An Era of Progress in Pediatric Neurodegenerative Diseases: Dr. Mary Kay Koenig, UTHealth Houston McGovern Medical School

Michael Carrese

Hi, I’m Michael Carrese, welcoming you to Raise the Line with Osmosis from Elsevier, an ongoing exploration about how to improve health and healthcare.

Today we continue our Year of the Zebra series focused on rare disorders by welcoming a leading figure in the field of pediatric neurodegenerative disease, Dr. Mary Kay Koenig of the University of Texas McGovern Medical School.

Dr. Koenig holds multiple senior-level roles there including director of the Center for the Treatment of Pediatric Neurodegenerative Disease, director of research for the Division of Child and Adolescent Neurology, and director of the Mitochondrial Center of Excellence.

Among Dr. Koenig’s specific research interests are Leigh Syndrome, Tuberous Sclerosis, and other neurogenetic disorders. I’m looking forward to her insights on caring for people with these complex conditions and learning about her efforts to develop therapies for them.

Thanks so much for joining us today.

Dr. Mary Kay Koenig

Thank you, happy to be here.

Michael Carrese

We always like to start by learning more about the background of our guests. You came to a career in medicine after a detour into teaching, as I understand it. Tell us about that.

Mary Kay Koenig

Sure, I wasn’t exactly sure I wanted to go into medicine, to be honest. I started my career as a microbiologist after completing college. I went and got a graduate degree in microbiology. Both of my parents were actually teachers. My mom taught college and my dad taught high school, so it seemed kind of a natural fit.

I started teaching as a TA in my graduate program. When I finished my master’s program, I started teaching at the local community college and I loved it. What most people don’t really think about is that academic physicians are still teachers. We teach all the time. We teach our patients—especially in neurology and in neurodegenerative disease—I spend a lot of time teaching my patients about their conditions, about how to take care of themselves.

I also spend a lot of time teaching students. I teach medical students, college students, residents, fellows. I’m constantly surrounded by people that I’m teaching. So, I get to combine both worlds here in my current job. I work both as a physician taking care of patients, and I still get to follow my passion for teaching.

Michael Carrese

And why medicine and pediatrics?

Mary Kay Koenig

Medicine was a passion I had from a very young age. I was really interested in it, but I diverged because I got very interested in science and wanted to do what I would call “real science” working in a lab. When I started spending all of my time in a lab during graduate school, I realized I wanted to work with people.

So, I went back toward medicine because I just like being around people and found it very rewarding. I get to do both—I do a lot of research now, a lot of science, and I get to be around people all the time. It’s really the best of both worlds.

As far as pediatrics and neurology, the one thing I did know going into medical school was that I would never work with children.

Michael Carrese

Ha ha ha ha.

Mary Kay Koenig

They’re very difficult. They don’t do what you ask them to do. But you find out very quickly in medical school that kids are also very resilient. They bounce back from anything, especially kids with chronic conditions. They don’t realize there’s anything wrong with them, whereas adults complain about everything.

Michael Carrese

Yeah.

Mary Kay Koenig

Kids complain about nothing. If they’re in the hospital or if they’re sick, they don’t seem to realize there’s anything wrong. They’re wonderful to work with. They’ll let you do anything to them, and then they forgive you instantly. They’re just beautiful.

Michael Carrese

Ha ha ha.

Mary Kay Koenig

They also, from a neurologic perspective, have an amazing ability to recover—much more so than adults do. That potential for recovery and improvement, and that potential for their future, is so amazing that it was impossible for me to resist. So, I decided to go into pediatrics.

The other thing I realized very quickly when I started medical school was that I did not want to go into neurology.

Michael Carrese

Ha.

Mary Kay Koenig

My first neurology class in medical school was so difficult and confusing. There were all these pathways we had to memorize. They were boring and didn’t mean anything. When I got into my fourth year of medical school, they started making sense because we could integrate those pathways with people, syndromes, and conditions. Suddenly, everything I had memorized became so interesting and meaningful.

I became fascinated by neurology. In particular, I started understanding how much there was we still didn’t know, and that sparked the research side of me. I became very interested in neurology and in trying to answer some of these unanswered questions.

Michael Carrese

Was there a mentor or key doctor along the way who led you toward neurology?

Mary Kay Koenig

Not really, though one person did lead me toward mitochondrial medicine. When I was in neurology training, I was taught by a man named Ian Butler. Anyone in child neurology knows Ian Butler—he’s been around for a long time. He still works here as an emeritus professor and had an amazing teaching style, kind of like a parent figure, letting you figure things out but being there to guide you.

He always talked about learning through stories and experience. I’ll never forget seeing a young woman, about twenty years old, who had been going around for five years without a diagnosis. We determined she had a mitochondrial disease. I was thrilled and said, “This is great! Now we can treat her.”

He said, “No, there’s no treatment for this. But at least she knows what she has now.”

I said, “Well, I don’t like that. I want to do something.”

He told me, “Go figure out what you can do,” and gave me the leeway to research on my own. He paid for me to attend a conference on mitochondrial disease, which allowed me to explore what could be done.

Ultimately, I realized there wasn’t anything we could do at the time, but that experience sparked my entire career in mitochondrial medicine. If you ask me who influenced my career the most, it was Ian Butler.

Michael Carrese

That’s a great story. Just to get everybody on the same page here, remind us of the role of mitochondrial cells and how their dysfunction leads to neurodegenerative diseases in both kids and adults.

Mary Kay Koenig

Sure. Mitochondria make a lot of people cringe because we always have to go back and talk about things like the TCA cycle and the Oxfos pathway and biochemistry, which for a lot of physicians is a sore subject. They don’t want to think about biochemistry—it’s too hard, too complicated, too much.

I always say, like I said before, I’m an educator so I have to teach patients about this. The basic role of mitochondria is to take your substrates—your food—and turn it into chemical energy in the form of ATP. You take your sugars, your proteins, your fats, run them through glycolysis, beta oxidation, and the TCA cycle. Ultimately, it goes through the electron transport chain in the mitochondria and turns it into ATP.

Everything needs ATP to function. If your ATP isn’t being produced at the level it’s supposed to be, you have global system failure. Nothing in the body is going to work the way it should. Everyone has to make some ATP, but how much you make and where you make it in the body determine how you function.

If you have a mitochondrial disease where your mitochondria aren’t working well in your heart, you may have heart failure because you’re not producing enough ATP in the heart. If it’s in your brain, you may not produce enough for cognition to function, or you may develop epilepsy. If it’s your muscles, it may be more of a muscular problem.

So mitochondria take your food and turn it into chemical energy so the rest of your body can work. Depending on how severely affected your mitochondria are and what part of your body is affected, that’s going to influence what type of mitochondrial disease you have and how sick you are.

Michael Carrese

So you must see everything. The range of presentations must be quite wide.

Mary Kay Koenig

We see everything. It can begin at any time—from birth all the way up through old age—and we care for patients at all ages, sometimes into their eighties. The severity of the condition can range from very mild to very severe. Some patients present with mild weakness of their eyelids or inability to move their eyes. Others just complain of fatigue or mild muscle weakness.

At the other end of the spectrum, there are very severe, devastating presentations that can result in early death, even in infants.

Michael Carrese

And it can be happening in multiple systems at the same time—it might not just be your heart, but two or three other things as well?

Mary Kay Koenig

Yes. There are literally hundreds of different types of mitochondrial diseases, and which one you have depends on where and how severe the problem is. We currently know of about fifteen hundred different genes required for mitochondria to function appropriately. Depending on which gene is dysfunctional, that will influence what type of mitochondrial disease you have.

Even people with the same gene defect can have very different outcomes. So many factors can influence it—your environment, your age, and exposures. If you’re exposed to a certain metabolic stressor, that can alter your mitochondrial function.

Michael Carrese

I’m remembering what you said in that early anecdote about there not being much that could be done for that patient you encountered. That story has changed somewhat, partly because of the work you’ve been doing down there at Texas McGovern Medical School. Tell us about the UT Mitochondrial Center of Excellence and how it’s evolved in almost twenty years since you founded it.

Mary Kay Koenig

We opened our doors in 2007—and when I say we, I mean me. I decided back in 2007 that I wanted to start a mitochondrial clinic, and I remember at the time being told I was crazy. I was told there weren’t enough patients with mitochondrial disease in the world to have a successful clinic.

Here we are twenty years later. We now have two dedicated neurologists and an entire team of subspecialists including endocrinology, cardiology, gastroenterology, palliative care, and social work. We have therapists and a full care team for our mitochondrial patients.

We also have a comprehensive research team. Currently we have two interventional studies, two observational studies, and several expanded-access research programs providing experimental therapies to patients who otherwise would not have access to them.

So we have a full center where we care for people with mitochondrial disease, providing therapies that are being investigated or that we believe may provide benefit. We’re also engaged in international collaborations to study the natural history of these conditions so we can understand more about them and be part of the effort to develop future therapies.

Michael Carrese

What are some research highlights that you’d like our audience to know about?

Mary Kay Koenig

Since I started doing this, we’ve learned so much more about these conditions. One of the biggest successes is that we can now recognize these diseases much more often. When I started, someone told me, “We only diagnose one of these every five years.” Now, I diagnose one about every five days. They were always there; we just weren’t recognizing or diagnosing them.

Michael Carrese

Yeah, right.

Mary Kay Koenig

So now they’re being diagnosed a lot more frequently, and with that comes increased understanding. That’s been a huge win, not just here in Houston but worldwide. It’s led to improved survival and quality of life in our patients. If we know what you have, we can manage you better and understand your disease more deeply.

We still don’t have any FDA-approved therapies for mitochondrial disease, but some therapies are showing very promising results. As a community, we’re hoping to see some approvals soon. Two drugs are currently under review by the FDA, and there’s a lot of hope they’ll be successful.

There’s also been increased collaboration among the mitochondrial disease community and physicians. We have much more data on natural history, stronger collaborations, and a clearer understanding of what outcome measures we need for successful clinical trials.

Another thing that excites me is improved education for the younger generation. Mitochondrial disease is now being taught in medical schools. Students and residents learn about it here. You don’t get out of McGovern Medical School without knowing what a mitochondrial disease is or having seen patients with it. When I was in medical school, no one had even heard of it.

People used to say, “You can’t get a disease from a problem with your mitochondria.” Now that’s just accepted fact. Everyone knows that. It’s really exciting to see how education has changed the way people think about mitochondrial disease.

Michael Carrese

That’s an amazing arc in the course of one career—to travel that far. In terms of the therapies you mentioned, is there a commonality in their method of action? People hear a lot about gene editing and other technological advancements. Talk about how that plays into what you’re doing.

Mary Kay Koenig

There are a lot of different directions people are exploring right now, and it’s hard to know what will work and what won’t. Things that look great in a petri dish often don’t translate well to people.

One approach researchers have tried is modifying the redox state. In mitochondrial disease, we know there’s a lot of free radical production and oxidative stress within cells. So people have targeted that by trying to reduce oxidative stress.

I compare it to someone who has a cough—you could have a cough for many reasons: lung cancer, pneumonia, or asthma. If you give someone a cough suppressant, they stop coughing regardless of the cause.

A lot of mitochondrial therapies developed so far have targeted those global problems—too much oxidative stress and not enough ATP production. The theory is that if you boost ATP and reduce oxidative stress, it should work for all types of mitochondrial disease.

There have been some studies, but results haven’t been overly positive. It’s hard to say whether the therapies aren’t working or if the trials themselves are too new and varied. We also don’t fully know the natural history of these disorders, so it’s difficult to measure improvement.

I think the more data we collect, the better our trials will get. The more homogeneous our patient populations and the more experienced our research teams, the more successful the outcomes will be.

Other therapies are more disease-specific. If we know the gene and the mechanism, we might be able to target it directly. For example, there’s a therapy developed for thymidine kinase 2 deficiency, where a specific nucleoside isn’t being formed properly. Researchers created a nucleoside replacement therapy, and clinical trials have shown impressive efficacy.

That’s a targeted approach—it only works for one type of mitochondrial disease, but it’s more precise. I think there’s room for both types of therapies: global and targeted. Both are being investigated, and as our ability to conduct clinical trials improves, I believe results will follow.

Michael Carrese

It’s a very complicated, long road to do clinical trials, as most people listening can appreciate. I mentioned earlier that you also focus on tuberous sclerosis. What would you like our audience to know about your work in that area?

Mary Kay Koenig

Tuberous sclerosis is, in many ways, the opposite end of the spectrum from mitochondrial disease. It’s a condition that’s been well known for a long time, and when I entered the field, there was already a lot of research and natural history data.

What was most exciting at that time was the emergence of an effective therapy. The first publications appeared in 2006, and I joined the field in 2007. Since then, we’ve had four FDA approvals for targeted therapy within about ten years—a remarkable pace for a rare disease.

It’s been rewarding to work in this field and watch treatments advance so rapidly. Unlike mitochondrial disease, tuberous sclerosis is relatively homogeneous. Instead of fifteen hundred different genes, there are only two that cause it, and all patients have a similar clinical presentation. The severity varies, but the phenotype is consistent.

Watching these new treatments transform patient care has been incredible. For instance, patients used to need multiple surgeries to remove brain tumors—astrocytomas—throughout their lives. Now we have medications that can shrink those tumors and also help with kidney tumors and seizures, all with limited side effects.

It’s been wonderful to help patients transition into this new therapeutic era. There’s still much research to do, but the progress and optimism in the community have been inspiring.

Michael Carrese

As you may know, Osmosis is a teaching company, and one of the things we like to do is fill knowledge gaps. What’s a gap in knowledge or a myth that really bothers you—something not well taught in medical school or misunderstood by the public—that you think we should make a video about?

Mary Kay Koenig

I think there’s still a lot of misunderstanding about genetic testing. I’d love to see a comprehensive video about what genetic testing actually is, the different types, when to order it, and which kind to use.

Working in genetic neurodegenerative diseases, I still see people who either don’t order testing, order the wrong kind, or don’t know how to interpret the results. Even new graduates often struggle with what to do when they get a “variant of unknown significance” result. Which test is best? When should I order it? Those are still open questions for many clinicians.

Michael Carrese

That’s a very good point. Genetic testing has become so common that it’s almost routine, but that makes understanding it even more important.

Mary Kay Koenig

Physicians need to be better at explaining to patients what they’re ordering, why they’re ordering it, and what it means when the results come back.

Michael Carrese

As we wrap up, I wanted to ask two questions related to advice for learners and early-career professionals. The first is about dealing with rare disease patients and their communities. What special considerations should they keep in mind?

Mary Kay Koenig

One of the most important things is remembering it’s okay not to know everything. Many physicians—especially early in their careers—feel like they’re supposed to be the expert teaching the patient. But with rare diseases, the patients and families often know more about their condition than you do, unless it’s your specialty.

Don’t pretend to know more than they do. Be honest and say, “I don’t know that much about this—can you help me or tell me where I can learn more?” Patients appreciate that honesty. What they don’t appreciate is when a doctor dismisses their knowledge or contradicts their specialists without understanding the condition.

If you’re dealing with rare disease patients, listen to them. Admit what you don’t know. That goes a long way.

Michael Carrese

That’s a common theme we hear: listen to the patient. If you start there, things tend to go more smoothly. The second question is about general career advice. It’s always a complicated time to enter medicine—maybe even more so now with AI and other changes. You work with med students all the time, so what’s your go-to advice?

Mary Kay Koenig

Don’t get stuck on anything. I was sure I wasn’t going into pediatrics and sure I wasn’t going into neurology—and here I am. Never be certain about what you will or won’t do. Keep an open mind, especially at the start of medical school and even throughout your career.

Many physicians change directions because they realize their first choice wasn’t the right fit. This is a great field with so many different paths. The key is that you have to enjoy what you’re doing.

When you finish medical school, you don’t get a job as a doctor—you become a doctor. You are a doctor twenty-four hours a day, seven days a week. If you’re at the park and someone starts choking, you’re the one who steps up. It’s who you are. You need to love it and love your life. Find something you truly enjoy and do that.

Michael Carrese

That’s great advice. It’s better to stay open to opportunities rather than lock yourself into one path. Well, Dr. Koenig, this has been a real pleasure. Thank you for spending time with us and sharing your work.

Mary Kay Koenig

You’re welcome. It was nice talking with you too.