Ep 69 Huntington’s disease: Let’s talk frankly

when I found out. I guess I was twenty eight, I'd just been married, you know, there's so much optimism, and then I find out for my parents that there's this terrible shadow, you know, that's going to be potentially hanging over my life. And it was.

coordination issues, balance issues, also difficulty swallowing and drinking. So that's how it's starting to affect me, and it got to a point where I was ready to be tested, and so I did that, I guess a few months ago actually, and now I have the official results that I'm positive for a huntidian disease. At that point, I guess it wasn't as bad as I thought. Actually, to get those words for me, it was, I guess, a little bit freeing to finally have some solid answers and

to know what my reality would be. You know, I'm really lucky to have a really supportive husband with me. He's been a rock for every step of the way, being understanding for all my decisions. One in particular is that I feel really strongly that I don't want to pass this on to my children. I know that's maybe a controversial opinion, but I just can't imagine potentially burgeoning them with this same difficulties that I'm experiencing. So we'll

be using IVF. They have this cool technology where they can test the embryos, and that's the route we'll be taking. But obviously it's also time consuming and expensive and not a guarantee.

my aunt also possibly my brothers. So it's really difficult to not feel like you're being a burden if you want to, you know, share your feelings with your family members and reach out to them without being potentially a burden to them when they are also dealing with this kind of stress, and also being a burden to my husband. Of course, eventually you know he'll be caring for me more and more.

talked to about it. But we don't even know how to tell our friends about this because we just don't have we don't have the words, and we don't know how to. I guess like we're not looking for sympathy, but we also don't. It's we don't want to keep it a secret, and given that it's not something that can be cured like cancer or COVID, this is something that is not going away, and I think that has been one of the really stressful parts. We haven't really figured out a good way to to share with it

with those that are even closest to us. I think that has definitely weighed on me. At least two have this information and not be able to really talk to people about it yet because just we don't know how. Another thing that we've kind of been thinking a lot about is just, you know, like, what do we do right Unlike some diseases again that do have cures, when

do we need to tell insurance? Because we definitely will want some of you know all as much of the care to be covered by insurance, but that's not something that a lot of people have been able to give us advice on, or there's not a good rule book or a guidebook out there. And because everybody's path with hunting teens is different than the solutions and how they

resolve it are all different. I think one of the really difficult parts is that Jay's grandfather showed symptoms in his eighties, and his path and how he dealt with it was very different than her father, who was in his fifties when he was diagnosed, and that's very different

from Jay, who started displaying symptoms in her thirties. And so there's even when we look for comparisons to how to manage and how to deal with it, we don't have a particularly good role model or something to compare to, and we're kind of going at our own pace, in our own direction and hoping that we get it right, but also being really aware that we don't have a lot of flexibility that we have to get it right the first time, because all these days are precious.

are bad. But it's my reality now. And you don't really have a choice anymore, right, You just have to. You're on the train, so you kind of have to deal with it. And I guess that's been how I'm trying to look at it, and hopefully I can just keep some optimism as things progress, you know, despite what might come.

to have disease. So that's already different from the other two genetic disorders that we've covered in the past, namely sickle cell and cystic fibrosis, which are both autosomal recessive, so you have to have two copies of a mutated gene in order to have disease. But before we can actually talk about Huntington's disease, I think we need to step back and talk about our genes in more detail than I think we have on this podcast, at least recently.

So here's where road begin. Our DNA is made up of little building blocks like legos, called nucleotides, which we give letters A, T, C, and G. So three of these nucleotides grouped together form what's called a codeon because that is what codes for an amino acid. Well, it codes for RNA, which codes for amino acids, but will ignore them. Right, Okay, when you string a bunch of amino acids together, you get essentially a protein scattered throughout

our genome. Throughout not just human genomes, but like every genome animals, plants, bacteria. We have these short repeat sequences of nucleotides that are called microsatellites. They are like one to six nucleotide sequences that are repeated like tata ta, all in a row. So that's some basic definitions. Now on this podcast we talk a lot, usually in the context of viruses or bacteria, but this is true for

human cells too. How every time our cells or any cell replicates, it sometimes makes mistakes, and we call these mistakes mutations. Most of the time, these mutations result in like a single or small base pair change like one addition or a deletion, or a substitution like a T

for an A or something like that. But within these repeat regions, these microsatellite regions, a single mistake can lead to very big changes because what it often leads to is the gain or the loss of an entire repeat sequence.

So how does that happen. We don't fully know, but we think that what happens is that as our DNA polymerase that's helping to replicate our DNA is chugging along copying tatata all in a row, it kind of slips out of position and then it loses its place, and when it picks it back up, it does so earlier

along that DNA chain. So if you have a region that's like TATA four times in a row and it gets a little bit wonky during replication, the next cell as after it replicates, would end up with TATA like six times in a row or eight times in a row. So that's microsatellites. They exist throughout our genome, and the mutation rate tends to be higher in these repeat regions

than in other parts of our genome. And the longer a microsatellite region is, the more likely it is that this type of slippage and mutation can happen, and the more likely that the mutation results in large changes, especially expansion or growing of those regions and getting longer. So

let's talk about how that relates to Huntington's disease. Yeah, Huntington's disease is a disorder that's known as a trinucleotide repeat disorder, So that means it's caused by an abnormal number of trinucleotide three nucleotides in a row C, A, and G that repeat a whole bunch of times. Aka, this is a microsatellite.

where on chromosome four. There's a series. In everyone where we have this microsatellite, we have these CAG repeats, But in the vast majority of the population we have anywhere from five to like twenty eight copies of CAG all

in a row. And another thing that's important about this repeat on chromosome four is that it's located in what's called an exon or a coding region, which means that our body, every human body and other animals too, we make a protein from this region that's called Huntington that's

really clever name. But now we know that these microsatellite regions can sometimes be unstable and expand, And it turns out that once you get to above twenty eight re repeats, that is when this region becomes unstable, and that means that when those cells replicate, that particular region is likely to expand. It could contract, but it's more likely to expand, and once it expands above forty repeats, that is when a person will develop Huntington's disease.

kind of like a gray zone. But essentially, the reason why once you have a certain number of repeats you end up with disease is because that trinucleotide repeat is located in an exxon in a coding region, So that abnormally long set of repeats causes the production of an abnormal Huntington protein, and the more this repeat expands, the more abnormal this protein is, and probably the more abnormal protein you are producing as well.

We think that it's involved with like trafficking of stuff inside of the cell, like moving things from one place to another within the cell, within a cell, within a cell. But we don't know that for sure. We don't know the real function of normal, typical what they call wild type Huntington protein. But that still doesn't answer the question

of like, how does this actually cause disease? Like, Okay, we have an abnormal protein, so what Yeah, the short answer, I'm going to try and give the shorter answer, even though I think it's going to be less satisfying. Don't we don't really know.

of this abnormal protein is what's involved. It's not that the Huntington protein is no longer doing whatever Huntington protein is supposed to do. It's that it's doing something new and different and.

And while Huntington protein is found kind of throughout our body, like this gene is expressed in a lot of different tissues for whatever reason, this abnormal protein causes damage primarily to the central nervous system. So that's why we see this as a neurodegenerative disease, because it's causing cell death in neurons.

So while we do see eventures the entire brain becoming involved and like widespread atrophy, this striatum of the basil ganglia is the first and hardest hit area. So what is the basil ganglia? We actually talked about this way back in our encephalitis lethargic at episode a million years ago. Do you remember that?

us to the symptoms of Huntington's disease. The characteristic symptoms which gave Huntington's disease an earlier name that I'm sure you'll talk about, Aaron. The characteristic symptoms are Korea or

Korea form movements. These are involuntary motor movements especially in the extremities, so like arms and legs, fingers, and toes, the involuntary movements, they're kind of like muscle twitches essentially that usually start out early in the course of disease in smaller muscles, so like fingers, face twitches that, especially early in disease might not be noticeable to anyone other than the person who's experiencing them, like you wouldn't even

notice them, and they might not interfere very much at all with daily life. But eventually they spread to affect essentially any or every voluntary muscle, which includes the muscles of the face and the throat that are involved in talking, chewing, swallowing, and so then dysarthria, which is difficulty speaking, can become a problem, as well as dysphasia or difficulty swallowing and eating, which is very problematic.

disease as well. You have a lot of rerigidity in Parkinson's disease, right, Yeah, So of course, all of these symptoms can have huge effects on a person's activities of daily living. Things like walking become very difficult and can result in frequent falls, which can be very dangerous. But even activities like getting out of bed, showering, getting dressed, all of these can become difficult because you don't have

control over the movements of your muscles. And then dysphasia, so difficulty swallowing is particularly problematic because that can result in aspiration of food into the lungs, which can result in pneumonia. But Huntington's disease is not just a motor disorder, which is why the old name is no longer the name. Huntington's causes a range of neurocognitive, and psychiatric changes as well.

So first, not first in terms of the course of disease, but just first of what I'm going to talk about is depression, which is far more common in people with Huntington's disease than in the general population, and I think what's important is that it might be easy if you just aren't thinking, to dismiss this as the result of being diagnosed with an incurable fatal disease. But it's not

just that. Even though we don't fully understand depression in general and the effects of depression on the brain, or every single change that happens in Huntington's disease in the brain, we do have a lot of evidence that the effects of Huntington's on the structure of the brain itself is what makes people more at risk for depression and other psychiatric illnesses like anxiety, psychosis, menia, et cetera.

each other for different reasons. But unlike Alzheimer's dementia, which tends to affect memory first, especially short term memory, the dementia and cognitive decline with Huntington's disease tends to affect what we call executive functions first, So that's things like decision making, planning, kind of like mental flexibility to new

scenarios and reaction. And so this can result in behavioral changes, and this is something that friends and family can sometimes notice, even sometimes before a person experiencing these changes might notice anything, but they can be very subtle and often can happen before any of these motor side and can stay very mild for a long long time throughout the course of disease. Okay, And this is likely because the vasal ganglia is involved

with a lot more than just motor coordination. So these kind of small changes and small amounts of neuronal death scattered throughout can result in these changes. And because Huntington's does eventually affect the entire brain, eventually memory becomes impaired as well.

time we consider symptomatic to be symptomatic with motor symptoms. Okay, But then a lot of times, you know, if you are talking with someone and you and they think about it, they're like, yeah, well, maybe I have noticed like a little bit of a personality change, or I was having difficulties at work before that, but they wouldn't have attributed it because they didn't know that they had Huntington's right

until the motor symptoms happened. But to answer your question, no, there isn't a sequence to this, okay, and it can be very very variable from person to person, and the sequence does not depend on the number of repeats. So the vast majority of people with Huntington's disease will have onset sometime between their thirties and fifties, and everyone that has more than forty of these CAG repeats will have

symptoms by age sixty five, pretty much. But while the length of repeats doesn't correlate to like what symptom is going to be first, or even how quickly the symptoms are going to progress, or anything like that. What it does correlate to is the early onset of symptoms. Right, So the longer this CAG repeat, the earlier you're likely to see symptoms onset.

a longer repeat could have earlier onset of disease. Once you get to above like sixty repeats, you can have what's actually called juvenile onset Huntington's, which happens if someone has symptoms before age twenty, and that does tend to look a little bit different than Huntington's that has a normal onset of thirty to fifty, where you have more of that slow rigid movement early on in the disease

rather than the Korea form involuntary movement. But what is kind of universal is that once symptoms begin then this disease does progress, and it continues to progress. It is essentially universally fatal within about ten to thirty years of initial onset of symptoms. Most of the time, death is not from the disease itself, but from complications associated with fun or more commonly with pneumonia due to aspiration because of that, dysphasia and difficulty swallowing.

happen absolutely. I think I think I read I should double check this number, but I think I read about eight percent of the time. Okay, yeah, so not super common, but absolutely possible. So that's the biology of Huntington's disease.

Huntington in your cells? And how long does it then take to accumulate this toxic protein.

tell from this really short description in this newspaper. First, it shows us that Saint Vidas's dance still seemed to be widely known if you remember for our Dancing plague episode. I'm going to go over that like briefly again later. Anyway, The point is it was still widely known. Also that the disease can be extremely emotionally traumatic, especially due to its familial nature, like you talked about, Aaron, And also that the exclusion or stigmatization of families where Huntington's was

known to occur wasn't the rule. That in some communities, like apparently in East Hampton, these families or individuals that had Huntington's were highly respected and very much integrated into and accommodated by the community.

outbreaks in the following years. And by the eighteen hundreds these epidemics had stopped happening pretty much entirely, but the name of the condition or the condition itself didn't fade from public memory, because other people still experienced these similar movement disorders, like, for instance, Phoebe Hedges. So I just mentioned earlier, but what Phoebe was experiencing in eighteen o

six was not an outbreak of dancing plague. Of course, there was just no other name for it at the time, and Saint Vitas's dance or just korea was a sort of catch all term for any kind of movement disorder at that time. Really only starting in the eighteen hundreds is when clinicians start paying closer attention to these Koreas, especially those that happened in children, possibly because of the rise in rheumatic fever due to like population growth, cities growth.

and it's typically adult onset. It was descriptive yet to the point and in the decade after it was published, the disease that would later be called Huntington's Korea for this amazing description would get a whole lot more researchers interested in it, and not always for good reason. But before we get to that, I want to talk a bit about why the disease might have only been described in the late eighteen hundreds, which seems kind of late

to me. Yeah, Like, you know, Saint Vidas's Dance had been around for a long time.

obscure the inheritability aspect of it. But having said that, it's not like the eighteen hundreds, Like, it's not like the year from like seventeen ninety nine to eighteen hundred came with this huge, huge boost.

mortality was so high, et cetera. But anyway, so other people argue that it actually wasn't the slight increase in life expectancy, but rather the reframing of heredity overall and how we thought about the inheritance of traits.

George's grandfather, Abel, who was also a doctor, moved to this area of Long Island, New York in the late seventeen hundreds, where he set up a medical practice, and shortly after he arrived he learned of a few families in the area who were affected by something that people generally referred to.

would go on rounds with his dad. And so when George finished medical training, he not only was equipped with the ability to observe and describe certain conditions, he had the generational knowledge of his father and grandfather, and he also happened to live in a town which had a higher prevalence than in surrounding areas, and so this set him up to write his on Korea in eighteen seventy two. It was the only article he ever published apparently wow yeah.

When his paper came out, other reports of Huntington started to trickle in, and not just from the US, Germany, France, Italy, Britain, Austria, Cuba, Poland, Russia and many other places reported case descriptions of what had started in eighteen eighty seven to be called Huntington's Korea. And this research on the late eighteen hundreds filled in

the details of the clinical picture that Huntington had painted. So, for instance, insanity was mentioned as a defining feature in George Huntington's description of the disease, but later physicians noted that the mental impairment due to the disorder was not always severe, or it was variable or at onset differently, And it was essentially their understanding of how cognitive function worked became more nuanced.

Sydenham's Korea. William Osler, who was super interested in all types of Korea, got in touch with Huntington to ask whether he could arrange a meeting with some people who were affected by the disease in the town, and Huntington said, no, I don't think that's a good idea. I want to respect these people of privacy and you shouldn't bother them. Wow, which like in the late eighteen hundreds, I'm shocked.

do more research on the disease. It could increase awareness that could lead to more support and medical treatment and cures, But on the other hand, it could bring increased scrutiny and unwanted attention to these people without their consent. Osler never did end up visiting East Hampton. He did conduct research on Huntington's disease on other families and other places.

But in the last few years of the nineteenth century and in the first several decades of the twentieth, Huntington's and Osborne's initial fears were realized as the focus on Huntington's turned to one of the defining characteristics of the disease its heritability. So, like I mentioned, general patterns of inheritance had been figured out for a while by the end of the eighteen hundreds, thanks to livestock breeders, who really could be considered like the first geneticists, even more so,

I would argue than Mendel. By the time Mendel was playing with his p's in the eighteen sixties, these breeders already knew about dominant and recessive forms of inheritance. Like maybe not in that formal language, but they were incredibly knowledgeable. But interest in the field of heritability grew throughout the late eighteen hundreds and into the nineteen hundreds, especially when Mendel's work, which was published in eighteen sixty six but was sort of like lost, like no one talked about it,

and it was rediscovered in like nineteen hundred. Yeah, and Mendel's work gave this like form and calculation and structure to these patterns, and the interest grew even more broadly beyond that. It wasn't just plant or livestock breeders or natural historians that had an interest in which traits were passed down, but also so called social thinkers quote unquote who began to take these biological concepts and apply them to what they saw as social problems. So begins the

story of eugenics. And this is a story that I've touched on so many times in this podcast. If you remember back in any of the episodes where I talk about eugenics, especially I think the birth control episode, you may remember how the term race suicide quote unquote really gained traction in the early twentieth century in the US.

It was one of Teddy Roosevelt's favorite terms. Basically white middle class Americans began to be fearful of the influx of immigrants, the growth of the lower class, their own declining birth.

the gradual decline of society whatever that meant. However, they wanted it to mean eugenics, and this concept of race suicide focused particularly on who was procreating and how to control it. They wanted to encourage certain people to procreate more and prevent others from procreating at all, by force

if necessary. The first few decades of the twentieth century saw the rise of eugenics from this like niche theoretical biology concept to a widespread public movement, with state laws legitimizing this way of thinking and genetic research providing a scientific basis for it. Marriage prohibition, involuntary sterilization, racist immigration laws, those.

But just as the twentieth century birth control movement in the US has its roots in eugenics, so does the study of genetics.

Charles Davenport may not have started the eugenics movement in the US, but he was friends with Francis Galton, who was the father of eugenics, and he also founded the Eugenics Record Office in nineteen ten, where field workers and scientists were trained in how to collect and analyze data to push their eugenic propaganda. Osborne's fears about the increased attention to the residence of Easthampton and elsewhere with Huntington's

disease were about to come true. After read about the genetic basis of Huntington's and its patterns of inheritance, he viewed it as a perfect subject for a large scale project in which he would identify the source of the disease in the US, as well as shed more light

generally on heritable disease. The person responsible for carrying out much of this study was the eugenics field worker, which, like I can't believe is an actual phrase a job title eugenics field worker in the nineteen hundreds, Yes, yeah,

named Elizabeth Munsey. Munsey would go around to towns in different states where families with Huntington's had been identified, both to interview them as well as constructive family tree Over her years as a field worker, she created pedigrees with over five thousand people and identified nearly one thousand people with Huntington's, about two hundred and fifty of which were

still living at the time of her survey. And while I was reading about this, I just could not stop thinking about how horrifying it is that there was a eugenics records office collecting the names and locations of people with certain diseases. And we can get a taste as to what could have happened with this info in the US hypothetically by looking at what did happen in Germany in the years leading up to World War Two. People with Huntington's were among the hundreds of thousands of people

forcibly sterilized in Germany. Of the three hundred and fifty thousand to four hundred thousand people sterilized in Germany during nineteen thirty three to nineteen thirty nine. Around three thousand to thirty five hundred of those people were people that had Huntingtons. And then when the war started, so did the exterminations. And we don't really have good numbers for that with regards to people with Huntingtons. Anyway, back to Munsey and.

Oh this person is like really well respected in the community.

age of onset in general. Though the paper was terrible statistically, and broad claims were made about the unfitness of these families and the bad care characters at the top of the family tree, this article was essentially used as this platform for his eugenic propaganda, and this way of thinking about Huntington's didn't die out with Davenport. Unfortunately, if anything, this article and that research quote unquote research added fuel

to the fire. Based in part on Davenport and Munsey's publication, there's a Connecticut psychiatrist named Percy Vesi who created an origin story of Huntington's in the US as one in which witchcraft and scoundrels featured prominently from the very beginning. Come on, I mean this account was based on like horrible research and just an absence of facts. Everyone in his story was either described as a criminal or a low life of some kind, and he smeared the name

of every person he listed. He then blamed Huntington's disease for their behavior, and in nineteen thirty two he used this article to sterilization His fiction of witchcraft and criminality associated with the disease was thoroughly, entirely, completely disproven, but only in the nineteen sixties.

I was shocked, but also not shocked to find out that in nineteen fifty one, there was an article published in the Journal of Science, like this extremely prestigious journal, in which the authors claimed that there was enormously higher fertility in men with Huntington's compared to their siblings that did.

if you're pushing some sort of propaganda. And I think in the US we have this tendency to ignore the dark part of our history and pretend like we were the heroes, we were the saviors in like all of our stories. We have to acknowledge our past, our dark past.

the same year that her husband. And this is what cracks me up, Aaron, because every time I said this to you, you were like, I don't know who that is.

finally was diagnosed in nineteen fifty two. And Marjorie when he got his diagnosis, she was asking the doctors all these questions and the doctors were just like, well, that's it, sorry, Like there's nothing we can do. There's no advice I can give you. That's it. And she was like this, no, this, I'm not going to accept that, Like this isn't it, Like, you know, I want to talk to other people who've

experienced this. I want to bring us all together so that we can get support, so we can get advice, so we can raise awareness, to get more information about this disease. And so in nineteen sixty seven, which was the same year that Woody Guthrie died of the disease.

She founded this organization where other people could find information and get support, and this organization, her mission, was instrumental in shedding light on this disease, getting people to talk about their experiences and how the medical establishment was frankly failing them, and later on in navigating the very comp

lloicated issues of testing, insurance, financials, genetic counseling. Because of all of these years of prejudice surrounding Huntington's and stigma and shame, there was sort of this like culture of almost like silence around the disease, so like even within families,

it wasn't necessarily acknowledged. And I think that in more recent years, due in part and large part to this organization and other organizations that were founded, there's been a push to like increase awareness and to stop talking about it in these like, you know, eggshell tiptoe terms like hushed, Let's talk frankly about this disease and what we can do about it and what is you know, what are the different options, what is the research telling us, what

support can be provided? And on the other side, of things. There was another organization that was founded more were on the scientific angle, on the scientific research angle, called the Hereditary Disease Foundation, started by doctor Milton Wexler, whose wife Leonora died of Huntington's. Also two of their daughters, one named Alice, is a historian, I believe, and she wrote like one of the books I read, oh wow. And another of their daughters, Nancy, is a geneticist that helped

to do like a ton of Huntington's disease research. So very cool, that's great. So this foundation had a different aim. They wanted to understand the mechanism of the disease. So in the early nineteen sixties, researchers came across a large cluster of people with Huntington's disease in the Zulia region

of Venezuela by the shores of Lake Maracaibo. In this group of people, Huntington's was at a particularly high prevalence, so there were even some people suspected of being homozygous for the trait, meaning they had two copies of the

mutated aaliele. And this group of people was studied by the Foundation and ultimately just to sort of like long story short it in nineteen eighty three, a marker for the gene was found and its location was identified as being on the fourth chromosome, and ten years later, in nineteen ninety three, the last big point in the timeline of Huntington's disease so far, the exact gene was found, and isolating the gene for Huntington's disease was huge on

the scientific front. It allowed for researchers to understand how this allele produced the effects that it did, to tried to come up with potential therapies, and from the patient's point of view, it held answers because identifying this gene meant that you could be tested for the disease.

far lower. That's where it's kind of the lowest worldwideestimated there at about zero point five per one hundred thousand people in western, Central and Eastern Europe. So all over Europe as well as the UK, prevalence estimates have varied between two and seven per one hundred thousand in Africa, where we don't have as good of estimates, they varied between one and four per one hundred thousand. In Oceania it's estimated at five per one hundred thousand, and then

in North America seven per one hundred thousand. But this also varies a lot within North America, Okay, South America, outside of that region in Venezuela that you mentioned, which is much higher. We really don't have good numbers on like the rest of South America, very limited data, but so worldwide overall like five to ten per one hundred

thousand people. And like I said in the biology section, the mean age of onset is around forty years, so thirty to fifty years, and then life expected see tends to be about ten to twenty maybe thirty years once symptoms appear, Okay, And that part doesn't vary based on income, based on country, based on anything. And that's largely because even though individual manifestations of this disease can vary, like,

the overall course doesn't really vary. And the way that we deal with it in all these different countries, regardless of country's income doesn't really vary either. So to kind of get into both what we can do for treatment. And then also what you are mentioning Aaron about this ethical dilemmas when it comes to genetic testing. The bottom line is that right now, in terms of treatment, we

have nothing that can change the course of disease. We don't have any medicines or treatments that can yes the underlying issues or the progression of disease. We have symptomatic treatments, especially for the Korea form movements, those involuntary motor movements. We have drugs that affect like dopamine pathways and some

other things that can help with those involuntary movements. We also have drugs that can treat things like depression and anxiety, antipsychotics if psychotic symptoms develop, So we have those kind of psychiatric drugs, but we don't have anything specific to Huntington's and we don't have anything to address the underlying issue itself. And so in part because of that, this is not a genetic disorder like for example, cystic fibrosis or sickle cell disease that we've talked about before, where

early identification can lead to vastly improved outcomes. Because of the treatment options that we have available right this is not that, and so genetic testing can tell a person that they have this gene and can tell them that they are going to develop Huntington's or not. But it has sparked quite a lot of debate about when and whether to do genetic testing, especially when it comes to children, like at what age should someone be allowed to decide

that they want to get tested? Yah, But it also brings up ethics in regards to the idea that, of course, ethically, everyone has a right to know their own health status. Right. I have a right to know what's going on in my body. If there's a test that can tell me that I have a genetic disorder and I want to know it, I have a right to know that. But every person also has a right to not know. And I have a right to keep all of my information secret to me if that's what I want.

It's a very person specific and so this is the kind of thing that really has to be a discussion between an individual and their healthcare provider, yes, and genetic counselors especially. But Aaron I like to try to end these episodes on more hopeful notes. So let's talk.

really incredible. So there are a lot of different possibilities, and there are people working on kind of all of these different I have links to a number of papers that go in a lot of detail on all of the different research that's being done and the different kind of ways that you could target Huntington's disease from a variety of different angles with gene therapy. So a lot of it is maybe using something like RNAi, which are little small pieces of RNA that can go in and

kind of make changes. I think that the most exciting prospect is Crisper, Oh, Yeah, which we talked about in a lot more detail in the sickle Cell episode, because there, I think we're a little bit further along than we

are in Huntington's. But Crisper, just for anyone who hasn't listened to that or who has forgotten, is a way by which you can go in to a cell and make very specific, targeted changes one time that persist for the life of that cell, So you can actually change the DNA very specifically and cut out that mutant Huntington gene and replace it with a non mutated like a normal type Huntington gene, and you can do so with one treatment, whereas most gene therapies that are in development

would require a lot of infusions, which is especially difficult for neurodegenerative diseases where you have to be able to get that into the brain. So that requires going directly into the brain, which is very problematic or very difficult. Yeah, sounds very risky, Yeah, but there are a number of different strategies. Some gene therapies might try to reduce the expression of this mutant protein, so you might still make some of it, but you just wouldn't accumulate those toxic

levels because you're making less of it, Okay. Others like I mentioned, especially Crisper, would just cut that mutated region out and replace it with a normal region. And then there are other therapies that are being developed aside from just gene therapy to try and address the downstream effects as well, like try and improve cognitive decline by addressing things like mitochondrial function, which we think is very involved in dementia and cognitive decline in general. So there's a

lot of research being done. If you look at Clinicaltrials dot gov and you search for Huntington's, you can find over fifteen hundred studies that are being done. Not all of those are drug studies or treatment studies, but that is a lot. It's like on par with cystic fibrosis and things like that when you kind of just search for those studies. Okay, if you check, I'll link to a website where you can check specifically gene therapy studies. There are six studies currently listed on the gene Therapy

Clinical Trial Database. Several of them are stem cell studies, because that's another possibility, is using stem cells to just like regrow the brain tissue that is damaged a whole nother mechanism, and some of those kind of addressed dementia in general, not just only Huntington's. But there are at least two gene therapy studies specifically that are in phase one and phase two trials, so human trials for kind of safety and feasibility.

I believe it's possible. Yeah, Yeah, so that's Huntington's. Wow, that was a big one.