Ask the Mito Doc – June 2024 Q&A
All answers today are based on personal experience of the participants. As always, please consult your personal physician prior to taking any action.
Ask the Mito Doc Panel Session
Q: What can best help maintain and boost the immune systems in people with mitochondrial diseases?
A: Peter McGuire, MS, MD: The Immune system has many different aspects that are important to maintain good health. One of which actually has to do with diet. There are many nutrients that we get from our diet that help support immune health, which can be certain amino acids and certain types of fats. You can probably pinpoint somewhere in the immune system any type of nutrient you can think of and where that nutrient is important and actually necessary. So good health is one thing. Second, exercise to the degree which an individual can exercise. Exercise can help not only with things like muscle, strength, and balance, but it can also help bone and bone marrow in terms of its function and helps our bodies generate more healthy mitochondria. Another thing that is important to all is in regards to vaccination. This was amplified during Covid. The concern is there may be a severe reaction. We periodically check to make sure our patients are keeping up with their vaccinations, i.e., chicken pox and measles seem to have reduced immunity.
Q: Are there any known medicines/supplements/treatments to offset muscle weakness? And what about energy levels?
A: Amy Goldstein, MD: Exercise is one of our best treatments. The type of exercises depends on your baseline function. I invite you to look up Dr. Mark Tarnopolsky’s publications for more information on exercise. There are ongoing clinical trials to look at muscle function in specific mitochondrial muscle disorders. Energy is a mixed bag – depends on baseline fatigue, sleep, and other medical issues. It is important to consider all these factors when considering fatigue.
Q: Which supplements are recommended for mitochondrial myopathy due to a POLG mutation in adults, and what alternative treatments are available to help improve quality of life?
A: Ibrahim Elsharkawi, MD: A “Mito Cocktail” is often prescribed that contains many different cofactors and antioxidants that we know help mitochondria in various ways. Your mito provider will likely prescribe different supplements depending on the specifics of the condition, and some mito providers prescribe specific supplements in response to specific symptoms. Common mito cocktail supplements include Coenzyme Q10, a B50 vitamin complex, riboflavin, creatine, alpha lipoic acid, etc. It is important to realize that these are not disease-modifying treatments or curative treatments. There isn’t strong clinical evidence that they work or don’t work. Exercising to the degree possible is also recommended. Addressing any other components of the disease that affect quality of life: sleep, sexual dysfunction, etc., are also important for quality of life optimization.
A: Melissa Walker, MD, PhD: The precise supplements and doses are something that your personal doctor will have to advise you on. None of these supplements or vitamins are proven to help, but most “mito” docs will recommend a combination of certain B vitamins, Coenzyme Q10, and an antioxidant, at least as a trial to see if the patient experiences even a subjective benefit.
A: Austin Larson, MD: The POLG variant is recessive, so I would not expect symptoms without a second variant. Also, in POLG and affecting the other copy of the gene, I would recommend meeting with a genetic counselor or medical geneticist to discuss their interpretation of the variants in MCM3AP and MYH2 and whether they could be relevant for your symptoms. Typically patients with the p.Thr251Ile mutation do not have symptoms unless there is also a second change in POLG.
Q: What one helpful tip can you recommend for adults aging with mito?
A: Austin Larson, MD: A few things to emphasize with aging: 1) both aerobic and resistance exercise (to any degree that you are capable of); 2) making sure you have adequate nutrition so that you don’t lose muscle mass (particularly protein intake); 3) consider a sleep study if you have any symptoms of sleep apnea.
Q: There are so many different genes that affect mitochondria. My daughter is rare. How can I push for research for her gene and also work toward a common goal for all types?
A: Melissa Walker, MD, PhD: Joining patient registries, like the one UMDF has, is a great way to start. Being part of communities like UMDF can help make you aware of any possible research studies that you might be able to help with and also to increase the visibility of the community through advocacy.
Q: I am an adult with Leigh syndrome. What research is being done, and what are the current treatments for adult Leigh syndrome?
A: Austin Larson, MD: There are a few causes of Leigh syndrome that do have specific treatments, but most causes have primarily supportive care. It is important to seek out a genetic diagnosis for those with Leigh syndrome.
Q: I have MS and mito. My MS specialist told me that MS causes mito dysfunction but was not aware of anyone working with mito and MS dually diagnosed patients. They were not aware of the research and treatment interventions you just mentioned being done with these patients. Who should we seek out or ask for a referral to? Which doctors and facilities are currently working with these populations?
A: Amy Goldstein, MD: I’m assuming your MS neurologist is talking about neurodegenerative processes in MS (more in progressive phases), which is a secondary mitochondrial process (not primarily genetic). There is a study showing mild benefit in alpha lipoic acid, but the data is not robust. We have an ongoing study at UCSD with UCSF evaluating N-acetylcysteine supplementation in progressive MS.
Q: Thank you for your answer on progressive MS. Are there current studies with relapsing remitting MS and mito? Do you know who is doing that work?
A: Amy Goldstein, MD: MS is a not a single gene disorder, so the mitochondrial dysfunction is likely a result of the immune system working over-drive due to the heightened inflammation. We did some preliminary studies looking at immunosenescence (dying immune cells). There is mitochondrial dysfunction with aging, and we know that diseases like MS accelerate biological aging.
Q: What significant role does the ATP6 gene play in mitochondrial disease? What does it mean to the individual if the ATP6 is missing?
A: Ibrahim Elsharkawi, MD: ATP6 is a subunit/part of Complex V which is the part of the mitochondria that releases ATP. Typically, pathogenic/disease causing variants and changes in MT ATP6 likely means there is some interference with how Complex V works/is assembled which can lead to mitochondrial disease, varying in severity. It can be associated with different clinical manifestations. These might include Leigh syndrome, NARP (Neuropathy, ataxia, retinitis pigmentosa), or can have milder symptoms such as heat intolerance, fatigue, migraines, and muscle weakness.
Q: Can elevated respiratory lactate contribute to stroke-like episodes occurring?
A: Amy Goldstein, MD: In MELAS, lactate is usually elevated when there is an acute metabolic crisis, either metabolic stroke or seizure, or during an illness with or without seizures/strokes.
Q: What is the best treatment and/or medicine for ataxia?
A: Austin Larson, MD: There are a few genetic causes of ataxia that have specific treatments, but for most patients, the management of ataxia is supportive – physical and occupational therapy, strengthening muscles, ensuring that vision and hearing are supported if needed, and modifying the environment in the home to reduce the likelihood of falls.
Q: Are there any new advancements in genetic testing that we should know about?
A: Amy Goldstein, MD: Whole genome sequencing is now clinically available; other techniques are becoming available, i.e., RNA sequencing, with awareness of need for reanalysis periodically.
Q: My Whole Exome Sequencing came back with nothing. Does that mean that I don’t have mito?
A: Austin Larson, MD: Exome sequencing is a very good but not a perfect test. It does make primary mitochondrial disease much less likely.
A: Ibrahim Elsharkawi, MD: Depending on your symptoms and presentations (what we call phenotype), certain genetic tests may be warranted. For kids with developmental delay or multi organ involvement that we cannot readily explain, we often do whole exome or whole genome sequencing, although we arrive at a precise diagnosis only about less than half the time. Identifying a precise molecular diagnosis, if there is one to find, is important. Consider discussing further with your geneticist or asking for a second opinion.
Q: Might there be any clinical trials on the horizon that will be accepting pediatric patients? Where are trial drugs available? And are there more generalized trials, rather than ones specific to a condition such as MELAS, LHON, Kearns Sayre, etc.
A: Melissa Walker, MD, PhD: Because it’s often more likely that a clinical trial will be “successful”, i.e., will give a result that is helpful if that trial focuses on a specific group, many trials are focused that way. We are hopeful that there will be more clinical trials and more that include children in the future. I would encourage you to check this website https://www.umdf.org/clinical-trials/ and also clinicaltrials.gov to see which clinical trials may be available in your area
Q: What kind of treatment do you believe will come first?
A: Austin Larson, MD: We do have some effective treatments for a few mitochondrial disorders: ketogenic diet for pyruvate dehydrogenase, CoQ10 for synthesis disorders, and riboflavin and thiamine for transport disorders. For some of the other more common mitochondrial disorders, we’ll need to see how the clinical trials turn out, but there are small molecules, gene therapies, and other approaches that are all in the running for different disorders.
Q: Are there any treatments and/or therapies to help alleviate mito-related fatigue symptoms?
A: Ibrahim Elsharkawi, MD: With mito, it is important to rule out or optimize specific conditions that contribute to fatigue. For example, sleep apnea, hypothyroidism, etc., are medical conditions that can occur in any one. Next, mito supplements can sometimes help with fatigue. We can use Creatine specifically, which the body can use to generate energy. Some of my patients have improvement with some of the other mito supplements as well, but there is less direct evidence that this is helpful.
Q: What is helping your patients most with fatigue?
A: Amy Goldstein, MD: For physical fatigue: some exercise plus rest; nutrition + hydration; some supplements may help, especially correcting vitamin D, B12 deficiency; treating any sleep disorders; pacing yourself, saving energy for most preferred activities; and trial of mito supplements such as coQ10, creatine, alpha lipoic acid, etc.
Q: How is mitochondrial OXPHOS related to stroke or other neurological diseases?
A: Amy Goldstein, MD: It depends on what genetic disorder we are talking about, since there are so many; but several lead to stroke like episodes (especially MELAS) or can cause a variety of neurological symptoms including headaches, dementia, seizures, neuropathy, and myopathy, especially since the nervous system requires so much energy.
Q: How can we shed more light on the Secondary Mitochondrial Disease patients? It’s a real thing, not just in our heads. I’ve had some doctors say there is no cure so not going to help.
A: Melissa Walker, MD, PhD: We need a really good test of mitochondrial function. Until we get that, it will be hard. Barring that, as we find more and more patients with signs of mitochondrial dysfunction and other genetic causes, i.e., genes that don’t work inside the mitochondrion, we will understand more. Also, basic science will be critical to understand how other parts of the cell or body help or hurt mitochondrial health.
A: Amy Goldstein, MD: I am so sorry, but it is very unfortunate. Also, many symptoms are completely treatable so that is not fair. I would focus on treating symptoms despite a current lack of a cure which could change in near future.
Q: Have you had any success with using NAD precursors like NR or NMN in mito patients?
A: Amy Goldstein, MD: Yes, and some patients with mito have NAD+ deficiency. There are tests to detect this in whole blood. Dr Anu Soulumanien is an expert and has many publications in this area. She is in Helsinki, Finland.
Q: What medications are available to help sleep disturbances, especially if a child will not tolerate a CPAP?
A: Amy Goldstein, MD: Great question. I would address formally in a sleep medicine clinic with a trained pulmonologist or neurologist expert in sleep medicine, especially if told the child needs CPAP.
Q: After hearing Dr. McGuire’s recent talk on the effectiveness of measle and chicken pox vaccines, should children who are on immunoglobulin therapies receive live vaccines? I was told by my daughter’s immunologist that her 2nd round of these vaccines were not necessary/recommended because she is on immuno therapy.
A: Amy Goldstein, MD: There are specific vaccines you cannot get following IVIG. You need to discuss with your physician about which ones to avoid following this.
Q: Will CRISPR or does CRISPR have any bearing on research or will it? And do you think it will be used in the future?
A: Jennifer Yang, MD: I can definitely see a role of using that in mitochondrial disorders. But right now, I think that’s still under development. In a basic lab, it’s nice for single gene disorders where you can have a specific target using CRISPR technology, and if there could be a platform for which you could add in different genes for a similar technology, then you’d be able to expand and help a more heterogeneous group of disorders. So, I think it’s still in the early development phase.
A: Jennifer Yang, MD: There are other gene editing technologies seeing finger nucleases – something called talon. This morning, we heard about a technology called Arcus. There are mRNA therapies. So, there are a lot of gene therapies coming down the road. There were several gene therapies released for non-mitochondrial diseases like Duchenne’s muscular dystrophy and spinal muscular atrophy.
Q: Are there any stem cell treatments for Mito?
A: Melissa Walker, MD, PhD: There are no FDA approved stem cell therapies for mitochondrial disorders.
Q: I’ve been told by my neuromuscular specialist that it will likely take 20 years to develop gene therapy for mitochondrial disease. Do you agree? Why does it take so long? Is there anything we can do to make it go faster?
A: Amy Goldstein, MD: We certainly hope not, especially when we see that there is now gene therapy for so many other rare disorders becoming available. It depends on the genetic cause. Many people are working on this, so I would not give up hope. Many talks today are on gene therapy and techniques for mito coming down the pipeline very soon, e.g., MELAS.
Q: What are the main challenges in the application of a gene therapy method in favor of single large scale mitochondrial deletion diseases?
A: Ibrahim Elsharkawi, MD: Gene therapy is usually based on responding to an identifiable genetic change pinpointing a single gene that has a change in it that causes disease. With single large scale mitochondrial deletions, typically there isn’t a specific gene that has caused the deletion, it’s usually sporadic. So, gene therapy wouldn’t have a gene to target.
Q: Are you aware of anyone successfully using Glutamine to treat mito symptoms? I have read that it is a “conditionally essential” nutrient.
A: Austin Larson, MD: I’m not aware of using glutamine for mito disorders, but there is a metabolic disorder due to the gene GLUL for which glutamine supplementation is indicated. Here is a reference about that disorder: Glutamine Supplementation in a Child with Inherited GS Deficiency Improves the Clinical Status and Partially Corrects the Peripheral and Central Amino Acid Imbalance. Häberle J, Shahbeck N, Ibrahim K, et al. Orphanet Journal of Rare Diseases. 2012; 7:48.
Q: What is the current research on Mitochondrial dysfunction in patients with neuromyelitis optica spectrum disorders?
A: Amy Goldstein, MD: There is an unknown association at this time, but it is being explored. We don’t know a lot about NMOSD. Studies on secondary mitochondrial dysfunction are on MS, which is the most common disorder of the central nervous system. There is an early inflammatory disease and then the progressive for MS where there is degenerative disease, clinical degenerative disabilities, that overlap mito.
Q: What advances in the mito field encourage you the most?
A: Austin Larson, MD: I’m encouraged that we are able to accurately diagnose many more patients than in the past. The UMDF meeting has evolved over the years with many more folks presenting about the outcomes of rigorous clinical trials and drug development.
Q: What mitochondria structure issues are associated with mitochondrial disease and are all diagnosed with mito have these issues?
A: Austin Larson, MD: Some mitochondrial diseases are directly related to structure (like OPA1 or Barth syndrome). Other mito diseases do have structural changes to some degree as a secondary manifestation of the condition.
Q: How can we get the mito function Seahorse test approved and used on patients in this country? It’s been available for use on patients in Europe for a number of years now. What’s the hang up here?
A: Austin Larson, MD: It was available in the past here, but the lab that was offering this test was not able to get enough revenue continue to offer it. It is used quite frequently in this country on a research basis.
A: Melissa Walker, MD, PhD: Seahorse measurements of oxygen consumption have been used very successfully in research. It’s hard to come up with a clinical test because: What type of cells should be used (every cell type is different)? How many? What do we use to define what is normal? There’s a lot that needs to be perfect to a make a test that is reproducible, i.e., works every time. I think those are the major barriers, and it would take a lot of time and money to overcome them. I think a lot of us think other tests are more likely to work better.
Q: I have been recently diagnosed with LHON 3460. I am looking for any new information to reverse and restore my vision. My doctor saw me once and said come back in three months. I was 20/fc in one eye and 20/30 in the other; one month later it was 20/60. I experience extreme headaches and fatigue.
A: Amy Goldstein, MD: LHON.org is a fabulous resource. There is no gene therapy yet for the 3460. Despite the newest paper about Idebenone not being as effective for the 3460, I would still consider it as therapy and discuss with your doctor.
Q: If a person is diagnosed with NARP, will he have total vision loss because of RP in their lifetime?
A: Amy Goldstein, MD: I think this is hard to predict. It might depend on the percentage of heteroplasmy and could possibly be treated with lutein (a vitamin). It would be helpful to be followed by a retinal specialist familiar with mitochondrial disease.
Q: Is Elamipretide available through something called an expanded access program? If so, how would one look into this and would it be available to pediatric patients (nine year old)?
A: Amy Goldstein, MD: There are a handful of centers that may have this available; I would contact the drug company to inquire – Stealth BioTherapeutics.