochondrial replacement in embryos, termed three parent babies. Of course, all gene therapy techniques are going to be met with skepticism and must pass various ethical hurdles to be fully engaged. One of the more promising and wide spectrum gene therapies involves a newly discovered/invented technique called CRISPR, which was fi rst described only two years ago. This involves a highly efficient and rapid inactivation and replacement of a target disease gene with a functional one. For more information, please see Wikipedia or read its potential use in gene therapy in the December 2 014 issue of Scientific American, pp 42 - 46. William Copeland, PhD Q : My daughter was diagnosed with multi - complex mitochondrial disease . They called it multi - complex because all of her super complexes in her muscle biopsy were abnormal as well as complex 1 ,3, and 5. She has been having constipation issues. She is prone to dehydration even while being on a 16 hour continuous feed. My question is: Her GI doctor has placed her on mineral oil and on Senna because of constipation. Is it safe to use this with her history of dehydration? If she starts having complications of diarrhea from these meds I am afraid she will get dehydrated. I don’t want to go against the GI doctor but I want to get an opinion. A: In general, mineral oil and Senna are relatively mild tre atments. Because constipation can be so difficult to treat, it seems reasonable to try these laxatives, and taper back if there is any indication of diarrhea. Of course, monitoring your daughter closely for dehydration sounds like a good idea too given her history. - Greg