Ask the Mito Doc – November 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.
Understanding POLG Disorders
Understanding POLG Disorders: A Dual Perspective on Research and Clinical Practice
Clinicians:
William Copeland, PhD, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC
Bruce Cohen, MD, Akron Children’s Hospital, Akron, OH
Q: I’ve been flagged as a POLG carrier. How can I best help researchers figure things out?
A: Bruce Cohen, MD: A carrier typically signifies caring one pathogenic recessive mutation in an illness that requires two mutations to cause disease. Your genetic counselor can help figure out what this means. If you have the full illness (POLG) more testing may be needed to fully figure it out. It IS complex for sure.
Q: If a person has POLG and has a seizure disorder, which of the anti-seizure medications would be possible for them? Is there a list somewhere? What does the family do if they’re in that situation?
A: Bruce Cohen, MD: So the one thing about seizures and POLG disease is you’ve got to stay away from Depakote. I mean, that’s an absolute no-no drug. What we do know is phenobarbital is not particularly effective, Carbamazepine is not, phenytoin is not. We still use these drugs in some patients with POLG disease because we run out of other options. There’s 25 anti-seizure medicines, taking away Depakote, there’s 24. Levetiracetam, also known as Keppra or Roweepra, are probably the mainstays of therapy. I tend to use a lot of benzodiazepines, that’s Valium and valium-like drugs in my patients but there’s really more than a dozen other medications that can be effective. Russell P. Saneto, DO, PhD has written about this and his papers would be a good reference. I think we talk a bit about this in our paper that’s online on gene reviews as well so I don’t want to take up the time naming names, but they’re documented in the medical literature. We’ve also used the ketogenic diet to treat some patients with terrible epilepsy due to POLG disease.
Q: Can you discuss what a ketogenic diet is?
A: Bruce Cohen, MD: It’s basically a diet that’s extremely high in fat and very low in carbohydrates and proteins. We don’t know why ketosis (helps people) to get better, it’s not the ketones that are causing these seizures. But we don’t know what the special sauce is about the ketogenic diet that can make seizures better in mitochondrial disease but we’ve used it safely, sometimes effectively, sometimes not so effectively, in treating the seizures that are seen in POLG disorders.
Q: Thoughts about Mitochondrial Transplant/Augmentation for POLG disease?
A: William Copeland, MD: POLG is encoded in our nuclear DNA on chromosome 15, so mitochondrial transplantation wouldn’t help with POLG disorders.
A: Bruce Cohen, MD: There was a paper published by Jonathan R. Brestoff, MD, PhD, MPH, lab at Washington University talking about treating mice with Leigh syndrome with mitochondrial transplantation/augmentation; I know that paper well because my daughter was eighth author so I’m very proud of her and welcoming her to the mitochondrial therapy community. She’s a college student, but doing some really neat work in Dr. Brestoff’s lab. So I think there’s certain diseases that could be treated with mitochondrial transplantation, although POLG is going to be a difficult haul with that therapy.
Q: Is anATP-6 deviation related to POLG?
A: William Copeland, PhD: It could, possibly. ATP6 is encoded by the mitochondrial DNA and the mitochondrial DNA has to be copied by POLG. So it’s sort of a downward – downstream effect possibly. But usually they’re independent diseases.
A: Bruce Cohen, MD: Right, but someone with POLG disease is going to probably knock out some features of ATP6 and all the other mitochondrial genes.
Q: How does allele impact the diagnosis? If a patient has 2 POLG variants (One likely pathogenic, another VUS with conflicting interpretation) in the same allele, what does it mean?
A: Bruce Cohen, MD: This is a great question but would take an hour to type the answer. The basic answer is, correct – 99% of the time but there are nuances that make answering in this format difficult.
Q: Is there any chance that any drug/molecule designed for POLG gene defects, could be adapted or used to treat RRM2B gene defect? As I understood they are in the same MDMD group of mtDNA maintenance defects, but would be interesting to know if the path on research on POLG could be considered a step forward on RRM2B?
A: Bruce Cohen, MD: Any advances give hope for the same technology being adapted for similar disorders. But there is no slam dunk modification.
Q: Is MT1621 also used for Alpers-Huttenlocher syndrome? How does it work for this type of disease?
A: William Copeland, PhD: MT1621 is a deoxynucleoside substrate that targets TK2 mutations that cause MNGIE disease. It mimics the natural deoxynucleoside, thymidine. POLG needs to use all four deoxynucleotides to copy the mtDNA, so this drug would have limited effect on POLG disease.
Q: In the spirit of Thanksgiving, what advancement in mitochondrial science or mitochondrial medicine are you the most thankful for and do you think will help move us forward the most?
A: William Copeland, PhD: I would say the cost of sequencing. Let me compare to computer chips. So we know the cost of computer memory has come down a good thousand fold or so. And, memory, what we used to have when you’d buy a computer in the 90s now that is 100 times that is in your cell phone. But the cost of sequencing has come down over a million fold and that has made it more affordable for everybody to get the whole genome, whole exome sequencing. Insurance companies are paying for this and what used to be costing multi-million dollars is now you can sequence an individual for several hundred to a thousand dollars and that’s probably the best benefit for this molecular diagnosis of all these diseases.
A: Bruce Cohen, MD: I’m going to start with the same answer. I was actually at a small conference last week where I talked about bringing sequencing into the hospital, making it available to everybody. The cost has come down. Our state pays for sequencing in Medicaid patients. So we can get to a faster diagnosis. We’re going to be sequencing newborns when we don’t know what’s wrong with them so we can get to a faster diagnosis. This is not only going to help identify POLG patients, but patients with other diseases many of which actually have treatments that are available now. The second thing that’s coming into play is gene therapy. Actually, this got a bump forward by the pandemic. Because mRNA vaccines and gene therapy are nearly the same concept and the problem with POLG disease is that we’re not trying to treat one organ. We’re not trying to treat the liver because if you treat the liver without the brain, you’re seldom going to have success, although patient three is a patient who got her liver treated with a liver transplant and has had quite a prolonged survival after that, even though she is sick with POLG disease, treating the brain without treating the liver is not going to do any good. And it’s hard for gene therapies to target, at least at this stage, target different organs or more than one organ at the time.
Q: Is there a specific genetic panel test for POLG diseases?
A: Bruce Cohen, MD: There are, but I basically feel very strongly that panel testing is going to miss diseases and it also gives you the false sense of security as you look at everything. Whole genome sequencing is the best thing you can get today. It’s going to be replaced by something better a year from now. I have patients that had normal whole exome testing two years ago where we found the answer on whole genome testing.
Q: How much do we know about how all of these things work together and relate? Is that something that we’re going to see advancing in the future?
A: William Copeland, PhD: Do you mean in terms of all the complexities of all these diseases and what? Well, that’s sort of what I was touching on. In terms of genetics, the whole genome or whole exome has been just wonderful in terms of getting a wealth of data, but sometimes it’s actually too much. I mean, there’s six billion copies of our nuclear DNA and any one individual even within family members, there’s over a million variations. And so trying to tease out what’s the causative mutation versus the benign, there’s not one that’s not important. We leave that up to the bioinformatics and then tie that into environmental effects, nutritional diet, and everything else, just how people live. It’s a complex question.
Q: What do you think the next generation sequencing is going to look like? What do you think we’ll learn then?
A: William Copeland, PhD: We’ll be sequencing neonates and newborns readily.