Huntington’s Disease

Podcast Transcript

Neuro Pathways Podcast Series

Release Date: October 15, 2025
Expiration Date: October 14, 2026

Estimated Time of Completion: 30 minutes

Huntington’s Disease
Adam Margolius, MD

Description
Each podcast in the Neurological Institute series provides a brief, review of management strategies related to the topic.

Learning Objectives

• Review up to date and clinically pertinent topics related to neurological disease
• Discuss advances in the field of neurological diseases
• Describe options for the treatment and care of various neurological disease

Target Audience
Physicians and Advanced Practice providers in Family Practice, Internal Medicine & Subspecialties, Neurology, Nursing, Pediatrics, Psychology/Psychiatry, Radiology as well as Professors, Researchers, and Students.

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  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
  
  Participants claiming CME credit from this activity may submit the credit hours to the American Osteopathic Association for Category 2 credit.

• American Nurses Credentialing Center (ANCC)
  Cleveland Clinic Center for Continuing Education designates this enduring material for a maximum of 0.50 ANCC contact hours.

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  A certificate of participation will be provided to other health care professionals for requesting credits in accordance with their professional boards and/or associations.

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  Successful completion of this CME activity enables the learner to earn credit toward the CME requirements of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

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Podcast Series Director
Andreas Alexopoulos, MD, MPH
Epilepsy Center

Additional Planner/Reviewer
Cindy Willis, DNP

Faculty
Adam Margolius, MD
Center for Neurological Restoration

Host
Glen Stevens, DO, PhD
Cleveland Clinic Brain Tumor and Neuro-Oncology Center

Agenda

Huntington’s Disease
Adam Margolius, MD

Disclosures

In accordance with the Standards for Integrity and Independence issued by the Accreditation Council for Continuing Medical Education (ACCME), The Cleveland Clinic Center for Continuing Education mitigates all relevant conflicts of interest to ensure CME activities are free of commercial bias.

The following faculty have indicated that they may have a relationship, which in the context of their presentation(s), could be perceived as a potential conflict of interest:

Glen H Stevens, DO

DynaMed Consulting

All other individuals have indicated no relationship which, in the context of their involvement, could be perceived as a potential conflict of interest.

CME Disclaimer

The information in this educational activity is provided for general medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options of a specific patient's medical condition. The viewpoints expressed in this CME activity are those of the authors/faculty. They do not represent an endorsement by The Cleveland Clinic Foundation. In no event will The Cleveland Clinic Foundation be liable for any decision made or action taken in reliance upon the information provided through this CME activity.

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Go to: Neuro Pathways Podcast October 15 , 2025 to log into myCME and begin the activity evaluation and print your certificate If you need assistance, contact the CME office at myCME@ccf.org

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

Glen Stevens, DO, PhD: Huntington's Disease is a rare, inherited neurodegenerative disorder that gradually erodes a person's physical and cognitive abilities. But behind the progressive symptoms lies a story of hope, one that includes advances in genetic research, multidisciplinary care, and a growing understanding of how to support patients and families through every stage of the disease.

In this episode, we'll explore how Huntington's Disease presents across the stages, the ethical complexities of genetic testing, and the promise of emerging therapies aimed at modifying disease progression. I'm your host, Glen Stevens, neurologist, neuro-oncologist in Cleveland Clinic's Neurological Institute. And joining me for today's conversation is Dr. Adam Margolius.

Dr. Margolius is a neurologist and Director of the Huntington's Disease Clinic at Cleveland Clinic, where he leads a multidisciplinary team recognized as a center of excellence for Huntington's care. Adam, welcome to Neuro Pathways.

Adam Margolius, MD: Thank you for having me today.

Glen Stevens, DO, PhD: So, let's start by having you introduce yourself to our audience. Where did you train and what do you do on a regular basis here at the Cleveland Clinic?

Adam Margolius, MD: Sure. I'm a neurologist, and then I got extra training in movement disorders, so I'm what they call a movement disorder specialist. Movement disorders is anything that makes you shake or twitch or any kind of involuntary movements. I did my med school in Cleveland at Case, and then I went to Northwestern for residency, and then Cleveland Clinic for Fellowship.

Glen Stevens, DO, PhD: Well, we're happy to have you here. So, not that long ago I saw the movie A Complete Unknown, which was the early stages, the '60s of Bob Dylan's life, and in the movie he meets his idol. He's 19 years old, he goes to New York City and he meets his folk idol, Woody Guthrie, who's hospitalized for some period of time. And I wasn't paying enough attention to the movie, I'm not even sure in the movie if they said specifically what his disorder was, but of course, he had Huntington's Disease and was hospitalized probably for at least the last 10 years of his life. And his mother died from Huntington's Disease, and I think a couple of his children died from Huntington's Disease. And in some ways, I guess it's too bad they didn't highlight that a little bit more in the movie to help with awareness of the disorder. But as a background, tell us a little bit of a brief overview of what Huntington's Disease is, how it presents, how it progresses, maybe the genetics.

Adam Margolius, MD: Sure. So Huntington's Disease is a neurodegenerative disorder, which means that brain cells die over time, gradually. It is genetic, it's autosomal dominant. So generally, for someone to have Huntington's, it means that one of their parents must have had it and passed it down. Each time someone with Huntington's has a child, there's a 50% chance that they pass on the Huntington's gene. For most people, they don't become symptomatic until their 30s or 40s or 50s, although it's a very wide range, both younger and older. So, someone won't know if they have the gene until they become symptomatic later in life or if they choose to get genetic testing. The symptoms that someone can experience are very variable, even within the same family, Huntington's can look very different.

In general, the symptoms can be grouped into three buckets, so to speak. One, which maybe we're most familiar with is the movement disorder aspect or the motor symptoms they call it. The cardinal symptom there is something called chorea, and that's a type of involuntary movement. It's different than a tremor. A tremor is more regular and predictable, chorea is more random or dance-like, they call it. And there are other motor symptoms too. Dystonia. Sometimes people can have symptoms that look like Parkinson's, a little bit Parkinsonism, they call it, and a multitude of other things. Also, gait and balance disorders, that sort of thing. So, those are the motor symptoms. Then there are cognitive symptoms which progress to dementia. It's mostly frontal lobe impairment. So decision-making, planning ahead, there can be personality changes, that kind of thing. Last bucket is psychiatric symptoms. Most common are depression, anxiety, apathy is very common, lack of motivation. And then more rarely you can see things like psychosis.

Invariably, as time goes on, people will develop symptoms from all three of those groups, but early on it can present with any of those symptoms that I listed.

Glen Stevens, DO, PhD: And what generally brings people in to say, "I need to get evaluated?" Other than I guess if they knew they had a family member that has it.

Adam Margolius, MD: Yeah, so that'll be the most common thing, is someone grows up with Huntington's in their family and they know that one of their parents has it. So at some point in their life, they learn that they're at risk, and then they can choose whether or not to get genetic testing. And it's a personal choice, so some people will come in when they want to basically be able to plan for the future and not have that uncertainty anymore. So, that's the most common reason people come in to get tested.

But people also might not know their family history. Maybe they were only raised by one parent, or for a variety of reasons they might not know that Huntington's was in their family, or it could have been misdiagnosed. There's lots of things we see. So then they might develop neurologic symptoms and get referred to a neurologist and an astute neurologist will say, "Hey, this could be Huntington's," and they'll refer them to us for genetic testing.

If they see chorea and identify it correctly, that's probably the main reason that someone would come from a neurologist. Sometimes a psychiatrist will refer people to our clinic if something's not sitting right and there's a strong family history of neurologic disorders. Those are the main reasons, I'd say.

Glen Stevens, DO, PhD: So, talk to me a little bit about the concept of anticipation and how that affects future family members and what does it do too?

Adam Margolius, MD: Yeah, so let me take a step back first, just about the genetics of Huntington's in general. The gene that we're looking at is called the Huntington gene. Everybody has two copies of the Huntington gene, one from each parent, and everybody actually has a section in that gene where the DNA repeats itself over and over again. There's a little set of three, it's a trinucleotide repeat disorder. So, the section that repeats is CAG, so they call it CAG repeats. It's normal to have somewhere between 10 to 25 of those repeats, and then those people will not develop Huntington's. If you have 40 or more of those CAG repeats, then if you live a normal lifespan, you will develop symptoms of Huntington's Disease. In between 25 and 40 is a little bit of a gray area. From 35 to 39, they call that incomplete penetrance range, so some people develop Huntington's, some don't. And 25 to 35, that person will not develop Huntington's but their offspring is potentially at risk of developing Huntington's because of that phenomenon you asked about called anticipation.

Anticipation is a genetic term for when someone with trinucleotide expansion has children. The number of repeats can expand. I think you asked why that happens. I don't know if I have a great answer for that. That's a genetics type question. It tends to happen, and this I think for reasons we don't know, but it tends to happen more in males or fathers. So, when fathers have children, that number tends to expand a little bit, usually just by one or two, sometimes more, sometimes stays the same. And when a woman with Huntington's has a child, if they pass on the abnormal gene, usually that number stays the same, although it can grow a little bit sometimes too.

Glen Stevens, DO, PhD: My understanding is male-female is pretty much one-to-one though, right?

Adam Margolius, MD: Oh, in terms of prevalence of disease?

Glen Stevens, DO, PhD: In terms of prevalence-

Adam Margolius, MD: Correct.

Glen Stevens, DO, PhD: ... of the disease, right.

Adam Margolius, MD: Yeah, because whether you have a son or a daughter, it's still going to be a 50% chance.

Glen Stevens, DO, PhD: Obviously a somewhat difficult question just to answer, but how do you distinguish when you see somebody coming in that has Huntington's Disease from some other movement disorder?

Adam Margolius, MD: Well, what I tell patients, the way to get a definitive answer is the genetic testing, and without that, you're making educated guesses mostly. If that patient had a family member who had genetic testing, which showed Huntington's, and then they have neurologic symptoms that could fit with Huntington's, that's actually enough to make the diagnosis too. So, you don't necessarily need genetic testing as long as you have a confirmed family history.

That chorea is a pretty unique symptom in movement disorders. If it's not coming a side effect of a medicine, if someone develops chorea spontaneously and gradually, it is very likely to be Huntington's, actually. There are other genetic causes too, but they're a lot less likely.

Glen Stevens, DO, PhD: And so, a person comes in to see you and you want to order genetic testing. We'll go into this a little bit later, we won't go into too much detail right now, but can you order it, or do you have to send them to medical genetics?

Adam Margolius, MD: We have a geneticist or a genetics counselor, I should say, in our clinic. So we work together. Anytime someone comes in for new testing, they'll actually have three appointments. They'll see me, they'll see our genetics counselor, and we actually have them see a psychologist also. You mentioned at the beginning that we're a center of excellence, that's the designation from the HDSA or Huntington's Disease Society of America, founded by Mrs. Guthrie. Their recommendation for testing involves those three appointments.

The reason we have a genetics counselor is to explain what those numbers mean, what they might get for results with the CAG repeat, and what a positive or negative result means for other family members, that sort of thing. And we actually have everyone see a psychologist too, to explore a little bit about why they're getting tested because it is optional. Sometimes people come in because they feel like a family member told them to or even their doctor might've told them to, and they don't necessarily realize that it's optional. We also want to make sure someone's not severely depressed at the time of testing, because getting that result is life-changing news, and I don't believe it's ever happened at our center but there have been reports of suicide after getting an abnormal result. So, that's part of the reason for the multidisciplinary care in that step.

Glen Stevens, DO, PhD: And if I'm a private practice neurologist listening to this, can I... I know you have very complex system with other people involved, but could I order the test or myself? Is there a send-out you can do it, or?

Adam Margolius, MD: There's nothing stopping you from ordering the test. And people do do that, but I would say I would recommend that refer the person to a center of excellence to get tested. Often, we've seen people who were tested by a primary care doctor or a local neurologist, and then they get their results over the phone and no one can tell them what that means or offer support to them or tell them what the future looks like or tell them what the next step should be. So, patients can be in a very tough spot after testing if it's not done appropriately.

Glen Stevens, DO, PhD: Yeah, it's a good point. With opening of the medical record, we see this so much now. Patients will be able to look at their MRI, they'll be able to look at a lot of their medical records, but they can't really interpret it. And it's kind of the good news, bad news, right? You want patients to have full access, but I think most of us would like to be able to see a patient and talk to them about their findings before they're reading it and then misinterpreting it or have a five-alarm fire at their house because of what they perceive it to be. And as you said, in extreme cases, do something dramatic that would be a very unfortunate thing to have done.

So, somebody comes in to see you and they have a diagnosis of Huntington's. Treatment, what do you tell them?

Adam Margolius, MD: Well, so yeah, generally we'll do our assessment first and see where they stand, what symptoms they have and what's affecting their quality of life. There's no cure for Huntington's right now, so that treatment is focused on symptom management. So we try and figure out what symptoms are bothersome or affect their quality of life, and then go from there. So, all those types of symptoms that I mentioned at the beginning, they do all have treatments, symptomatic treatments. So not disease modifying, but we do have medicines that can lessen the chorea, the severity and the kind of amplitude and body parts involved, and can have it lessen the effects that it has on their ADLs or activities of daily living. And then we have medicines of course for anxiety, depression, that sort of thing. Even memory there are things that we try sometimes.

Yeah, the number one thing, many patients come in with chorea, but I think it's really important to figure out how the chorea is affecting them. The medications that we have help, they don't make it go away completely. So, that's not a realistic goal for most people. If someone has chorea and it's not bothering them at all, generally we're not going to treat that. If someone has chorea and it's either socially bothersome or it's affecting their ability to eat or perform hygiene activities, that's when we think about the medicines that we have that can suppress chorea.

Glen Stevens, DO, PhD: Well, that's what I was going to ask you, is that, does the chorea bother the patient much or is it bothering the loved ones more? Is it painful? Is it-

Adam Margolius, MD: Oh, and there's no pain with it.

Glen Stevens, DO, PhD: Okay.

Adam Margolius, MD: Yeah, there are exceptions to that when it's very high amplitude and people can injure themselves and can lead to pain that way. Or as you can imagine, if you have some arthritis and then you have a lot of involuntary movements. So, indirectly there can be some pain, but the movements themselves generally are not painful. It is often more distressing to a caregiver or loved one. It might just be a reminder that we're living with this disease or it just makes it hard to forget and then do a normal activity without thinking about Huntington's. Usually, the patient's less likely to be bothered by it. Sometimes they are, often they're not.

Sometimes you'd be surprised, even with moderately high amplitude movements, the patient might not even be aware that they have chorea. I've seen patients who are moving all over and I always ask kind of objectively, "Are you having any abnormal movements that you've noticed?" And sometimes they say "No." That anosognosia is the term for that when they're not aware of the neurologic symptoms they're having that's very common in Huntington's.

Glen Stevens, DO, PhD: Is it usually bilateral?

Adam Margolius, MD: Yeah, it tends to be generalized. So, it's usually symmetric and bilateral. Sometimes for whatever reason, it can appear asymmetric or start asymmetrically first. But yeah, it tends to be bilateral.

Glen Stevens, DO, PhD: And sleep, does it suppress in sleep?

Adam Margolius, MD: Like most movement disorders, it should completely stop in sleep. If a caregiver or their spouse says, "No, I think it's still happening when he's sleeping," then you say, "Maybe they're pretending to sleep." They're not quite fully asleep if they're still having chorea.

Glen Stevens, DO, PhD: The utility of an MRI scan?

Adam Margolius, MD: Low. Yeah, unless we see some sort of red flag that makes us think there's something besides Huntington's going on, we're not routinely ordering MRIs. There are changes you can see on an MRI. Atrophy, especially of the caudate, it's part of the basal ganglia, although the atrophy does go on to become global. But whether you see that atrophy or not and how severe it is, doesn't affect how we treat someone. So, you wouldn't make the diagnosis doing an MRI, by the way. The genetic test is the way to make that diagnosis if you suspect Huntington's.

Glen Stevens, DO, PhD: Well, as I imagine how things go these days, most people probably come in with an MRI, they've already had one.

Adam Margolius, MD: Yes, correct.

Glen Stevens, DO, PhD: Not that you would necessarily order, but they probably have one. So, utilization of a medicine called tetrabenazine. Can you talk about its use in this disorder?

Adam Margolius, MD: Yeah. So, tetrabenazine is one of those medicines that can suppress Chorea. Tetrabenazine, I believe, has been around since the '70s or so, it's been around a long time. Somehow it's still pretty expensive often. There are a couple newer medicines which tend to be preferred to tetrabenazine, but really, they're just modifications of tetrabenazine. Valbenazine and deutetrabenazine, main difference being that they have a longer half-life. Probably they cause less side effects because of that more blood level and without those ups and downs, although they haven't really been compared well head-to-head. So, those newer medicines are the ones we tend to prescribe these days.

Glen Stevens, DO, PhD: And the mechanism of action of the tetrabenazine?

Adam Margolius, MD: So, all three of those drugs, tetrabenazine and the two analogs are what they call VMAT2 inhibitors. So VMAT2 is a channel on the presynaptic side of a synapse. In the vesicles there, that's the little containers that load up neurotransmitter. It's a VMAT2 inhibitor, excuse me. So VMAT2 is the channel that loads dopamine into those presynaptic vesicles. If you have less dopamine in those presynaptic vesicles, then there's less dopamine being passed on from neuron to neuron, and that helps to suppress these movements. So actually, dopamine antagonists or medicines that block dopamine suppress chorea also. So, any anti-psychotic can actually be helpful for chorea too, and can help some of the psychiatric symptoms that our patients have. So, we end up using those a lot in our clinic also.

Glen Stevens, DO, PhD: So, my recollection is that Parkinson's, they don't have enough dopamine. So, are we initiating or putting people at risk or they're young when they start these things so the risk is lower, or do they get slower? Do they get [inaudible 00:17:19]?

Adam Margolius, MD: Yeah, so we're not causing Parkinson's disease. You can cause drug induced Parkinsonism. These VMAT2 inhibitors like tetrabenazine are less likely to cause drug induced Parkinsonism as compared to an actual dopamine antagonist, but it can still happen. In the trials where they got approval, FDA approval in the Huntington's population, apparently they did not see any drug induced Parkinsonism, though in clinical practice I think we see it occasionally.

Glen Stevens, DO, PhD: Are there non-drug treatments?

Adam Margolius, MD: For chorea, probably not. There are things that are good for your health in general that will lessen your chorea. So, people who are sleeping better, not in pain, have euthymic or good mood, their chorea will be less as compared to someone who has no regular sleep cycle and is depressed or anxious. So, there are indirect ways to modify chorea.

Glen Stevens, DO, PhD: What are you excited about in the pipeline?

Adam Margolius, MD: So, most of the research currently, all those drugs we talked about are symptomatic treatments for chorea. Most of the research is looking for a disease modifying drug or something to slow the progression of Huntington's Disease. And these days, most of those drugs are genetic therapies. So, they're in one way or the other, trying to target that mutant Huntington gene itself. It's challenging, drug delivery into neurons is very difficult to begin with. And then by the time these people are enrolled in clinical trials, the cellular processes are already probably somewhat far along, so that can make it harder to show benefit from these drugs. So, the most recent studies are aiming towards earlier, milder, less symptomatic patients.

Glen Stevens, DO, PhD: Which I guess would also, and we'll get into this in a sec, but will also lead to earlier testing before people are necessarily symptomatic, which-

Adam Margolius, MD: Currently it's one reason that you might, another reason that someone might want to get tested is so that they can participate in research as soon as they're eligible for it. If one of these drugs ends up working, then there will probably be a big change in how we do testing, because if people are eligible for that drug before they have symptoms, we should be offering testing to everyone and let them know that the stakes are a little bit different. There's a more definitive reason, a concrete reason to know your status.

Glen Stevens, DO, PhD: Do we have any clinical trials here currently?

Adam Margolius, MD: We are being evaluated for some, we don't have any drug trials currently. We do participate in an observational study, the biggest Huntington's Disease registry called Enroll HD. But hopefully, in the next 12 months we'll start at least one disease modifying trial here.

Glen Stevens, DO, PhD: So, let's move over to the ethical dilemma of testing. My father has Huntington's Disease. I'm 30 years old, thinking about getting married, doing fine, not having a problem. I come to see you and I say, "I got a 50/50 chance that I'm going to get this disorder. I'm fine right now. I want to get married and have kids." What do you say to me?

Adam Margolius, MD: Yeah, so that's to me, everything you've said is reasonable. And that's probably the most common patient we see who's coming to get tested is someone who wants to plan ahead, thinking about children and that sort of thing. Even when someone knows their gene status, there are ways through IVF to make sure that they don't pass the gene down to their own children. So that is actually a good reason to get tested if you're planning to have kids.

Things can be more complex if someone already has children. Say someone's in their 40s and they have children in their early 20s. Now, if that person in their 40s finds out they do or don't have Huntington's, that affects the risk of their children. Even more complex, maybe the child wants to get tested, a 20-year-old, and their dad is 40 and they don't know their status. If the 20-year-old has the Huntington's gene, that means they inherited it from their father, so that person is in a sense being tested even though they didn't participate in the consent process and all that. So, things can get complex.

One thing I want to point out for asymptomatic patients, we do not test children, anyone under the age of 18. The person needs to be able to make that decision on their own, and that means they have to be an adult to do so.

Glen Stevens, DO, PhD: Yeah, I was going to ask you that. If I'm 13 and I say I want to get tested and my parents say they want me to get tested.

Adam Margolius, MD: Yeah, even no matter how many people say they want to get tested, yeah, we wouldn't do that because that as a child, they're not, in the way we view things, not fully capable of making that decision. And right now there's no treatment, so that we wait until they're 18. Things can be different. If that person might be developing symptoms of Huntington's, which can sometimes happen in teenage years, we call that juvenile Huntington's Disease, then we would do testing if we were concerned that something they're experiencing could be a symptom. Usually, we'll only do that if there are motor symptoms, if someone has some trouble in school or attention issues or something like that, probably not specific enough to put the child through testing.

Glen Stevens, DO, PhD: Yeah, that's where I was going to go next was the juvenile. What's the age cutoff for juvenile?

Adam Margolius, MD: There's no actual cutoff. I think there have been case reports of kids who are like three or four developing symptoms, young children. The older you are, the more common it is. So most juvenile Huntington's is starting as a teenager or late teens.

Glen Stevens, DO, PhD: And it's also a disorder with the trinucleotide repeats?

Adam Margolius, MD: Exact same, except those patients will tend to have higher numbers, usually 50 or higher or even 60 or higher.

Glen Stevens, DO, PhD: And I would assume a more rapid progression, but maybe not?

Adam Margolius, MD: Yeah, I think slightly, but not as much of a difference as you'd think. Yeah. So, if someone is developing symptoms as a teenager, just like if you're developing symptoms as an adult, average, although it's a wide range, maybe 20 years from time of diagnosis to time of death, some patients much longer, some patients shorter.

Glen Stevens, DO, PhD: And the cause of death typically is what?

Adam Margolius, MD: Similar to the end stage of other neurodegenerative disorders. So, there might be swallowing difficulties that develop later in life, which can lead to aspiration pneumonias, which can lead to complications from that, it can lead to death, or from the gait and balance disorders, big falls with head injuries, broken bones, that kind of thing. Towards the end, weight loss can be progressive and that can lead to issues that can lead to end of life also.

One other thing that's unique about Huntington's, often these patients are impulsive, often they have high rates of depression like we talked about. So, that combination leads to a high rate of suicide attempts. So, that's a not uncommon way of end of life. That's one of the reasons that we emphasize the multidisciplinary care in our clinic, including psychologists, therapists, psychiatrists, to treat all aspects of the disease.

Glen Stevens, DO, PhD: Yeah. I think the tagline is that if you're having Huntington's patients and you're... I'm a solo neurologist and I have Huntington's patients, they probably should be seeing a multidisciplinary group, I would think.

Adam Margolius, MD: Yeah, that's what I would recommend. If it was a friend or family, I would certainly refer them to a multidisciplinary clinic, one of the centers of excellence. That being said, some neurologists are doing a good job, especially when they have those networks already of psychiatrists they can refer to and get in with quickly, and their own social worker and all these other resources that you need. It's much harder for someone to do that on their own. I think that's what these centers of excellence are for.

Glen Stevens, DO, PhD: And so go through again the members of the team. It's a neurologist, geneticist?

Adam Margolius, MD: Genetics counselor.

Glen Stevens, DO, PhD: Genetics counselor, psychologist.

Adam Margolius, MD: Uh-huh, so we have a couple psychologists that contribute to our Huntington's Clinic. I will say in the clinic, on our Huntington's Clinic day, it'll be a psychiatrist, me, the neurologist, genetics counselor like you mentioned, and probably our most important team member is social worker.

Glen Stevens, DO, PhD: Yeah, I think we can't underestimate the importance of it. I'm sure the dynamics and the difficulties would be significant.

Adam Margolius, MD: Yeah, because this is a genetic disorder it's affecting generations of these families. So, often those support networks that might be there for other neurologic diseases aren't the same. So, that can lead to challenges.

Glen Stevens, DO, PhD: Percentage of cases that are sporadic?

Adam Margolius, MD: It depends how closely you look at it, probably, because truly sporadic, we mentioned that thing called anticipation. So, there are some people who have a repeat number of say 36, don't develop symptoms of Huntington's, and then their kid does. That can happen. It's a minority, I'd say less than 10%. More often, a person might die at a younger age from cardiac death, car accident, whatever else. So even though they were going to go on to develop Huntington's, they didn't have that chance.

Other possibility, especially longer ago, someone presents with neurologic symptoms. They get diagnosed with a neurologic disease, but it's not the right one. So then they'll say, "Oh, everyone in my family has Parkinson's. They all got it, my dad, my dad's brother all got diagnosed with Parkinson's." But then as you ask them more about what they know from the family, probably it was Huntington's and just misdiagnosed.

In a Parkinson's patient, when they take a Parkinson's medicine, as a side effect, they can get involuntary movements that are chorea form, those dyskinesias from levodopa. And at that point, once they're already on Parkinson's medicine, then they can be tough to tell. If they have those irregular movements before the Parkinson's pill, that's when you should be thinking about Huntington's.

Glen Stevens, DO, PhD: So you alluded to this a little bit, but the research and treatment, where's it going?

Adam Margolius, MD: Genetic treatments are the near future and hopefully the definitive treatment for this disease. Multiple drug companies are looking at different ways to modify that mutant Huntington gene, make it so your body is not expressing it into protein. In some way, we don't really even know how, the mutant Huntington protein is toxic to neurons and leads to cell death. So, anything as that DNA is translated to RNA and then into protein, anywhere in that pathway if we can stop that process, that's what the drugs are trying to do now.

Glen Stevens, DO, PhD: Well, I'd like to look at the bright side of things, and with dementias now, we can give drugs that can clear amyloid from the brain. So, I know it's a different process, a different drug, a different mechanism of action, but we are making strides, we're making movements, so we'll all be hopeful.

Adam Margolius, MD: And Huntington's, in my mind, there's even more reason for optimism because the relationship between your DNA and the disease is so clear, whereas in these other neurodegenerative disorders, it's less clear what role the amyloid or whatever protein is playing in the disease. There are a lot of challenges. Like I said, you have two Huntington's genes. One's a normal number, one's an abnormal number. That Huntington's protein is necessary for normal brain development in life. So whatever treatment you have, you can't completely knock out the normal Huntington's protein, at least not early on.

Glen Stevens, DO, PhD: Well, that's an important point, for sure. Final takeaways or something we haven't talked about that you think is important for the audience?

Adam Margolius, MD: I'm optimistic about treatment, about the future. I think in my career, hopefully in the next five years, there's going to be major breakthroughs in Huntington's. But I would say the most important takeaway is even though we don't have a cure now, there is treatment available that helps patients. It helps their families, it helps caregivers, it helps improve quality of life. So, if you come across patients with Huntington's, I would recommend finding whatever center of excellence is near them, then referring them that direction, I think you'll be doing them a big favor.

Glen Stevens, DO, PhD: Well, I couldn't agree more with you, Adam, and appreciate your joining us today, and best of luck.

Adam Margolius, MD: Thank you. Thanks again for having me.

Closing: 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 for further learning, 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 the Cleveland Clinic Neurological Institute on LinkedIn. And thank you for listening.