Ask the Mito Doc – April 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.
Topic: Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes (MELAS) – MELAS 101
Clinicians:
Michio Hirano, MD, Columbia University, New York, NY
Fernando Scaglia, MD, Baylor College of Medicine, Houston, TX
Q: How common is adult onset of MELAS (after age 45)? Is adult onset MELAS typically fatal? Are seizures common with MELAS and is that a sign of the disease progressing? Are the “stroke like episodes” with MELAS the same as a TIA? Why do the stroke like episodes cause aphasia?
A: Fernando Scaglia, MD: The clinical manifestations of MELAS will typically present between ages 20 to 40 years of age. The onset after 45 years is less common. Adult onset of symptoms may not necessarily be typically fatal. Seizures can be observed with stroke-like episodes and they may predate the stroke-like episodes. Seizures can be controlled with anti-seizure medications and in some cases if they are under control that may prevent the onset of stroke like episodes. TIAs are different. The metabolic strokes do not follow the pattern of typical vascular distribution. If areas that control language are affected then that may lead to aphasia.
A: Michio Hirano MD: So we don’t know exactly why some people are affected by the stroke like episodes at an earlier age than others, but there’s quite a variation from early childhood up to people in their sixties who have their first MELAS stroke-like event. It may be related to the level of the mutation in the brain. In general, the higher the level of the mutation, the more severe the disease, and those who have very high levels will most likely have the strokes at an early age and those with a high but not super high level may develop these stroke like episodes later in life.
Q: Can you explain the differences between MELAS stroke like lesions and white matter lesions that are reportedly benign. Is it the location of the lesions?
A: Fernando Scaglia, MD: White matter lesions may be areas of abnormal myelination in the brain. These lesions are seen as hyperintensities on specific sequences on brain MRI whereas there is a different pattern of diffusion restriction observed in metabolic strokes typically seen in posterior areas of the brain.
Q: What is the difference between MIDD symptoms and MELAS?
A: Fernando Scaglia, MD: MIDD is not technically MELAS as it presents with diabetes and hearing loss, whereas MELAS requires the presence of stroke-like events.
Q: What is the optimal diet to eat when one has MELAS? If they are diabetic, they already have to reduce carbohydrates.
A: Fernando Scaglia, MD: It depends whether the patient has glucose intolerance or diabetes. In that case, those patients need to be followed by endocrinologists and their intake of carbohydrates may need to be reduced.
Q: Are you aware of whether MELAS seizures respond to the ketogenic diet?
A: Michio Hirano MD: Ketogenic diet has been used with modest success in treating seizures in some patients with mitochondrial disease; however, anti-seizure medications are usually more effective than the diet.
Q: Is it common for MELAS patients to have Raynaud’s symptoms?
A: Michio Hirano MD: Raynaud’s phenomenon is typically a sign of autoimmune diseases and not common in MELAS, which is a genetic disease.
Q: Can MIDD turn into MELAS?
A: Michio Hirano, MD: We should define MIDD, which is the acronym for Maternally Inherited Diabetes and Deafness, and yes the disease can evolve over years. What may start out as diabetes and then deafness may stay that way for decades or it may evolve into a MELAS picture. And unfortunately that’s the problem. Dr. Emmanuel is trying to sort out if there is any way to predict who will convert to MELAS and if so, what are the factors that might influence that and can we intervene and prevent the stroke like episodes. She’s in the process of analyzing her data now. We will need more information from patients and their families.
A: Margaret Moore, UMDF: Thank you for bringing that up because I’d also like to take this moment to thank all of the folks impacted by MELAS that are on this call that have participated in clinical research and have tried to get into these studies because we need you and this is how things are going to change.
Q: Is it common to have heat and cold intolerance with MELAS?
A: Michio Hirano, MD: Dysautonomia is a frequent feature of MELAS and there was a report by Patrick Hoffman about that.
Q: My mom did not develop stroke like symptoms until about 45-50. She passed away at 69. Her blood percentage was 20-25%. My son and I both have 25-30%. Does this mean we will develop the same issues/symptoms later in life?
A: Fernando Scaglia, MD: There is a lot of variability and I think that maybe the person who unfortunately passed away may have had much higher levels in muscle and brain. When I say variability, there is variability in the sense that if the source of the test was a blood specimen, the percentage of the change of the mutation or the heteroplasmy can decline over time. Muscle may actually give a more reliable measure. There are other groups that are looking beyond the heteroplasmy, maybe (there is) some background defect of the mitochondrial DNA or maybe nuclear genes that have some type of modifier effect on this. So yes, we all think that the higher the mutation load, maybe the worse the outcome could be, but there could be other factors too.
Q: Do you recommend any change in management of individuals found to have very low (<10%) heteroplasmy for the current mtDNA variant who appear asymptomatic? (i.e., unaffected mothers, siblings)
A: Michio Hirano MD: I would recommend annual medical checkups for potential manifestations of the mt3243 variant. For example, screening for diabetes is important because this is a treatable manifestation.
Q: What would the typical doses for Arginine and Citrizine be? Is that something that varies from patient to patient?
A: Fernando Scaglia, MD: For Citrizine I prefer to have final data analysis before I present that. I’m not trying to withhold information, I think it’s good to analyze the data and then once we present it will be presented to colleagues and to the public. The doses for Arginine, well, that I think has been published, initially was published by a group in Japan. They were using 500 milligrams per kilogram per dose, or I would say per day, and that was being divided if it was oral. If it was given through an infusion, then it was also 500 milligrams per kilo. There was some variability there. The paper published by some members of the mitochondrial medicine society in German neurology, the dose that was used was 500 milligrams per kilogram per dose. That paper actually focused more on the IV dosing of Arginine.
Q: I recently had blood genetic testing done and was wondering if someone can review it for me? Does 2% heteroplasmy for MT-ATP6 cause symptoms?
A: Fernando Scaglia, MD: Typically a 2% heteroplasmy is not associated with symptoms.
Q: Is it possible to have adult onset mitochondrial disease with no significant blood genetic mutations? Is there opportunity for further analysis available?
A: Michio Hirano MD: Yes, because levels of mitochondrial DNA mutations are often lower (and sometimes undetectable) in blood, it is often useful to screen cheek swab or urine, which usually show higher levels of mitochondrial DNA mutations.
Q: How do cheek swab and urine tests for 3243 compare?
A: Fernando Scaglia, MD: Good question. We used to rely on urine because certainly blood sometimes was not reliable in the sense that you would get declining percentage over time, urine was more reliable.
A: Michio Hirano, MD: I think that in general, the levels of mitochondrial DNA mutations are higher in urine and cheek swab than in blood. But I don’t think there’s a consistency, between urine and cheek swabs, I think sometimes one is higher than the other. And in other cases, the opposite is true. I think we often use the cheek swabs now just because it’s, it’s more convenient. And there are kits that some of the commercial companies send to the patient’s home and they could just swab themselves. And so I think that’s why the field has moved towards cheek swabs as a screening test, but it’s not perfect.
Q: As a female carrier of the most common mutation of child-bearing age, are there any methods/strategies that can be taken when I decide to have children to limit the risk of the development of MELAS in my children?
A: Michio Hirano MD: Yes, there are reproductive options that can reduce the risk of MELAS in your children. You should talk to a mitochondrial disease specialist, clinical geneticist, or genetic counselor about the options.
A: Bonnie Bonner, UMDF: I can send you a physician’s list for your region if you are interested. My email is bethany.bonner@umdf.org.
Q: What exact testing should families be doing?
A: Michio Hirano, MD: If this is a family with MELAS, it’s most likely a mutation in the mitochondrial DNA and because the sequencing technology has advanced, it’s possible to sequence the entire mitochondrial DNA and pick up not only the most common MELAS mutation, but any other known pathogenic mutation in mitochondrial DNA in a single test. So the technology has improved dramatically. It makes it easier to make the diagnosis.
Q: What testing is recommended for family members of a MELAS patient?
A: I think if there is a family history that obviously one family member is affected with MELAS, then I think it’s pertinent to test other family members because they could have other issues. When we obtain a family history I think that we tend to do everything that is connected with this particular genetic letter change, the 3 2 4 3 I think that now there is a movement to call this 3 2 4 3 related disorder. There may be family members, maybe one family member who first had MELAS with metabolic strokes or stroke-like episodes, but other family members may have hearing loss and diabetes or they may have hearing loss and short stature. So it may be pertinent to test them, it’s not putting a label on them, but if you diagnose somebody with a genetic condition, then that person can be screened and go through a surveillance protocol.
Q: What accommodations do children with MELAS need in school? Can they participate in regular school activities such PE/recess?
A: Michio Hirano MD: It is important to avoid stressors that can provoke seizures or stroke-like episodes and to control the seizures with medications. I generally advise MELAS patients to avoid overly strenuous activities including competitive sports, which can be stressful and provoke seizures.
Q: Is it likely for carriers of the ACO2 and SURF1 genes to have symptoms?
A: Michio Hirano MD: Carriers of a single ACO2 or SURf1 gene pathogenic variant usually do not show symptoms.
Q: My niece has POLG, she is 6 months, are you investigating this mutation? Do you have any trials? We are from Argentina.
A: Fernando Scaglia MD: There are no specific trials for POLG at the moment.
A: Bonnie Bonner , UMDF: There is a Registry. It is good to stay in touch with UMDF for updates.
Q: The two studies mentioned are for children and young adults over 12. Are there any studies for children younger than 12?
A: Fernando Scaglia, MD: The trial that was done as part of the registry at Baylor was for adults, 18 (to) 65. The new trial with this compound will not be done in the pediatric population, at least not initially. With planning our clinical trial, the FDA wanted to first target the adult population. The pediatric population is a vulnerable population. So for many conditions the FDA would prefer that the adult population be studied first.
Q: How long will it be before there is a treatment for MELAS and what about gene therapy? What’s getting in the way?
A: Fernando Scaglia, MD: How long before there will be a treatment. I think that what has been done so far with Arginine and Cetirizine hopefully we will be able to share those results at the UMDF meeting and obviously present at other meetings and publish that. It’s probably not going to get to the bottom of the problem here. I think that probably what will get to the bottom of the problem will be a genomic approach, which is probably what this person is asking about, gene therapy. There has been work done by a team in Miami looking not at patients but preclinical models and looking at enzymes or proteins that would actually target a particular segment of the mitochondrial DNA or the genetic letter change with the idea of hopefully eliminating that, right? But so far that was evaluated actually in a mouse model, not necessarily with the same change that patients have. But in cellular models I think it’s very important that if a group or a research group is planning to do a genomic approach or gene editing to make sure first safety, safety, safety. Safety is very important so you know we cannot rush through things and that’s why initially there is experimentation in preclinical models or animal models. So we are not there yet. You want to make sure that if something will be delivered or inserted that there’s not going to be toxicity to our organs or what people would call in the field like off-target effects. That’s not good.
A: Michio Hirano, MD: I just want to make 2 comments about genetic therapies for MELAS or mitochondrial DNA mutations in general. One is that you know we cannot put DNA into mitochondria. We can put DNA into cells, but they can’t get into the mitochondria so that’s a technical barrier. So we can’t do gene therapy for MELAS and the other mitochondrial DNA diseases in the same way that the gene therapy for other genetic diseases are treated. But there is an Achilles heel in the mitochondrial DNA because it’s a mix of wild type of normal and mutated mitochondrial DNA. So as Dr. Scaglia pointed out, there’s therapies to get rid of the mutated mitochondrial DNA through mitosis or other technologies that can lower the level of the mutation and presumably make a person less symptomatic from that same mutation because they lower the mutation burden.