Mitochondrial Diseases

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD: An estimated 1000 to 4,000 children are born each year in the United States with a mitochondrial disease. Because possible symptoms are highly variable and frequently affect multiple body systems, mitochondrial diseases can often be mistaken for other more common diseases. In this episode of Neuro Pathways, we're discussing the diagnosis and management guidelines for mitochondrial diseases and how experts are working to improve health outcomes for patients.

I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. And joining me for today's conversation is Dr. Sumit Parikh. Dr. Parikh is a pediatric neurologist in Cleveland Clinic's Neurological Institute and Director of Cleveland Clinic's Mitochondrial Disease Center. Sumit, welcome to Neuro Pathways.

Sumit Parikh, MD: Oh, thank you for inviting me.

Glen Stevens, DO, PhD: So, Sumit, I would like you to share with our audience who aren't familiar with you, a little bit about your background and how you came to the Cleveland Clinic.

Sumit Parikh, MD: Sure. Yeah. I am definitely not a scientist or a science person by interest. I was an English major quite a long time ago. Took the pre-med stuff to keep my parents happy, but really fell in love with being with families and being with kids. I was a daycare teacher to earn some money on the side when I was in college, and I also worked as a parent-support person in the pediatric intensive care unit. And that was the part that I really did enjoy, which drove me to medical school. Medical school, and then residency in pediatrics where I really enjoyed the genetics aspect of it. I enjoyed human biochemistry as opposed to more abstract biochemistry that we might get in undergrad, and that led me to become much more interested in biochemical genetics.

And then as often is the case in our field, I had a family that I became very involved with, a child who I became very involved with, whose care I became involved with, who had mitochondrial disease. And that's really what sparked my interest in wanting to learn more and become much more engaged in caring for these children and now adults. I came to Cleveland and Cleveland Clinic for two reasons. One, my wife grew up in Westlake, Ohio, and two, one of the people that I wanted to have as a mentor, Bruce Cohen, practiced at Cleveland Clinic, took me on for fellowship and additional training in metabolic genetic diseases. And so, I came here after pediatric neurology training and spent a couple years training with him as well as a group of other metabolic geneticists, and then stayed afterwards.

Glen Stevens, DO, PhD: Well, I love the story. I didn't know the story about your history, but you sound very caring and they're lucky to have you doing this. And of course, Bruce and I worked together for many years in neuro-oncology. And as you know, and I'm sure you'll share with us when you're looking after pediatric patients, hopefully they'll get older and then who looks after them and the lines blur quite a bit between OK, eighteen's OK. Nineteen's OK. 25's OK. 30's, OK. Hey, 40's OK. So, Bruce and I shared a lot of patients together in neuro-oncology, and I have a somewhat cursory understanding of mitochondrial disorders having worked with Bruce for so many years, but I'm looking forward to our discussion today and learning some more. So really a pleasure to have you here today. And I know that everybody in the department is thankful that there's someone that has a great interest in mitochondrial disorders because they can be quite complicated as we'll get into, I'm sure.

So, let's start with the basics. Give us a brief overview of mitochondrial disease and what's gone wrong.

Sumit Parikh, MD: The best way to think about this is really that the mitochondria are our energy generators. And so, every part of our body that needs energy to work, which is all of it, is either running short or there are sections that are not able to make energy at all, and therefore parts of the body decide to either work inefficiently or poorly or not at all. And in the process of all of this, some organs end up getting injured and not recovering fully. The brain, muscles, nerves are extremely energy hungry. They use almost a quarter of all the energy the body makes. And so, the nervous system is almost always involved in mitochondrial disease at some point along the way.

And so historically, the thought was that these individuals started with symptoms when they were children as pediatric patients. But we now know that sometimes the body is able to compensate in the adult years after which the presentation of the disease can start at any point along the way, whether you're in your 40s, 50s, or 60s. I have been able to see patients across the lifespan and manage patients across the lifespan who end up coming because of unexplained symptoms. Then we end up finding they either have a mitochondrial disease or another genetic disease.

Glen Stevens, DO, PhD: I find it quite fascinating that every cell in the body, I believe, has mitochondria except the red blood cells, which makes sense because the red blood cells are trying to get oxygenation to area and they don't want to be using all the energy from mitochondria to use up the oxygen that the rest of the body uses. But as you say, I mean, your area of expertise is other than the red blood cells, every cell in the body. That's pretty big shoes to fill as it goes through. So, thank you.

Sumit Parikh, MD: Yeah, sure. No, I think it is curious because we talk about mitochondria as energy production machines, but their role in the body, in pathophysiology across all systems, across all specialties is huge. The role of mitochondria in heart failure, in pulmonary disease, in cancer, and as our understanding of mitochondria has grown, our understanding of their importance in other disease pathophysiology has grown significantly as well.

Glen Stevens, DO, PhD: So, we'll get to in just a minute, the work that you produced in 2015 trying to standardize things, but who are we suspicious of that has a mitochondrial disorder? How do people generally present or is it so nonspecific that that's where the problem is?

Sumit Parikh, MD: No, we really do try to make it very straightforward for our clinicians. And the truth is that there are some what we consider red flags or sine qua non findings that still hold true. And for a busy clinician who is not necessarily just seeing mitochondrial disease who might be a generalist or a specialist, we really don't want them to have to worry about all the individual diseases and symptoms and conditions.

The most high impact symptoms are one, in a pediatric or adult patient, a combination of hearing loss and diabetes. That alone is such an odd combination that if those are not well explained by some other condition or problem, that person deserves a mitochondrial disease workup. And then in the neurology world, unexplained lesions in the brain in a certain pattern, in a symmetric pattern in the deep gray matter, basal ganglia, thalami, unexplained strokes at a young age, unexplained cerebellar disease with volume loss, unexplained myoclonic epilepsy are all reasons that a person should get worked up for mitochondrial disease.

Glen Stevens, DO, PhD: So, in 2015, you led a team of mitochondrial disease experts that developed a standardized approach to evaluating these suspected patients as you've just sort of outlined. What do the guidelines entail and what's happened to them over the last eight years?

Sumit Parikh, MD: So you, Dr. Stevens, may definitely know, but when we first started in this area, diagnosis was a big challenge and there was a lot of old tools that we had to use which were more biochemistry based, metabolic testing based, tissue-based analysis, whether it be looking at muscle under the microscope or electron microscopy or doing physiologic testing, such as what's called electron transport chain testing.

And what we learned over time is that these results of these tests were extremely nonspecific and that the person who was being poisoned with arsenic or a person who was completely bedridden for a year's time or somebody who might be taking hydroxychloroquine for rheumatologic disease may all show problems in how the mitochondria work and look underneath a microscope, but it doesn't mean that they have a genetic mitochondrial disease. So, a lot of what our generation of clinicians has worked on is really shoring up the diagnosis and making sure that we are truly diagnosing patients who might have or have these conditions.

And the good fortune, of course, was that genomics really took a huge leap forward and the ability to sequence multiple genes at one time and to look at hundreds if not thousands of genes at one time on a clinical level with a relatively cheap test is what allowed for these advances to happen. And so, before we ended up saying, OK, let's see how these patients do, we wanted to make sure that we were accurately identifying patients.

And so, our initial effort, and this was all done by a group called the Mitochondrial Medicine Society. We are a group of clinicians, academic clinicians who really are focused on patient care outcomes and treatment. We are not bench scientists or even translational researchers. And so the group came together and tried very hard in the face of limited evidence and data to come up with criteria where we could standardize the approach initially from the diagnostic side and making sure that when we were diagnosing a patient that if you went to different centers, you would end up with the same diagnosis and the same label. So that was that first effort, which was the diagnosis paper that we kind of came up with and the standardized guidelines for diagnostics, which yeah, amazingly, it's eight years ago.

Glen Stevens, DO, PhD: So, you are correct in that my recollection when I was training was essentially reviewing muscle biopsies, looking for ragged red fibers, and that's how we move forward. And I seem to recall lumbar punctures for lactate and pyruvate as well but go through the standardized approach for me. So, let's say you see that patient with the odd combination of hearing loss and diabetes. So, somebody calls you up and says, “holy cow, I listened to your podcast, and I saw somebody the other day that has hearing loss and diabetes." What is the standardized workup they should have?

Sumit Parikh, MD: If that really is the history, if there's a family history of the same, throw in a little bit of cardiomyopathy and endocrinopathy and neurologic symptoms in other family members, we really do go straight to genetic testing. It is that straightforward. And we look at both the mitochondrial DNA, we have the ability to look at all the base pairs of mitochondrial DNAS because it's a very small compact blueprint from front to back. We can look at it in blood, but it has a higher yield if we look at it in other tissues that are not as actively dividing, such as buccal swabs or urinary epithelial cells. And then we also look at the nuclear DNA, we look at the nuclear DNA because we now know of over 350 nuclear genes involved in helping build and maintain the mitochondria. And we can look at those with a single gene panel.

We still get some biochemical testing in blood and urine. We still get those older tests like amino acids, organic acids, lactate, pyruvate, but that's more to help support whatever we find. That by itself is not specific or sensitive enough for us to make or exclude a diagnosis.

Glen Stevens, DO, PhD: And I hate to ask this question, but insurance covers testing, doesn't it? Where does that sit?

Sumit Parikh, MD: The two or three biggest players from the commercial laboratory side, and I have no conflict, we use all of them. They work with the insurers to get this testing covered. There are some labs that have developed who feel their mission, their core mission is being able to offer genetic testing for everybody. And they, if insurance won't pay for it, have a blanket fee of just 250 dollars to get a test done. And then the bigger, what I might consider a more comprehensive testing, there might be a little bit more out of pocket, but that company works very well with the families to make sure that it does not burden them with an unexpected bill.

Glen Stevens, DO, PhD: And the time turnover?

Sumit Parikh, MD: So that's still something that we don't love. It's about six to eight weeks to get results back. Now, for a chronic disease, that may not be so bad, but if somebody's acutely ill in the intensive care unit, that's not ideal.

Glen Stevens, DO, PhD: And ability to interpret the results, if I can ask?

Sumit Parikh, MD: Yeah, like all things in medicine, there are clear cut results, there are clear cut negative results where we have to keep looking, and then there are some grays. And when we get the gray results, we actually have colleagues, whether they're on the research side or on the translational side, that can help us out. And those are the times where we start going back to our old tools, our biochemical tests, whether it be in blood, urine or muscle, to try and help us build a case or help us disprove that we have the right answer. It's not clearly diagnostic. We do go bigger. We now know of many mimics of mitochondrial disease that we never knew about before. So, if your initial panel comes back negative, maybe you do move on to more modern genomic testing where you're looking at whole exomes or whole genomes and covering the gamut so that any mimicking diseases will also be ruled in or ruled out.

Glen Stevens, DO, PhD: So, I get the sense that you would like to remove the term possible mitochondrial disorder from the vernacular. Tell me about that.

Sumit Parikh, MD: No, that's exactly it. And we have an international consensus on that, which was wonderful to achieve. Because there are so many different disorders, so many mimicking and overlapping disorders, and because when a person is diagnosed with mitochondrial disease, most of what you read on the internet is quite doomy and gloomy. Our effort has been to make sure that we are giving an accurate diagnosis and if we don't have a diagnosis, that we all feel comfortable saying, we don't have a diagnosis, but we're not going to box you in just to put a name to this because you as a family member, a lay person, may still choose to read all about it and go down a rabbit hole of this potentially being your disease. And then us getting smart three or five years later and giving you the accurate diagnosis and then having to take this away while you have lost three to five years worrying about your health and how something might progress. But you're following the completely wrong playbook, and you are looking at the completely wrong forecast as to what's going to happen for your condition.

Glen Stevens, DO, PhD: So, let's move forward to treatment options. So, we feel comfortable with the diagnosis. Treatment options?

Sumit Parikh, MD: So that's where there have been some exciting changes. So, the truth is, up till now, we have not had treatment options. We know that active surveillance and preventative care is optimal for all of our health, and that is absolutely true for mitochondrial disease. If somebody is going to develop heart block or cardiomyopathy, you don't want to pick it up after they're symptomatic and severe. You want to be able to pick it up at the earliest onset so that you can intervene, whether it be with medicine or a pacemaker in this example. And so we worked as a group to come up with guidance on what type of surveillance and preventative care was necessary and in baby steps and in its own way, this has been helpful in improving outcomes because somebody is not just coming in distress passed out through EMS, but we are actually picking up the earliest signs of heart block and getting that pacer put in as soon as we need in this scenario.

But the best development that has happened is the interest that the pharma and other industries have taken in wanting to develop treatments, actual treatments and interventions for mitochondrial disease, whether they be curative or whether they just be disease modifying. They understand that mitochondrial dysfunction, unhealthy mitochondria are a key contributing driver for the pathophysiology of so many human conditions and diseases from, as I was mentioning before, aging or cardiac failure or pulmonary disease or cancer, that if they can develop something that truly impacts and improves mitochondrial function, their hope is that this treatment can then get generalized from a rare disease population to a much larger pool of patients.

A great example of that is something called mitochondrial transplant and transfer therapy that's being developed. So it really sounds a bit science fiction-y, but it is about taking healthy mitochondria from a family member, from placental tissue, from other sources and being able to deliver it either into an organ that is failing or into a body system or into stem cells where it can now take up home and then hopefully distribute to the rest of the body. And so there are companies that are actively working on this technology. The other nice evolution that has happened in the treatment space is gene therapy and genetic modifications, which are now starting to move outside of the lab into the clinical trial stage, into the stage of studying the response in non-human primates. And so, the hope in the field is that in a five-to-10-year window, we will have human clinical trials of gene therapy for mitochondrial diseases.

And on the side of developing disease modifying therapy, having novel compounds and agents that can either boost mitochondrial function or improve the body's ability to make more healthy mitochondria, there are over a dozen compounds that have been found, a couple that have now completed their FDA studies that have not met endpoint. A couple that are actively in the midst of clinical trials with some early data showing benefit. And these are all blinded randomized trials that are being run internationally. We have had the good fortune to be a part of many of them. And so, the hope is that we will have the same type of combination therapy many of our patients in the other disease specialties do, where we can start with something medical and medical management and preventative care, and then at some point offer things along the lines of extra mitochondria as an infusion treatment. And in the cases where gene therapy is available, hopefully reverse the disease.

Glen Stevens, DO, PhD: And treatment of adults versus children? Different treatments, same?

Sumit Parikh, MD: Yeah. So that has been a challenge and partly because the FDA has been much more open to studying adults. So, all of the clinical research that is being done has been done in the young adult population, 16 and up. There are some therapies, such as mitochondrial transfer therapy, that have been studied in the pediatric age group. But the suspicion is, and the expectation is, is that the FDA will be approving treatments for adults before it accepts treatments for pediatric patients.

Glen Stevens, DO, PhD: So, my understanding is you're leading a study looking at analyzing mortality in patients with genetic mitochondrial disease. Can you tell us a little bit about the study?

Sumit Parikh, MD: Sure. One of the biggest challenges, not just for clinicians trying to provide information to patients and families about how their family member's going to do, but even to better study the outcomes and expectations of an interventional agent has been that we don't understand the natural history of these diseases fully. Partly because we're not talking about one disease. Mitochondrial disease is truly at least a hundred individual diseases, if not more than that. And so, each one does behave quite differently, but there is a core group that has a lot of similarities and overlaps. And so, something as simple as what if the lifespan in some of these diseases, now that we have accurate genetic diagnoses, what is the cause of mortality? What is potentially something we can do to intervene and help and improve quality of life and lifespan?

Those were the questions we were hoping to answer. And so, we were able to evaluate an international cohort. This information is still not published. It was presented at an annual meeting and is in the process of being published. And that's exactly what we looked at, which diseases, how long do you live, what is the thing that gets you into the intensive care unit? And might be not because of the disease, but just because of the course of the disease and the impact it takes on the body, what might be the thing that does you in? It was quite informative, I think maybe not surprising, but quite informative in being able to look at the lifespans of various diseases across hundreds of patients across the world. Maybe the impact of healthcare systems and the differences between the U.S. versus socialized medicine and how that may or may not impact the disease course. And then last but not least, maybe to no surprise to anybody in the neurology world, the impact that infections and pulmonary infections and pulmonary insufficiency and respiratory insufficiency can have on expediting death and mortality in these patients.

Glen Stevens, DO, PhD: Well, it sounds like we may have to have you come back once that's published and get all the details. You covered a broad range. Anything else research-wise on the horizon that is important for us to know?

Sumit Parikh, MD: I think, again, as somebody who really does not love science, some of the coolest developments that have happened in the world of science have happened around the field of mitochondria. And for anybody who may not be a genetics-focused person or a metabolism-focused person just learning more about how mitochondria influence inflammation in the body, how mitochondria act when the human body is in space from cosmic radiation effects and microgravity effects, what happens to the mitochondria in cancer and how dysfunctional mitochondria allow cancer cells to become living zombie cells. These are the areas where we never understood or expected mitochondrial learning to take us, and it really has.

And so, my true hope is that whatever mitochondrial therapies that come about will not only just help our own patient population of this rare disease group, but really can get generalized to help all of these other human conditions and diseases.

Glen Stevens, DO, PhD: So, any final tips or takeaways for a provider who might encounter someone that they think has a mitochondrial disorder?

Sumit Parikh, MD: Sure. We have a national network. It's called the Mitochondrial Care Network. We offer something called The Doc Is In. And so, you can pose a question or present a case, and we all take turns helping answer those. So, if there is a question, should I be worried about a mitochondrial disease in this person? You can post a case and we can try and help you; provide some backseat driving as to whether you should worry about this and work them up more.

As part of our national network, which falls short of being able to provide geographically nearby care for every patient, we have started a national and international telehealth network. And so, we're hoping that as telehealth will allow for the families that cannot actually make their way to a center such as Cleveland Clinic, that we'll be able to offer some expertise and guidance virtually for these families and for these providers.

Glen Stevens, DO, PhD: So, I really appreciate your being here with us today. On a selfish note, how do I maximize my personal mitochondria? Is there anything that we can do?

Sumit Parikh, MD: That is actually a wonderful question, and sadly the answer may or may not be what you want to hear. It is all the boring stuff that doctors have touted for ages. Healthy nutrition, the healthy breakout of a third protein, a third healthy fats, a third healthy carbohydrates, not simple carbs, and then exercise, exercise, exercise - aerobic and strength training. These are things that we now know not just in animal models, but in human models and in mitochondrial patient disease patients and non-disease patients really boost mitochondrial function. And so, until we get the high-tech stuff, this is all we have.

Glen Stevens, DO, PhD: Well, that's great. This has been very insightful, and I appreciate your time today and I hope everybody out there gets some exercise today and eats just a little bit better. So, thank you very much for your time.

Sumit Parikh, MD: Thank you for having me. It was a pleasure.

Conclusion: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.