Genetics: The Cause and a Cause for Hope in Huntington’s Disease (Podcast)

A complex illness with no known cure, Huntington’s disease profoundly affects people in three life realms: physical and cognitive function, psychological health and bioethical issues related to genetic testing. Although a Huntington’s diagnosis can be life altering, the hope is that researchers soon will identify treatments capable of slowing or stopping the disease where it starts — in the genes.

So says neurologist Adam Margolius, MD, Director of the Huntington's Disease Clinic at Cleveland Clinic, which is designated a Center of Excellence by the Huntington’s Disease Society of America. 

In a podcast conversation with host Glen Stevens, DO, PhD, Dr. Margolius describes development of the condition, which begins with the Huntington gene.

“Everybody has two copies of the huntingtin gene, and everybody actually has a section in that gene where the DNA repeats itself over and over again,” he explains. “There's a little set of three, it's a trinucleotide repeat disorder. 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 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. From 35 to 39, they call that incomplete penetrance range, so some of those people develop Huntington's and some don't. And with 25 to 35, that person will not develop Huntington's but their offspring is potentially at risk of developing Huntington's.”

Treatment currently focuses on management of symptoms, including medications that can address chorea, the involuntary movements that are a hallmark of the disease. But gene therapy is “the near future and hopefully the definitive treatment for this disease,” says Dr. Margolius.

“Multiple drug companies are looking at different ways to modify that mutant huntingtin gene, making it so your body is not expressing it into protein. In some way — we don't really even know how — the mutant huntingtin protein is toxic to neurons and leads to cell death. So anything that DNA translates to RNA and then into protein, anywhere in that pathway, if we can stop that process, that's what the [investigatory] drugs are trying to do.”

In the latest episode of Cleveland Clinic’s Neuro Pathways podcast, Dr. Margolius discusses the following Huntington’s topics and more:

• Genetic mechanisms of the disease
• The pressing need for a multidisciplinary approach to care
• Genetic testing pros and cons
• Why psychology matters

Click the podcast player above to listen to the episode now or read on for a brief excerpt. Check out more Neuro Pathways episodes at clevelandclinic.org/neuropodcast or wherever you get your podcasts.

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Podcast excerpt

Podcast host Glen Stevens, DO, PhD: Let's (discuss) 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?

Dr. Margolius: That's probably the most common patient we see come in to get tested, 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 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. So things can get complex.

One thing I want to point out for asymptomatic patients: we do not test 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.

Dr. Stevens: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 ...

Dr. Margolius: We wouldn't do that because a child is not fully capable of making that decision. So we wait until they're 18. If that person develops 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, they are probably not specific enough to put the child through testing.

Dr. Stevens: What is the age cutoff for juvenile?

Dr. Margolius: There's no actual cutoff. I think there have been case reports of kids who are 3 or 4 developing symptoms — young children. But the older you are, the more common it is. So most juvenile Huntington's starts in teenage years or late teens.