The Challenge of Rare Disease Diagnosis with Heather Gatcombe, MD

Many thanks to Heather Gatcombe, MD, a physician and mother of a child affected by a rare mitochondrial disease. Her son experienced normal development until age eight, when he suffered a sudden stroke at school. After five years, he was diagnosed with a nuclear DNA mutation. Now 16, he has endured multiple strokes, hearing loss, and heart failure, but has successfully undergone a heart transplant and is currently preparing for college.

In addition to her clinical work, Heather serves on the Board of Trustees and the Scientific Medical Advisory Board Clinical Training and Education Committee of the United Mitochondrial Disease Foundation (UMDF). The UMDF is dedicated to raising awareness of mitochondrial disease, which can present in both children and adults—the average age of diagnosis is 30.

During our interview, Dr. Gatcombe highlighted the challenges of obtaining an accurate diagnosis for mitochondrial disease, noting that precise identification is essential for effective treatment. The UMDF offers free genetic testing, and two FDA-approved medications are now available for patients.

For more information or to support the UMDF’s mission, visit https://umdf.org. Physicians interested in continuing medical education can learn more at https://umdf.org/mito-university.

#mitochondria #raredisease #DNA

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Transcript

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[Heather Gatcombe, MD] (0:08 - 1:20)

Welcome to the Art of Medicine, the program that explores the arts, business, and clinical aspects of the practice of medicine. I'm your host, Dr. Andrew Wilner. I've planned a great program for today, but first, a word from our sponsor, locumstory.com.

Locumstory.com is a free, unbiased educational resource about locum tenens. It's not an agency. Locumstory answers your questions on their website, podcast, webinars, videos, and they even have a locums 101 crash course.

Learn about locums and get insights from real-life physicians, PAs, and NPs at locumstory.com. And now to my guest. Today, I have the pleasure of speaking with Dr. Heather Gatcomb. Heather is a physician and mother of a child with a rare mitochondrial disease. She's on the board of trustees and the scientific medical advisory board, clinical training and education committee at the United Mitochondrial Disease Foundation. Dr. Gatcomb is here to discuss her child's diagnostic odyssey and the need to increase awareness of mitochondrial disorders. Welcome Dr. Gatcomb.

[Andrew Wilner, MD] (1:21 - 1:23)

Thank you so much. Thank you for having me.

[Heather Gatcombe, MD] (1:24 - 1:33)

All right. Well, before we get into mitochondrial disease, tell us a little bit where you're coming from. What's your medical background?

And then we'll talk about your son.

[Andrew Wilner, MD] (1:34 - 2:14)

So I'm a radiation oncologist. I trained at Emory in Atlanta. I was in private practice for 10 years.

So I did community-based practice. I came back to Emory almost six years ago now. I primarily treat breast cancer with some palliative mixed in.

I did not know anything about mitochondrial disease until our disease journey began quite unexpectedly. How, let me ask, how did you, how old is your son now? He is 16.

He is turning 17 in two weeks.

[Heather Gatcombe, MD] (2:15 - 2:30)

Excellent. And when did you first suspect, you know, with babies, they all look great, you know, but then there's something that isn't right that makes you wonder, gee, is something wrong? When did that happen?

[Andrew Wilner, MD] (2:31 - 3:31)

That did not happen until second grade. So he had a normal childhood. He met all of his developmental milestones.

He was a smart kid. He was quick to learn skills. He was a very athletic kid.

He was a fast runner and sprinter. He was playing soccer and T-ball and swimming. And it was in second grade, we received a call from his school from, I believe it was the principal.

And they said, we think your son had a stroke because he couldn't move half of his body. He had a facial droop. He was weak on half of his body.

By the time the ambulance came, he was actually back to normal. So that terrifying phone call when he was eight years old was the first time anything medically off had happened.

[Heather Gatcombe, MD] (3:32 - 3:44)

So isn't that strange? Because we're going to talk more about how this is a genetic disorder, right? An inherited disorder or a spontaneous mutation, I guess, but such a late presentation.

[Andrew Wilner, MD] (3:45 - 5:12)

So, yeah. So many people think of mitochondrial disease as a disease of childhood and many severe cases present in childhood, but patients can actually die, be diagnosed in their 40s, 50s and 60s. It's a very heterogeneous group of diseases.

So primary mitochondrial diseases are caused by a DNA mutation, either in your mitochondrial DNA, that's inherited through your mother. And there's 37 genes on your mitochondrial DNA, but it can also be caused by a mutation on the nuclear DNA. And there's over 1500 genes that code for proteins in the mitochondria.

So it could be caused by mutations from both parents. And that's what was actually found with our child. It took us five years to actually get a genetic diagnosis after he first started having symptoms.

Some people, depending on how severe the mutation is, some patients can be stable for years until they have some type of stressor that precipitates symptoms. So some people can be diagnosed in adolescence, 20s, 30s, 40s, 50s. I met a woman at the MitoMed conference that the United Mitochondrial Disease Foundation holds in the spring.

She was diagnosed, I think, in her early 50s. Her only symptom was hearing loss at that time.

[Heather Gatcombe, MD] (5:15 - 5:56)

So I remember learning about mitochondrial disease in the context of epilepsy. I'm a neurologist and an epileptologist. And there was MIRF, MELAS, and Kerns-Scherr-Schei syndrome.

And those are the ones I had to memorize. And since then, I've seen only a very, very few cases that fell into those categories. But those were sort of clinical syndromes that I guess they're working out now, the genetics that go with the presentations.

[Andrew Wilner, MD] (5:58 - 6:33)

Correct. So we've only known about mitochondrial diseases for the past few decades. I think it was in 1988 that Doug Wallace identified the first mitochondrial DNA mutation.

But now with genetic advances in genetic sequencing, we're learning that more and more, there's very different variants of mitochondrial disease that can present. And so they're finding new mutations. They're finding mutations almost every month that we now know can cause a pathologic mitochondrial disease.

[Heather Gatcombe, MD] (6:35 - 6:43)

Were you able to determine what that particular stressor was that day in school that caused your son to have such dramatic transient symptoms?

[Andrew Wilner, MD] (6:43 - 7:19)

That's an excellent question. No. So normally, a metabolic stressor such as a fever or an infection or fasting or being exposed to heat could predispose someone to have decompensation.

But we did not identify any that day. It was a normal day for him in school. He wasn't overexerting himself at recess.

They were inside. They were in air conditioning. So I don't have a cause for the first time he presented.

[Heather Gatcombe, MD] (7:20 - 7:38)

You know, if he came to my department, we would rule it, look at it as a stroke or transient ischemic attack, and he'd have an echo and an MRI. And then we might talk about complicated migraine because it came and went. Is that what you heard?

[Andrew Wilner, MD] (7:38 - 8:33)

Yes. So our good friend who was actually a pediatric neurologist was on call. And the first thing he said is, you know, this is probably just a hemiplegic migraine.

I apologize for that. And so at first we thought everything was fine. His blood work was all normal.

His urine was normal. They did an LP. That was all normal until they did a brain MRI that saw some changes in the basal ganglia bilaterally.

And once he saw the MRI and they ruled out other types of toxic exposures, we were left with a diagnosis that this is probably mitochondrial disease. And we actually had that diagnosis for about three years before he had a muscle biopsy. And it was another two years before he had that DNA mutation found.

[Heather Gatcombe, MD] (8:35 - 9:07)

All right. So we've done some other programs on rare disease. And, you know, we always talk about it's a lot better to have diabetes, you know, because doctors know what they're dealing with.

And there's drugs on the shelf. And it's a lot more straightforward. But when you get something that only one in a million people have, then, you know, that's a lot tougher.

What, if you're a physician out there, you know, or a provider, a nurse practitioner, what should make you think that, hey, this could be mitochondrial disease?

[Andrew Wilner, MD] (9:07 - 10:20)

Excellent question. So as you know, there's mitochondria in every cell of your body, except for mature red blood cells. So that's the trouble.

It could potentially affect any organ system in the body and different types of mitochondrial disease can present differently, even within family members who have the same diagnosis. But the organs that require the most energy are the ones that are most commonly affected by mitochondrial disease. So the heart and the skeletal muscle are commonly affected.

So cardiomyopathies, exercise intolerance are very common symptoms. And as you said before, with epilepsy, seizures, or any unexplained lesions in the gray matter would also be suspicious for possibly for mitochondrial disease. And especially when you have a constellation where three or more organ systems are involved, and there's no other known diagnosis, that should make you suspicious.

And also hearing loss and actually diabetes, whether it's in a child or an adult is also suspicious for mitochondrial disease as well.

[Heather Gatcombe, MD] (10:22 - 10:36)

Back in the day, I remember as a resident, we used to do a bedside lactic acid test. I think we exercised the patient and then drew blood to see if the lactic acid was abnormally elevated. Do they still do that?

[Andrew Wilner, MD] (10:37 - 11:17)

So biochemical testing, like testing for blood lactic acid is done, but it's only elevated in certain kinds of mitochondrial diseases. So my son has never had a lactic acidosis when he's presented with a metabolic stroke or stroke-like episode. So it could make it suggestive of possible mitochondrial disease, but it doesn't rule out.

And that's why genetic testing is so important to identify the mutation, because we actually think there's a lot of undiagnosed patients out there that just have not been referred to specialists to get that diagnosis.

[Heather Gatcombe, MD] (11:18 - 11:23)

I remember also something about coenzyme Q. Is that a treatment?

[Andrew Wilner, MD] (11:24 - 13:05)

So many patients with mitochondrial disease are on certain mitochondrial or mito cocktails. For our son, they actually did functional testing on his, they did a muscle biopsy three years after he had his initial symptoms and genetic testing had been negative for three years. So they did the muscle biopsy.

I believe they sent it to Colorado and they did functional testing to see what parts of the oxidative phosphorylation pathway were not working well. And depending on which complexes were not working well, his doctors at CHOP in Philadelphia created a mito cocktail to help push that pathway through. So he is on a lot of antioxidants, including ubiquitinol.

So most patients with mitochondrial disease are in some type of mitochondrial or mito cocktail that's specific for them. And so their specialists can do functional testing. So our son, when they did his muscle biopsy, that was three years after his initial symptoms.

They were able to see that not only did he have less mitochondria in his muscle than he should have, but that they were not as functioning as well. His mitochondria weren't functioning as well. And which complexes weren't functioning as well.

So his team at CHOP created a cocktail that included a lot of antioxidants like ubiquitinol, vitamin D, vitamin E. So he has his own specific cocktail based on what abnormalities they saw in his biopsy.

[Heather Gatcombe, MD] (13:07 - 13:47)

Oh, just one general comment for those listening. This is why science is important. You know, you don't always know what the scientists are doing in the lab or how that's going to translate into some, you know, improvement of quality of life or economic gain.

But what we now understand about mitochondrial disease since the 40 years or so when I started learning about it is a lot more detailed and is allowing us to get in close to helping people like Dr. Gatcombe's son. So just a plug for science.

[Andrew Wilner, MD] (13:47 - 13:48)

Plug for science.

[Heather Gatcombe, MD] (13:48 - 14:01)

Let me ask though, why do you think that he was, you know, he was a runner, he was an athlete, that none of this presented earlier? What was different? Did it have something to do with adolescence or, you know, was there a change?

[Andrew Wilner, MD] (14:02 - 14:52)

It's a good question. So in many patients with mitochondrial disease that present later, they can be stable for years until their body just compensates until at one point it can't compensate anymore. So usually when he has a metabolic stroke or he loses the ability to move half his body, he develops an aphasia, he has an inability to speak, it's usually caused by some type of stress.

So either he was fasting for a procedure or he was under anesthesia prior to that, or he had an infection or a fever. So some type of metabolic stress or catabolic state kind of precipitated that, but he's had two or three where we don't know what the known cause is.

[Heather Gatcombe, MD] (14:53 - 15:03)

Now, I guess your son falls into the category kind of broadly of a child with special needs. Would you agree with that?

[Andrew Wilner, MD] (15:04 - 15:30)

You know, for a while I was calling myself the mother of a medically fragile child. He's in a good state right now. I mean, he does have some special needs.

He is on grade level. And I mean, he's a very intelligent, smart kid. And he's looking at colleges now, he's taking SAT prep.

So I think that's its own spectrum.

[Heather Gatcombe, MD] (15:32 - 15:55)

Well, I just wonder how you dealt with it emotionally, because it's kind of a big shock. Here you've got this normal kid, everything's fine. And one day he had a stroke.

And then you mentioned earlier, we were chatting, he's had a heart transplant and there's a lot of organs involved. And I mean, there's a psychosocial aspect to this that's not insignificant.

[Andrew Wilner, MD] (15:57 - 17:10)

Yes. I mean, it's been quite a journey. So the first time we received the diagnosis that this is probable mitochondrial disease, we met with a geneticist at the bedside when he was an inpatient.

And we were told you always need to be near a pediatric ICU, because if he has another metabolic stroke, it may not be reversible, the neurological symptoms. And that was terrifying. So that led to a fear for both my husband and I, that's still in the back of my mind.

You know, it kind of ebbs and flows depending on how well he's doing. He went into heart failure. It's been five years now.

Actually, five years ago from today, he was in the ICU. He was intubated. He was on ECMO.

And they were trying to place an LVAD so that he can be transitioned to eventually get a heart transplant. That was a horrible time in my life. And I only got through it because of support of friends and family.

[Heather Gatcombe, MD] (17:10 - 17:13)

Yeah. I was just going to ask you, what helped you?

[Andrew Wilner, MD] (17:14 - 17:42)

The people around me, the people around us, our community. We are lucky enough that we live in Atlanta and we have, most of my siblings are here. I'm the oldest of five.

My parents are here. My husband's parents were here. And we just have an amazing community of friends and family and friends that are basically family who just kind of supported us during that time and who still support us, whether I just need a vent to a friend.

[Heather Gatcombe, MD] (17:45 - 17:48)

Well, I guess you didn't want to leave him alone, right?

[Andrew Wilner, MD] (17:49 - 17:51)

Oh, when he was in the hospital?

[Heather Gatcombe, MD] (17:51 - 17:53)

No, when he was home, right?

[Andrew Wilner, MD] (17:54 - 19:08)

Yeah. So, I mean, there's different aspects of this. So when he had the LVAD, one of us always had to be physically with him at all times.

And then there was the fear of him going back to school, of this happening again after he had his first metabolic stroke. There was a lot of meetings with the school nurse and his teachers. And it was very raw and fresh and new then.

Now it's kind of become second nature. I've had that talk so many times with so many teachers. He's actually going on a school trip to New Orleans coming up with his high school class.

And so this is the first time he'll be going away without one of us. So there is a fear associated with that. I mean, we always have a game plan.

We always talk to the adults. We always make sure he's going somewhere where there is a wonderful children's hospital nearby. God forbid they need to go there for any reason.

It's better to have a plan, but we also, we want him to live a life. There's a fear that we have as parents, but I don't want to trap him in that fear. There's a balance, right?

[Heather Gatcombe, MD] (19:10 - 19:18)

So I want to take one step back for those of us who, well, for the audience who may not know what an LVAD is. Could you tell us what's that?

[Andrew Wilner, MD] (19:19 - 20:03)

So an LVAD is a left ventricular assist device. It's a pump that does the work of the left ventricle. It's implanted into the heart and it's a continuous pump.

So it's doing all the work that the heart would normally do, the left ventricle of contracting, pushing blood to the rest of the body. For him, it allowed his body to heal when he developed acute heart failure. After he had his LVAD, about six weeks later, he was then healthy enough to be put on a heart transplant list.

And he had his LVAD for four months before he was lucky enough to be gifted a new heart.

[Heather Gatcombe, MD] (20:04 - 20:20)

Let's talk about your son for a minute. How, what does he think about all this? Which part?

Like, gee, mom, I was just minding my own business going to school. Now I got an LVAD and a heart transplant. It's like, what's the deal?

[Andrew Wilner, MD] (20:22 - 22:36)

It's been an evolution. I mean, when he, so if I go back even further to when he had his first metabolic stroke, there was a state of, there was a fear there because he didn't know when it was going to happen again. And we didn't know what caused it that first time.

He is actually at a point where he knows when he's about to have a metabolic stroke. He almost has like a prodrome, like you have with a migraine, where he'll tell us, mom, I'm going to have an episode. He starts feeling funny and part of his body starts going numb.

Other patients can present differently, but this is what happens with him. And so it's scary, but he, he knows he needs to find an adult, tell them what's going on. Cause eventually, usually when he has a metabolic stroke, he loses the ability to speak.

Whether it's for minutes or hours or even a few days. And so the first part is finding support and help. With the LVAD, that was a much scarier process because he developed heart failure very suddenly.

My husband and I did not know what was going on. This was during the COVID epidemic. Everyone thought all his visits were telemedicine and everyone thought he had a GI viral illness, maybe COVID.

And we brought him in for a PCR test and for IV fluids. And they examined him and they listened to his heart. This is the first time anyone had listened to his heart because it had all been telehealth visits.

And they said, he's in heart failure and they rushed him. He was admitted urgently to the cardiac ICU. And it had, he, he deteriorated within, within 12 hours, he was on ECMO.

And then he woke up a few weeks later with the LVAD in. So he, he had no idea what was happening. We were able to speak to him before they put him on ECMO.

We had the ability to say, you know, you're really sick. They have to do a procedure to help your heart to rest. That was its own terrifying.

[Heather Gatcombe, MD] (22:37 - 22:39)

And what's, what's ECMO again?

[Andrew Wilner, MD] (22:39 - 23:28)

So ECMO stands for extracorporeal life support. It's basically doing all the work of the heart and the lungs. So for patients with severe lung failure, patients with severe heart failure, and all of your blood is being pumped outside your body and being oxygenated by a machine.

So he was in this cardiac ICU room where he had his own cardiac ICU nurse 24 seven. And then he had a separate cardiac ECMO nurse that just took care of the machine. And it's, I mean, it's terrifying.

You see this catheter with all of your child's, like if you dislodge that, I'm, it was, it was, it was horrible. I'm laughing, but I, I don't.

[Heather Gatcombe, MD] (23:29 - 23:33)

Your, your journey as, as parents has been more exciting than most.

[Andrew Wilner, MD] (23:36 - 23:38)

I hope no one else has to go on that journey.

[Heather Gatcombe, MD] (23:39 - 23:47)

Right. So tell us about your work with the mitochondrial disease foundation, which I guess it was your son's experience that aimed you there.

[Andrew Wilner, MD] (23:48 - 25:13)

Yes. So I have actually only been involved with the United mitochondrial disease foundation. It's been, it's been just over a year.

They reached out to me. They're an amazing organization, you know, after he had his heart transplant, I started getting involved with pediatric heart transplant research, nonprofits like enduring hearts. And then I got in touch with UMGF about a year.

It was about two years ago when they were posting about heart month is in February. And I was just sharing our son's journey and they reached out to me. And I went on their podcast.

It was my first podcast. And it was the first time I'd really publicly shared our son's story to the public. But I got such amazing feedback from other family members and friends, and actually from work colleagues that had a family member with mitochondrial disease.

And we didn't know that we were both going through the same journey. And that's why I realized, you know, it's really important to share your story to help others, especially for patients with mitochondrial disease. There are a lot of patients we believe who, you know, don't have a diagnosis or they're diagnosed too late.

And so that's really why I'm here talking to you today.

[Heather Gatcombe, MD] (25:14 - 25:23)

Well, you know, mitochondrial disease is not number one on my differential diagnosis when I see a young person with a stroke, but it's now moved up.

[Andrew Wilner, MD] (25:25 - 25:37)

It shouldn't be number one on your list. But if you see someone with stroke like symptoms, where their MRI, it's not in a vascular distribution, then that should be number one on your list.

[Heather Gatcombe, MD] (25:37 - 25:44)

Okay, well, I think that's helpful. And I assume that the United Mitochondrial Disease Foundation accepts donations.

[Andrew Wilner, MD] (25:44 - 26:36)

They do accept donations. They do such amazing work for our patients. We have support groups available for patients, including teens.

We hold a conference every year. It's called the MitoMed Conference. And it is an amazing conference because not only are there clinicians and researchers, but patients and families attend as well.

And so we have our own tracks, but we actually intermingle and mix for certain talks and for certain events. So it's very exciting and motivating to all be in the same room. We as families also get to vote on which grant proposals seem most promising with the researchers in the room.

So it's very exciting and motivating. And for the researchers in the room, they get to see the patients that they're impacting.

[Heather Gatcombe, MD] (26:39 - 26:47)

Dr. Gacom, this has really been informative and interesting and helpful. Is there anything you'd like to add before we wrap up?

[Andrew Wilner, MD] (26:48 - 28:16)

I would like to say, if you're a clinician and you see a patient who has three or more organ systems involved, especially if they have a history of cardiomyopathies or a family member with early death from a heart attack, maybe a family member has some hearing loss or diabetes. If you have a patient with unexplained stroke-like episodes or T2 or flare abnormalities in the gray matter, you want to consider mitochondrial disease. And the most important thing is getting these patients referred for genetic testing.

So referring to a medical geneticist. There is free testing available for patients. The United Mitochondrial Disease Foundation has grants available for free genetic testing.

And that is the gold standard to get patients tested so we can get patients diagnosed early. I would say that if we had had this talk six months ago, I would have said that there are no FDA-approved medications for mitochondrial disease. But we now have two.

My son's actually on one as a study drug. So there is hope on the horizon. And if you're a patient and you're interested in learning more, I would go to umdf.org or the United Mitochondrial Disease Foundation site to learn more information. And there's a lot of videos. Even for clinicians, they have a site called MitoU where you can earn CME credit.

[Heather Gatcombe, MD] (28:17 - 31:00)

Well, I like that. I might give that a try. Always need more CME credits.

Dr. Heather Gatcomb, thanks for joining me on the Art of Medicine. Thank you so much. It was a pleasure.

And now a final thanks to our sponsor, locumstory.com. Locumstory.com is a free, unbiased educational resource about locum tenens. It's not an agency.

Locumstory exists to answer your questions about the how-tos of locums on their website, podcast, webinars, and videos. They even have a locums 101 crash course. At locumstory.com, you can discover if locum tenens make sense for you and your career goals. What makes locumstory.com unique is that it's a peer-to-peer platform with real physicians sharing their experiences and stories, both the good and bad, about working locum tenens. Hence the name, Locum Story. Locumstory.com is a self-service tool that you can explore at your own pace with no pressure or obligation. It's completely free. Thanks again to locumstory.com for sponsoring this episode of the Art of Medicine. I'm Dr. Andrew Wilner. See you next time. This program is hosted, edited, and produced by Andrew Wilner, MD, FACP, FAAN. Guests receive no financial compensation for their appearance on the Art of Medicine.

Andrew Wilner, MD, is a professor of neurology at the University of Tennessee Health Science Center in Memphis, Tennessee. Views, thoughts, and opinions expressed on this program belong solely to Dr. Wilner and his guests and not necessarily to their employers, organizations, other group, or individual. While this program intends to be informative, it is meant for entertainment purposes only.

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