Ask the Mito Doc September 2023
Dr. Bruce H Cohen, MD, FAAN, Akron Children’s Hospital, Akron, Ohio
Dr. Abdulrazak Alali, MD, Akron Children’s Hospital, Akron, Ohio
Dr. Ian Rossman, MD, PHD, Akron Children’s Hospital, Akron, Ohio
Dr. Stephen Steiner, MD, PHD, Akron Children’s Hospital, Akron, Ohio
Dr. Matthew Ginsberg, MD, Akron Children’s Hospital, Akron, Ohio
Q: Are there any new treatments for difficulty swallowing, other than a feeding tube?
A: Matthew Ginsberg, MD This might depend on the specifics of the swallowing dysfunction. Speech therapists may be able to help with swallowing techniques if there are mild difficulties. Some individuals can use thickening agents for some kinds of difficulty swallowing as well.
Q: Is it better to have a local team of providers and check in with mito specialist a few times a year or see all the specialists out of town? I’m having difficulty organizing all appointments in one day out of town. I can only afford to go every 3-6 months. Problem is most doctor’s where I live do not know much about my condition. My PCP is fine with working with specialist out of town but not all providers are.
A: Bruce Cohen, MD, FAAN Every patient has a different ‘pair’ of local docs and mito specialists. Our group tries to work with the local docs over email and phone on issues between visits. Teamwork. Great question and there are likely other suggestions.
Q: Assuming Red Light Therapy is an effective treatment for enhancing mitochondria, what are the optimal power & frequency settings as well as the proper procedures for administering the treatment? i.e.: distance from the head and length of time per treatment as well as the interval between sessions?
A: lan Rossman, MD, PHD Currently there is not enough information to make recommendations about red light therapy (photobiomodulation). Hopefully over time we will learn more about the safety and efficacy of PBM across neurologic and other conditions including mitochondrial disease.
Q: 1. Have you tested Tiglylglycine levels in both primary and secondary mito patients? If so, what are your thoughts on its relevancy? https://healthmatters.io/understand-blood-test-results/tiglylglycine
- Are any of you using the Seahorse Test yet to monitor people’s mitochondrial functioning? My understanding is it is used by doctors on patients in Europe currently. If not, why not ?
- Are any of you using low dose methylene blue on your mito patients yet? Based on Dr Francisco Gonzalez Lima work at Univ of Texas, Austin showing its ability to support the cytochromes in the electron transport chain.
A: lan Rossman, MD, PHD
- Tiglylglycine may be picked up in a urine organic acid test, a standard screen test we use frequently in the diagnosis phase, and occasionally in monitoring mito and other metabolic disease patients. As a unique chemical in blood, this is not something we test for.
- The Seahorse test is not part of our clinical testing.
- Currently there is not sufficient clinical evidence for us to use methylene blue regularly in our patients. Potentially more data will become available to make this a clinical tool for use in our patient population.
Q: My 7-month-old daughter was diagnosed with MMDS3 Multiple Mitochondrial Dysfunction Syndrome Type 3 based on DNA Exome analysis. We are currently taking some vitamins as Q10, Thiamine, Riboflavin, Carnitine.
- What treatments are available?
- What is the best dosage of each vitamin?
- How can I get in touch with other MMDS3 families?
- Why is MMDS3 not listed on the UMDF disease list?
A: Matthew Ginsberg, MD Some conditions are rare even within the category of rare disease, and MMDS3 might fall into that category. That can make it hard to identify specific treatments or find other families or patients with similar stories. However, 1. Even when a specific therapy is not available for a specific genetic condition (meaning no FDA approve treatment or well-studied treatment), we can often still treat symptoms. Finding a good team of doctors and nurses, even if they are not highly familiar with MMDS3, can still be helpful. 2. Even in more common primary mitochondrial disorders, we don’t have good data on many of these. There are some listings of common supplements with doses used in other conditions. 3. If you are looking specifically for MMDS3, many families can find groups on Facebook and social media. If not, you might be the right person to found it! Many rare and ultra-rare disease communities pop up like this. UMDF is also good resource.
Q: What is the prospect for gene therapy for mitochondrial patients?
A. Stephen Steiner, MD, PHD Gene therapy is an exciting prospective treatment for mitochondrial disease. There are other disorders that have been treated using gene-targeting therapies, but with regards to mitochondrial disease, there are still several challenges such as, 1) targeting the affected tissue type since mito disease affects multiple parts of the body; 2) effective delivery systems for the genes in question; 3) toxicity related to the delivery system; 4) and how the expression of the gene in question may affect other genes. An exciting prospect, but certainly, several “kinks” to work out.
A: Bruce Cohen, MD, FAAN There are companies forming right now that are looking to design trials or treating mitochondrial disease with gene therapy.
Q: What are supports for Mito muscle loss after 50 years? Supplements? Type of exercises? Meds? Therapies, like red light / infra-red?
A: lan Rossman, MD, PHD I recommend working with a physical therapist knowledgeable in progressive neurologic disorders to develop a safe and enjoyable home exercise program that can help you maintain your overall wellness and potentially improve function. Supporting that exercise with a healthy diet, proper sleep, good hydration, and taking care of other medical problems is also important.
Q: Regarding anti-anxiety medicine, I have a 21-year-old daughter with a very rare mito genetic mutation in the 2nd complex playing out in cerebella atrophy, optic atrophy and poor proprioception, ataxia, cognitive. We’ve asked her mito doc, but he felt this is not his territory. To me it seems anxiety, which is clearly a part of mito issues, would be a part of a mito doctor’s understanding. Because some people, due to different wiring, a drug that works for one, may have the opposite affect for someone else. Do you have any suggestions? Flying is the most difficult anxiety for us to navigate with her, so we limit most of our trips to driving.
A:. Ian Rossman, MD, PHD Anxiety is common across many chronic conditions, mitochondrial diseases included. Typically selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, citalopram, etc., can be helpful. Psychiatrists are the experts in using these and other medications for anxiety disorders but may be difficult to find in your area. I recommend asking your neurologist for a referral to psychiatry, and to talk to your primary care physician. She/he may also feel comfortable managing anxiety using SSRIs and other medications. They can work with your mito team to ensure that their medication choices are safe.
Q: ProVigil for “exhaustion”?
A: Bruce Cohen, MD, FAAN Provigil is a medication used to improve alertness and is used to treat a variety of disorders of arousal (sleepiness simply stated) and sometimes attention deficit disorder. I have tried it in mito exhaustion in a few patients and have not found it to achieve the goals of the patients. Sleep disorders however are common in mito diseases, and one should consider sleep studies (starting with a polysomnogram) in those with mito. Short answer for a question that we all want answers for.
Q: Does Akron Children’s now treat adult-onset cases? I was told earlier that you could not help me because I was not a child.
A: Matthew Ginsberg, MD We do review adult patients on a case-by-case basis and see adults if we think we can be helpful to your care. Patients should go directly through the mitochondrial center site, though, and not through central scheduling for the hospital.
Q: Is there any resource for mito cocktail if you have fought with insurance and lost in appeals?
A: Stephen Steiner, MD, PHD Unfortunately, getting mito cocktail supplements approved through insurance is often insurance specific and dependent. There is no resource that I am aware of that can help provide access to the components of a mito cocktail.
Q: Is tissue hypoxia found in mitochondrial disease?
A: Abdulrazak Alali, MD With mitochondrial disorders, the function of the mitochondria is affected and thus the ability of the mitochondrial to utilize oxygen, as such, even in the presence of oxygen, the tissue will act like they are hypoxic and asphyxiating. Plus, many individuals with mitochondrial disorders will have sleep apnea and thus hypoxia. The apnea is many times mixed due to obstruction of the upper airways due to poor strength of the muscles supporting the airway and due to decrease drive from the brain itself.
Q: If the genetic tests (mitochondrial panel, WES, WGS) do not diagnose mitochondrial disease, but it is highly suspected and muscle biopsy is to be avoided (due to complex case, fragile health, slow/no healing wounds, etc), what are the other options of diagnosis. Can you please explain the fibroblast (?) testing mentioned by Dr. Alali?
A: Abdulrazak Alali, MD From the skin biopsy, special cells called fibroblast can be grown in the lab (takes weeks to be grown), then studies to measure the activity of the components of the electron transfer system-complexes- will be measured- even these may not be diagnostic as we know that many patients highly suspected to have a mitochondrial disorder will stay undiagnosed. We continue to learn and know more genes that are involved in mitochondrial disorders.
Q: If you have ragged red fibers and abnormal nerve conduction but so far no positive genetic testing, is it probably myopathy?
A: Matthew Ginsberg, MD Depends on the details. A small number of ragged red fibers can be seen with aging and other normal states. Other parts of the biopsy can help determine if there is a myopathy. There are also many other types of myopathies besides mitochondrial myopathies including non-genetic causes.
Q: Diagnosing with a cheek swab?
A: lan Rossman, MD, PHD A cheek swab collects cells from inside the mouth (buccal mucosa). The lab can extract DNA from these cells to run their DNA testing, both nuclear and mitochondrial DNA.
A: Matthew Ginsberg, MD This can be used for many patients. If a person has a nuclear gene mutation causing a mitochondrial disorder, it should be detectable on buccal swab. If it is a mutation in the mitochondrial DNA, it will probably be detected but could be present in only some tissues.
Q: How often should DNA testing be redone?
A: Matthew Ginsberg, MD Assuming a person has had a broad test such as whole genome testing, re-analysis is often recommended every 2-3 years.
Q: What genetic tests best diagnose mitochondrial diseases (gold standard tests)?
A: Matthew Ginsberg, MD Currently, most genetic tests vary primarily based on the number of genes covered and how well. The specific test for a patient depends on other factors. For example, if there is a family history of a specific condition, the best test would be sequencing the known gene that is affected in a family member.
Tests such as whole exome sequencing test all the coding regions of our DNA (about 1% of our DNA) and whole genome sequencing tests almost all of it. Even patients who have had negative testing may benefit from re-evaluation in the future.
Q: My brother and I have both been diagnosed with Mito mutation 11778. He’s 72 and I am 67. Diagnosed 4 years ago. Symptoms include double vision, severe imbalance, fatigue, and lower extremity weakness. Treatment? Clinical trials? CRISPR help?
A: Matthew Ginsberg, MD This may depend on some additional details. If myopathy is a part of the picture, it’s possible that you could qualify for a trial. The UMDF has a listing of some of these. CRISPR is still a ways off.
Q: Do you recommend Idebenone and Dalfampradine??
A: lan Rossman, MD, PHD I use dalfampradine in patients with multiple sclerosis and other central nervous system demyelinating disease. I would be cautious using this in a primary mitochondrial disease. Seizures can be a severe side effect of this drug. I would also be worried about this medication causing brain cells to use “too much” energy in a patient who has mitochondria that are already struggling to keep up with energy demands.
Q: What do you see in the future for Genetic Testing?
A: Abdulrazak Alali, MD: We need to look at all the pieces. Even when we do what we call a total genome sequencing. We are reading all your DNA. Our knowledge of the function of DNA is still limited. We know many genes in our DNA that are not associated with mito, a condition that we call co-morbidity. So many genes are still there, we just don’t know about them and there are other factors in play when we do this testing, we need to read inside the testing, something we call epigenetics, when the expression of the DNA itself is affected in one way or another. I think there is a gap in the knowledge itself is not the test itself, there is still a lot we don’t know yet. This will improve over time.
Bruce Cohen, MD, FAA The first clinical whole genome was released in 2013, that’s 10 years ago at a cost of about $16,000. It took about 6 months to get the results back. Although it was a wonderful test at the time, it is primitive compared to what we have today in its depth. In 10 years, the cost for a whole genome, which is probably a hundred times more sensitive than that first test, is in the $2,000 to $3,000 price range. Compare that to muscle biopsies. I don’t want to be critical of muscle biopsies, because I put about 200 of my patients through them between 1994 and 2010. Between the anesthesia evaluation, surgeon fees, operating room fees, and pathology fees, that testing was between $40,000 and $50,000, based off finances. What we can get out of the whole genome now is more specific than what we could get out of muscle biopsies. Unfortunately, the technology for muscle biopsy, the biochemical processing, has fallen by the wayside because the laboratories went out of business in part, because insurance companies wouldn’t pay for it, and patients just couldn’t afford to write the check themselves.
Abdulrazak Alali, MD: Another point about muscle biopsy, it might give you a diagnosis of mitochondrial disorder, but it will not give you a definitive. I want to tell you what mutation is causing that, and that was a limitation in the clinical trial, for example, that are directed to specific mutations or specific genes. So still, even if you get the diagnosis from that, it’s not specific. It’s more a generalized diagnosis.
Ian Rossman, MD, PHD. Thank you. We, just like our patients, want to know. When we go through all of the testing and still do not have a conclusive answer, we feel it, too. We, want to have answers to provide you. What it doesn’t mean is that we’re unable to provide care. And it’s important to remember that a lot of how we treat many neurologic diseases, not just mitochondrial diseases, is symptom management and making sure that we’re improving your wellness. So not having a genetic diagnosis, while there can be an emotional toll that takes place not knowing for sure, it doesn’t mean that you don’t have care options, and that there aren’t ways to make you feel better and make sure that your wellness is maintained. Testing has come a long way in 10 years and technology is racing ahead. So not having an answer now doesn’t mean that we won’t have an answer in the future. But we do definitely feel the same way you do when we get that non-diagnostic answer. It means that we still have more work to do. And that’s part of that ongoing dialogue.
Q: What gives you hope for Mito patients in the future?
A: Ian Rossman, MD, PHD. I think that, for me, it’s the families, the community of mitochondrial disease, the caregivers, the researchers. There is so much hope, even with the sadness that many of us endure, we know that there’s families that are grieving. That energy, the selflessness that families have expressed to try to help others, that collaboration, it really comes from just being part of this incredible community and just knowing I’m a small part of this gigantic global phenomenon of wanting to do better for our patients, push technologies ahead, bring bench science to the bedside, and that people are coming up with ideas that still have never been tested before and they’re being able to use those ideas for the first time and getting to patients at record pace. So it’s hard to be patient and I don’t want anyone to be so patient that they don’t ask the question. Ask the question, see if you can raise the money, see who you can contact. And knowing that I don’t have to tell people to do that. They’re already doing it. That’s what gives me hope.
Abdulrazak Alali, MD. What gives me hope is, the patients and their families. They are who we are fighting for, for cure and for new treatment, and they are who are involved in trials, and they are who are supporting. So I think they are the resource and they are the target. That’s what gives me hope as long as they are fighting, we will continue supporting them. We can do nothing without them. They are all warriors. That to live with such a disabling condition and you still continue to fight, that’s the source of all for me. Science and our care all comes after what they do.
Matthew Ginsberg, MD. I promise this isn’t a plan, but organizations that, like the UMDF, are patient advocacy groups, are really kind of a type of glue that brings together all these stakeholder Pharmaceutical companies, clinicians, basic science researchers, patients, families, regulators, and really just catalyzed so much growth both from a scientific standpoint and really act as sort of a beacon of hope for everyone. I have a lot of respect for the UMDF and other same organizations, as they serve as a source of hope for me, too. So I appreciate the work that you guys are doing.
Stephen Steiner, MD, PHD. So, for me, I think what drives me, and I think what drives me to continue hoping, and I try to impart that hope on patients, is kind of what we touched on earlier in terms of the advancements that we see, and the research that helps bring treatments or methods of detection and identification that we would laugh at 10 years ago, a reality today, or 5 years ago. I mean, these types of advancements are occurring for our patients. They’re occurring at a glacial pace and they’ll never occur quick enough, but they are occurring and they are happening. It’s not just research, and to piggyback on what everyone else has said, it’s a combined effort. It’s the advocacy from patients, their families, from groups like the UMDF, it’s a combined effort that drives this push, that drives the research. If there was no advocacy, if there was no interest generated, then there would be no advancement. And this continued interest, continued push, continued advocacy is what drives us and helps us identify these disorders and helps us identify ways to treat them and that’s why we keep pushing forward with this. I don’t think it’s any one thing. I think it’s the combined effort. That’s what ultimately drives hope.
Bruce Cohen, MD, FAAN. I agree with everything everyone said. I want to put a little bit of different spin on it. Sometimes all we have is hope. And that’s going to be enough. You know, when I started my career after graduating medical school 41 years ago, there was zero hope for children with spinal muscular atrophy. The disease occurs in one of 6,000 children. Ultimately fatal, generally before their second birthday. If you would have asked me 10 years ago, is there any hope for this disease? I would have said ‘no’. You know, some of the team members here treated some of the first patients with a novel brand new gene therapy. It wasn’t me. It was these guys. I forgot who was on that project, I think, Dr. Rossman was. This is now believed to be a survivable disease where the kids are walking. You know, it’s just unbelievable. The advances with gene therapy and Duchennes muscular dystrophy are also incredible. And again, this is just in the last few years. And these are diseases that none of us had anything but hope for, because that’s all there was. All there was is hope, and now there is science behind it. So I’d have to say, you have to be in this for the long game. And, never give up hope.