Speaker 1: My name is Jay, and I am thirty four years old,
Speaker 1: and I was recently diagnosed with Huntington's disease. My grandfather
Speaker 1: was diagnosed with Huntington's in his eighties, but I don't
Speaker 1: think he and my grandmother really understood this, you know,
Speaker 1: severity of the illness and its implications for their children
Speaker 1: and grandchildren. So they never really told us until my
Speaker 1: father started seeing some symptoms in his fifties. So that's
Speaker 1: when I found out. I guess I was twenty eight,
Speaker 1: I'd just been married, you know, there's so much optimism,
Speaker 1: and then I find out for my parents that there's
Speaker 1: this terrible shadow, you know, that's going to be potentially
Speaker 1: hanging over my life. And it was.
Speaker 2: Definitely really, really hard. I'm not gonna lie.
Speaker 1: Your priorities sort of shift, just trying to maximize the
Speaker 1: years that you might have with a good quality of life,
Speaker 1: you know. So I didn't get tested right away. I
Speaker 1: really wasn't ready. But over the years I started to,
Speaker 1: I guess, come to a point of acceptance, and I
Speaker 1: also started to see symptoms starting to appear, things like
Speaker 1: coordination issues, balance issues, also difficulty swallowing and drinking. So
Speaker 1: that's how it's starting to affect me, and it got
Speaker 1: to a point where I was ready to be tested,
Speaker 1: and so I did that, I guess a few months
Speaker 1: ago actually, and now I have the official results that
Speaker 1: I'm positive for a huntidian disease. At that point, I
Speaker 1: guess it wasn't as bad as I thought. Actually, to
Speaker 1: get those words for me, it was, I guess, a
Speaker 1: little bit freeing to finally have some solid answers and
Speaker 1: to know what my reality would be. You know, I'm
Speaker 1: really lucky to have a really supportive husband with me.
Speaker 1: He's been a rock for every step of the way,
Speaker 1: being understanding for all my decisions. One in particular is
Speaker 1: that I feel really strongly that I don't want to
Speaker 1: pass this on to my children. I know that's maybe
Speaker 1: a controversial opinion, but I just can't imagine potentially burgeoning
Speaker 1: them with this same difficulties that I'm experiencing. So we'll
Speaker 1: be using IVF. They have this cool technology where they
Speaker 1: can test the embryos, and that's the route we'll be taking.
Speaker 1: But obviously it's also time consuming and expensive and not
Speaker 1: a guarantee.
Speaker 3: So it's.
Speaker 1: One of the most disappointing things about this diagnosis is
Speaker 1: one of the few things I really knew I wanted
Speaker 1: was a baby, and.
Speaker 2: Now we can't just conceive.
Speaker 1: The natural way. We've got to go through all these hurls.
Speaker 1: Another aspect about it that's really difficult is because it's
Speaker 1: a family disease. You see, I saw my grandfather suffer
Speaker 1: from it, and now my father is suffering from it,
Speaker 1: and now I'm going to have the same symptoms, and
Speaker 1: my aunt also possibly my brothers. So it's really difficult
Speaker 1: to not feel like you're being a burden if you
Speaker 1: want to, you know, share your feelings with your family
Speaker 1: members and reach out to them without being potentially a
Speaker 1: burden to them when they are also dealing with this
Speaker 1: kind of stress, and also being a burden to my husband.
Speaker 1: Of course, eventually you know he'll be caring for me
Speaker 1: more and more.
Speaker 2: So Yeah, it's really really hard.
Speaker 4: Hi, this is Jay's husband. Some of the difficult things
Speaker 4: are trying to explain to say, my side of the family,
Speaker 4: what's going on on. My sisters have their families going along,
Speaker 4: and things like that. And at this point we've had
Speaker 4: your diagnosis, I guess for more than more than a month,
Speaker 4: but we still haven't found the right time or place
Speaker 4: or way to even tell our extended families or my
Speaker 4: family even. I think basically for you, it's just it's
Speaker 4: just your immediate family on one side that we've really
Speaker 4: talked to about it. But we don't even know how
Speaker 4: to tell our friends about this because we just don't
Speaker 4: have we don't have the words, and we don't know
Speaker 4: how to. I guess like we're not looking for sympathy,
Speaker 4: but we also don't. It's we don't want to keep
Speaker 4: it a secret, and given that it's not something that
Speaker 4: can be cured like cancer or COVID, this is something
Speaker 4: that is not going away, and I think that has
Speaker 4: been one of the really stressful parts. We haven't really
Speaker 4: figured out a good way to to share with it
Speaker 4: with those that are even closest to us. I think
Speaker 4: that has definitely weighed on me. At least two have
Speaker 4: this information and not be able to really talk to
Speaker 4: people about it yet because just we don't know how.
Speaker 4: Another thing that we've kind of been thinking a lot
Speaker 4: about is just, you know, like, what do we do
Speaker 4: right Unlike some diseases again that do have cures, when
Speaker 4: do we need to tell insurance? Because we definitely will
Speaker 4: want some of you know all as much of the
Speaker 4: care to be covered by insurance, but that's not something
Speaker 4: that a lot of people have been able to give
Speaker 4: us advice on, or there's not a good rule book
Speaker 4: or a guidebook out there. And because everybody's path with
Speaker 4: hunting teens is different than the solutions and how they
Speaker 4: resolve it are all different. I think one of the
Speaker 4: really difficult parts is that Jay's grandfather showed symptoms in
Speaker 4: his eighties, and his path and how he dealt with
Speaker 4: it was very different than her father, who was in
Speaker 4: his fifties when he was diagnosed, and that's very different
Speaker 4: from Jay, who started displaying symptoms in her thirties. And
Speaker 4: so there's even when we look for comparisons to how
Speaker 4: to manage and how to deal with it, we don't
Speaker 4: have a particularly good role model or something to compare to,
Speaker 4: and we're kind of going at our own pace, in
Speaker 4: our own direction and hoping that we get it right,
Speaker 4: but also being really aware that we don't have a
Speaker 4: lot of flexibility that we have to get it right
Speaker 4: the first time, because all these days are precious.
Speaker 1: Yeah, I guess that's definitely a downside of it being
Speaker 1: a relatively very disease unlike something like breast cancer. There's
Speaker 1: just not as much resources. There's not like, you know,
Speaker 1: the kind of community that you get when you're diagnosed
Speaker 1: with cancer. Let's say, there's not as much research, not
Speaker 1: as much funding. So yeah, I guess overall, I've been
Speaker 1: trying to just you know, do it day by day,
Speaker 1: a little by little. Some days are good, some days
Speaker 1: are bad. But it's my reality now. And you don't
Speaker 1: really have a choice anymore, right, You just have to.
Speaker 1: You're on the train, so you kind of have to
Speaker 1: deal with it. And I guess that's been how I'm
Speaker 1: trying to look at it, and hopefully I can just
Speaker 1: keep some optimism as things progress, you know, despite what
Speaker 1: might come.
Speaker 5: Thank you so so much for sharing your story with us.
Speaker 3: We really appreciate it.
Speaker 2: Yeah, thank you.
Speaker 1: Hi.
Speaker 2: I'm Aaron Welsh and I'm Aaron Allman Updike.
Speaker 5: And this is this podcast Will Kill You.
Speaker 2: And today we're talking about Huntington's disease. Yes we are.
Speaker 5: This is just one of a handful of the genetic
Speaker 5: diseases that we have covered, Aaron, right.
Speaker 2: Yes it is, and it's very different than the other
Speaker 2: genetic disorders that we've covered so far.
Speaker 5: So yeah, I mean, this is a big top to cover.
Speaker 5: So yeah, yeah, so let's like maybe get right down
Speaker 5: to business.
Speaker 2: I think that business we should cover.
Speaker 3: Yeah.
Speaker 2: The first business, as always is quarantiny time.
Speaker 5: It's quarantiny time, and this week we are drinking the Marjorie.
Speaker 5: The Marjorie named for Marjorie Guthrie, who was the founder
Speaker 5: of one of the of one of the biggest Huntington's
Speaker 5: Disease advocacy groups in the US, now called the Huntington's
Speaker 5: Disease Society of America.
Speaker 2: I believe excellent. And what is in the Marjorie.
Speaker 5: The Marjorie is vodka, orange juice, unsweetened crimeberry juice, and
Speaker 5: a little bit of amaretto.
Speaker 3: Excellent.
Speaker 2: We'll post the full recipe for that quarantini as well
Speaker 2: as our non alcoholic Plussy berita on our website. This
Speaker 2: podcast will kill You dot Com and all of our
Speaker 2: social media channels as always, and the usual business. I
Speaker 2: guess you know.
Speaker 5: We have transcripts, which is thrilling.
Speaker 2: Thrilling.
Speaker 5: You can find those on the Transcripts to Have of
Speaker 5: our website, and on our website you can also find
Speaker 5: all kinds of other fun things like a good Reads list,
Speaker 5: or a link to a good Reads list, a link
Speaker 5: to our bookshop affiliate page, any of the sources that
Speaker 5: we use in all of our episodes. Linked to Bloodmobiles
Speaker 5: music page on band camp. I mean, it's all there.
Speaker 5: Just check it out. You'll have a fun time.
Speaker 2: It's a very fun time website. All right, Well, this is,
Speaker 2: as you said, Erin, it's a very big topic. So
Speaker 2: shall we take a quick break and then dive right in.
Speaker 3: Let's do it.
Speaker 2: So right up front, Huntington's is a neurodegenerative genetic disorder
Speaker 2: that is inherited in an autosomal dominant fashion. So what
Speaker 2: does that mean. It means that this is a disorder
Speaker 2: that's affecting the brain and the nervous system, and you
Speaker 2: only need one copy of the mutated gene in order
Speaker 2: to have disease. So that's already different from the other
Speaker 2: two genetic disorders that we've covered in the past, namely
Speaker 2: sickle cell and cystic fibrosis, which are both autosomal recessive,
Speaker 2: so you have to have two copies of a mutated
Speaker 2: gene in order to have disease. But before we can
Speaker 2: actually talk about Huntington's disease, I think we need to
Speaker 2: step back and talk about our genes in more detail
Speaker 2: than I think we have on this podcast, at least recently.
Speaker 2: So here's where road begin. Our DNA is made up
Speaker 2: of little building blocks like legos, called nucleotides, which we
Speaker 2: give letters A, T, C, and G. So three of
Speaker 2: these nucleotides grouped together form what's called a codeon because
Speaker 2: that is what codes for an amino acid. Well, it
Speaker 2: codes for RNA, which codes for amino acids, but will
Speaker 2: ignore them. Right, Okay, when you string a bunch of
Speaker 2: amino acids together, you get essentially a protein scattered throughout
Speaker 2: our genome. Throughout not just human genomes, but like every
Speaker 2: genome animals, plants, bacteria. We have these short repeat sequences
Speaker 2: of nucleotides that are called microsatellites. They are like one
Speaker 2: to six nucleotide sequences that are repeated like tata ta,
Speaker 2: all in a row. So that's some basic definitions. Now
Speaker 2: on this podcast we talk a lot, usually in the
Speaker 2: context of viruses or bacteria, but this is true for
Speaker 2: human cells too. How every time our cells or any
Speaker 2: cell replicates, it sometimes makes mistakes, and we call these
Speaker 2: mistakes mutations. Most of the time, these mutations result in
Speaker 2: like a single or small base pair change like one
Speaker 2: addition or a deletion, or a substitution like a T
Speaker 2: for an A or something like that. But within these
Speaker 2: repeat regions, these microsatellite regions, a single mistake can lead
Speaker 2: to very big changes because what it often leads to
Speaker 2: is the gain or the loss of an entire repeat sequence.
Speaker 2: So how does that happen. We don't fully know, but
Speaker 2: we think that what happens is that as our DNA
Speaker 2: polymerase that's helping to replicate our DNA is chugging along
Speaker 2: copying tatata all in a row, it kind of slips
Speaker 2: out of position and then it loses its place, and
Speaker 2: when it picks it back up, it does so earlier
Speaker 2: along that DNA chain. So if you have a region
Speaker 2: that's like TATA four times in a row and it
Speaker 2: gets a little bit wonky during replication, the next cell
Speaker 2: as after it replicates, would end up with TATA like
Speaker 2: six times in a row or eight times in a row.
Speaker 2: So that's microsatellites. They exist throughout our genome, and the
Speaker 2: mutation rate tends to be higher in these repeat regions
Speaker 2: than in other parts of our genome. And the longer
Speaker 2: a microsatellite region is, the more likely it is that
Speaker 2: this type of slippage and mutation can happen, and the
Speaker 2: more likely that the mutation results in large changes, especially
Speaker 2: expansion or growing of those regions and getting longer. So
Speaker 2: let's talk about how that relates to Huntington's disease. Yeah,
Speaker 2: Huntington's disease is a disorder that's known as a trinucleotide
Speaker 2: repeat disorder, So that means it's caused by an abnormal
Speaker 2: number of trinucleotide three nucleotides in a row C, A,
Speaker 2: and G that repeat a whole bunch of times. Aka,
Speaker 2: this is a microsatellite.
Speaker 5: And there are other diseases that are this trinucleotide repeat diseases.
Speaker 2: Right, absolutely, yes. So fragile X is another example of
Speaker 2: a trinucleotide repeat disorder where you have a repeat at
Speaker 2: the end of the X chromosome. You also have Friedrich's ataxia,
Speaker 2: there's muscular dystrophe. There's a whole host of trinucleotide repeat disorders.
Speaker 2: This is one and this happens in a gene that
Speaker 2: we all have on chromosome four that's called the Huntington gene,
Speaker 2: where on chromosome four. There's a series. In everyone where
Speaker 2: we have this microsatellite, we have these CAG repeats, But
Speaker 2: in the vast majority of the population we have anywhere
Speaker 2: from five to like twenty eight copies of CAG all
Speaker 2: in a row. And another thing that's important about this
Speaker 2: repeat on chromosome four is that it's located in what's
Speaker 2: called an exon or a coding region, which means that
Speaker 2: our body, every human body and other animals too, we
Speaker 2: make a protein from this region that's called Huntington that's
Speaker 2: really clever name. But now we know that these microsatellite
Speaker 2: regions can sometimes be unstable and expand, And it turns
Speaker 2: out that once you get to above twenty eight re repeats,
Speaker 2: that is when this region becomes unstable, and that means
Speaker 2: that when those cells replicate, that particular region is likely
Speaker 2: to expand. It could contract, but it's more likely to expand,
Speaker 2: and once it expands above forty repeats, that is when
Speaker 2: a person will develop Huntington's disease.
Speaker 5: Why forty what happens at that point?
Speaker 2: Okay, great question. So the why forty is an interesting
Speaker 2: question because it could be a little bit earlier than forty.
Speaker 2: It really doesn't ever happen any earlier than thirty six,
Speaker 2: but especially that high thirty region, you can have what's
Speaker 2: called incomplete penetrants, where some people with that number of
Speaker 2: repeats might have disease and others might not. So that's
Speaker 2: kind of like a gray zone. But essentially, the reason
Speaker 2: why once you have a certain number of repeats you
Speaker 2: end up with disease is because that trinucleotide repeat is
Speaker 2: located in an exxon in a coding region, So that
Speaker 2: abnormally long set of repeats causes the production of an
Speaker 2: abnormal Huntington protein, and the more this repeat expands, the
Speaker 2: more abnormal this protein is, and probably the more abnormal
Speaker 2: protein you are producing as well.
Speaker 5: Okay, so what does this protein do?
Speaker 2: Okay, very good question. I'm not going to answer this
Speaker 2: satisfactorily because the answer is normally we don't know. So
Speaker 2: we know that this Huntington protein is essential to development
Speaker 2: because if you knock it out completely in mice, they
Speaker 2: don't live, like, they don't develop in utero and they die.
Speaker 2: So we know that this protein does something that's very important.
Speaker 2: We think that it's involved with like trafficking of stuff
Speaker 2: inside of the cell, like moving things from one place
Speaker 2: to another within the cell, within a cell, within a cell.
Speaker 2: But we don't know that for sure. We don't know
Speaker 2: the real function of normal, typical what they call wild
Speaker 2: type Huntington protein. But that still doesn't answer the question
Speaker 2: of like, how does this actually cause disease? Like, Okay,
Speaker 2: we have an abnormal protein, so what Yeah, the short answer,
Speaker 2: I'm going to try and give the shorter answer, even
Speaker 2: though I think it's going to be less satisfying. Don't
Speaker 2: we don't really know.
Speaker 3: That's not satisfying, give me the longer answer.
Speaker 2: I warned you, we don't fully know. There's a lot
Speaker 2: of hypotheses about the like specific cellular mechanisms that are
Speaker 2: involved with this abnormal protein. We have a lot of
Speaker 2: evidence that it's what's called a gain of function. So
Speaker 2: in for example, our cystic fibrosis episode, we talked about
Speaker 2: how when you have a mutation in the cystic fibrosis protein,
Speaker 2: you lose the function of that protein and that's what
Speaker 2: causes disease. Here we have the opposite where the production
Speaker 2: of this abnormal protein is what's involved. It's not that
Speaker 2: the Huntington protein is no longer doing whatever Huntington protein
Speaker 2: is supposed to do. It's that it's doing something new
Speaker 2: and different and.
Speaker 5: Bad, right, Okay.
Speaker 2: So we know that the accumulation of this abnormal protein
Speaker 2: it forms aggregates, it forms these beta pleated sheets, they
Speaker 2: aggregate into cells, and then also possibly the mRNA itself
Speaker 2: that codes for this protein is somehow toxic to our
Speaker 2: cells and it causes cell death. So that's the end result.
Speaker 2: Is what happens is cells die because of this abnormal protein.
Speaker 2: And while Huntington protein is found kind of throughout our body,
Speaker 2: like this gene is expressed in a lot of different
Speaker 2: tissues for whatever reason, this abnormal protein causes damage primarily
Speaker 2: to the central nervous system. So that's why we see
Speaker 2: this as a neurodegenerative disease, because it's causing cell death
Speaker 2: in neurons.
Speaker 5: Is it expressed more highly there or what's happening?
Speaker 2: Good question? Don't fully know? Okay, at least I don't
Speaker 2: fully know. We can get even more specific, and getting
Speaker 2: more specific will help us to understand the symptoms of
Speaker 2: Huntington's disease itself, because we know the cells in our
Speaker 2: brain that are the most affected. One of the main
Speaker 2: areas that we see the loss of neurons, and damage
Speaker 2: to neurons is in the striatum of the basal ganglia.
Speaker 2: So while we do see eventures the entire brain becoming
Speaker 2: involved and like widespread atrophy, this striatum of the basil
Speaker 2: ganglia is the first and hardest hit area. So what
Speaker 2: is the basil ganglia? We actually talked about this way
Speaker 2: back in our encephalitis lethargic at episode a million years ago.
Speaker 2: Do you remember that?
Speaker 5: Uh uh yeah, yeah don't I don't remember.
Speaker 2: Okay, well, let me tell you then. The basil ganglia.
Speaker 2: It's a set of brain structures that are deep in
Speaker 2: our forebrain that essentially helped to control movement. So the
Speaker 2: basil ganglia helps to coordinate inputs from the motor cortex
Speaker 2: of our brain. They process them and then they put
Speaker 2: outputs out to the thalamus and other places that go
Speaker 2: to our muscles and actually initiate smooth muscle movement, well
Speaker 2: skeletal muscle, but I mean like smooth, coordinated.
Speaker 5: Okay.
Speaker 2: It's also the basil ganglia is involved in a lot
Speaker 2: of other things like cognition and emotion. Like this is
Speaker 2: our brain, it's all very integrated, but one of the
Speaker 2: major functions is in this coordination of movement, and a
Speaker 2: lot of what the basil ganglia does specifically is actually
Speaker 2: to inhibit movements, so that when this basil ganglia is damaged,
Speaker 2: we lose that ability to inhibit movement, so movement becomes
Speaker 2: uncontrolled or uncoordinated.
Speaker 5: Okay, And is this a common structure that is damaged
Speaker 5: in other movement disorders like Parkinson's or something precisely?
Speaker 2: So, in Parkinson's, it's a different set of neurons and
Speaker 2: it they're more specific. And so that's why we actually
Speaker 2: have better treatments. We still don't have treatments to treat Parkinson's,
Speaker 2: but to treat the symptoms. We're better at Parkinson's that
Speaker 2: we are at Huntington's because of what is being damaged,
Speaker 2: but this region has more varied functions and so it's
Speaker 2: harder to target. Okay, gotcha. Yeah, So that finally brings
Speaker 2: us to the symptoms of Huntington's disease. The characteristic symptoms
Speaker 2: which gave Huntington's disease an earlier name that I'm sure
Speaker 2: you'll talk about, Aaron. The characteristic symptoms are Korea or
Speaker 2: Korea form movements. These are involuntary motor movements especially in
Speaker 2: the extremities, so like arms and legs, fingers, and toes,
Speaker 2: the involuntary movements, they're kind of like muscle twitches essentially
Speaker 2: that usually start out early in the course of disease
Speaker 2: in smaller muscles, so like fingers, face twitches that, especially
Speaker 2: early in disease might not be noticeable to anyone other
Speaker 2: than the person who's experiencing them, like you wouldn't even
Speaker 2: notice them, and they might not interfere very much at
Speaker 2: all with daily life. But eventually they spread to affect
Speaker 2: essentially any or every voluntary muscle, which includes the muscles
Speaker 2: of the face and the throat that are involved in talking, chewing, swallowing,
Speaker 2: and so then dysarthria, which is difficulty speaking, can become
Speaker 2: a problem, as well as dysphasia or difficulty swallowing and eating,
Speaker 2: which is very problematic.
Speaker 1: Yeah.
Speaker 2: And then eventually, as this disease progresses, this increase that
Speaker 2: we see in muscle movement actually transitions to what's called
Speaker 2: hypokinesia and Brady caynesia, which means slowing of muscle movement
Speaker 2: and less muscle movement, and this causes like a difficulty
Speaker 2: in initiating voluntary movement, so muscles become very rigid, and
Speaker 2: this is actually not unlike what we see in Parkinson's
Speaker 2: disease as well. You have a lot of rerigidity in
Speaker 2: Parkinson's disease, right, Yeah, So of course, all of these
Speaker 2: symptoms can have huge effects on a person's activities of
Speaker 2: daily living. Things like walking become very difficult and can
Speaker 2: result in frequent falls, which can be very dangerous. But
Speaker 2: even activities like getting out of bed, showering, getting dressed,
Speaker 2: all of these can become difficult because you don't have
Speaker 2: control over the movements of your muscles. And then dysphasia,
Speaker 2: so difficulty swallowing is particularly problematic because that can result
Speaker 2: in aspiration of food into the lungs, which can result
Speaker 2: in pneumonia. But Huntington's disease is not just a motor disorder,
Speaker 2: which is why the old name is no longer the name.
Speaker 2: Huntington's causes a range of neurocognitive, and psychiatric changes as well.
Speaker 2: So first, not first in terms of the course of disease,
Speaker 2: but just first of what I'm going to talk about
Speaker 2: is depression, which is far more common in people with
Speaker 2: Huntington's disease than in the general population, and I think
Speaker 2: what's important is that it might be easy if you
Speaker 2: just aren't thinking, to dismiss this as the result of
Speaker 2: being diagnosed with an incurable fatal disease. But it's not
Speaker 2: just that. Even though we don't fully understand depression in
Speaker 2: general and the effects of depression on the brain, or
Speaker 2: every single change that happens in Huntington's disease in the brain,
Speaker 2: we do have a lot of evidence that the effects
Speaker 2: of Huntington's on the structure of the brain itself is
Speaker 2: what makes people more at risk for depression and other
Speaker 2: psychiatric illnesses like anxiety, psychosis, menia, et cetera.
Speaker 5: It's like actual physical changes exactly right.
Speaker 2: And then the other hallmark of Huntington's disease is dementia,
Speaker 2: which is cognitive decline, so unlike Alzheimer's, so I think Parkinson's,
Speaker 2: Huntington's and Alzheimer's often get talked about in relation to
Speaker 2: each other for different reasons. But unlike Alzheimer's dementia, which
Speaker 2: tends to affect memory first, especially short term memory, the
Speaker 2: dementia and cognitive decline with Huntington's disease tends to affect
Speaker 2: what we call executive functions first, So that's things like
Speaker 2: decision making, planning, kind of like mental flexibility to new
Speaker 2: scenarios and reaction. And so this can result in behavioral changes,
Speaker 2: and this is something that friends and family can sometimes notice,
Speaker 2: even sometimes before a person experiencing these changes might notice anything,
Speaker 2: but they can be very subtle and often can happen
Speaker 2: before any of these motor side and can stay very
Speaker 2: mild for a long long time throughout the course of disease. Okay,
Speaker 2: And this is likely because the vasal ganglia is involved
Speaker 2: with a lot more than just motor coordination. So these
Speaker 2: kind of small changes and small amounts of neuronal death
Speaker 2: scattered throughout can result in these changes. And because Huntington's
Speaker 2: does eventually affect the entire brain, eventually memory becomes impaired
Speaker 2: as well.
Speaker 5: And so in terms of the progression, and like, first
Speaker 5: of all, how predictable is it? Are there you know
Speaker 5: stages that you know you could say, well, this is
Speaker 5: the typical stage, one stage, et cetera. And if it
Speaker 5: is predictable, why do we see, like why does that happen?
Speaker 5: Why does it progress in that order?
Speaker 2: Yeah, great question. There are stages in that there is
Speaker 2: pre symptomatic and then what we call clinical disease, which
Speaker 2: is after a person becomes symptomatic. And most of the
Speaker 2: time we consider symptomatic to be symptomatic with motor symptoms. Okay,
Speaker 2: But then a lot of times, you know, if you
Speaker 2: are talking with someone and you and they think about it,
Speaker 2: they're like, yeah, well, maybe I have noticed like a
Speaker 2: little bit of a personality change, or I was having
Speaker 2: difficulties at work before that, but they wouldn't have attributed
Speaker 2: it because they didn't know that they had Huntington's right
Speaker 2: until the motor symptoms happened. But to answer your question, no,
Speaker 2: there isn't a sequence to this, okay, and it can
Speaker 2: be very very variable from person to person, and the
Speaker 2: sequence does not depend on the number of repeats. So
Speaker 2: the vast majority of people with Huntington's disease will have
Speaker 2: onset sometime between their thirties and fifties, and everyone that
Speaker 2: has more than forty of these CAG repeats will have
Speaker 2: symptoms by age sixty five, pretty much. But while the
Speaker 2: length of repeats doesn't correlate to like what symptom is
Speaker 2: going to be first, or even how quickly the symptoms
Speaker 2: are going to progress, or anything like that. What it
Speaker 2: does correlate to is the early onset of symptoms. Right,
Speaker 2: So the longer this CAG repeat, the earlier you're likely
Speaker 2: to see symptoms onset.
Speaker 5: And then that happens in successive generations, right exactly.
Speaker 2: Yeah, so something called anticipation happens where because this microsatellite
Speaker 2: region is so unstable, which with each generation that length
Speaker 2: is likely to become longer. It doesn't necessarily, but essentially
Speaker 2: seventy five percent of the time when that cell replicates,
Speaker 2: when any cell replicates that has that unstable repeat, it
Speaker 2: will expand, and so that means that a child with
Speaker 2: a longer repeat could have earlier onset of disease. Once
Speaker 2: you get to above like sixty repeats, you can have
Speaker 2: what's actually called juvenile onset Huntington's, which happens if someone
Speaker 2: has symptoms before age twenty, and that does tend to
Speaker 2: look a little bit different than Huntington's that has a
Speaker 2: normal onset of thirty to fifty, where you have more
Speaker 2: of that slow rigid movement early on in the disease
Speaker 2: rather than the Korea form involuntary movement. But what is
Speaker 2: kind of universal is that once symptoms begin then this
Speaker 2: disease does progress, and it continues to progress. It is
Speaker 2: essentially universally fatal within about ten to thirty years of
Speaker 2: initial onset of symptoms. Most of the time, death is
Speaker 2: not from the disease itself, but from complications associated with
Speaker 2: fun or more commonly with pneumonia due to aspiration because
Speaker 2: of that, dysphasia and difficulty swallowing.
Speaker 5: So we talk about this as a genetic inheritable disease,
Speaker 5: But can it occur randomly?
Speaker 2: Yes, so it can certainly occur where there is no
Speaker 2: family history. And that's because if you have a CAG
Speaker 2: repeat length of anywhere from like twenty six to thirty
Speaker 2: five or twenty eight to thirty five, that is an
Speaker 2: unstable length. But you, yourself and anyone in your family
Speaker 2: wouldn't have disease from that. But that microsatellite could mutate
Speaker 2: in your eggs or your sperm, and then your children
Speaker 2: could have Huntington's disease. Gotcha, So we do see it
Speaker 2: happen absolutely. I think I think I read I should
Speaker 2: double check this number, but I think I read about
Speaker 2: eight percent of the time. Okay, yeah, so not super common,
Speaker 2: but absolutely possible. So that's the biology of Huntington's disease.
Speaker 5: I guess one question I didn't ask was why is
Speaker 5: it a later in life onset?
Speaker 2: Yeah, that's it's a good question. It's likely related to
Speaker 2: that it takes that much time for this abnormal protein
Speaker 2: to accumulate. So remember that, because this is an autosomal
Speaker 2: dominant disorder, you only need to have one copy of
Speaker 2: this gene. So how often is your cell copying making
Speaker 2: a protein based on that half based on that mutated
Speaker 2: gene versus based on your normal copy? So like, what's
Speaker 2: the ratio of normal Huntington in your cells to abnormal
Speaker 2: Huntington in your cells? And how long does it then
Speaker 2: take to accumulate this toxic protein.
Speaker 5: It's also interesting that there's not like a check system
Speaker 5: for abnormal proteins.
Speaker 2: So it's very interesting and it's something that people are
Speaker 2: working on in terms of treatment, Like can we change
Speaker 2: how cells process protein and deal with it so that
Speaker 2: we don't have this accumulation of these abnormal protein sheets?
Speaker 5: Right?
Speaker 1: Yeah.
Speaker 2: What I think is very interesting about the biology of
Speaker 2: Huntington's erin is that we know so much, Like I
Speaker 2: just gave you so much detail, right, like a lot
Speaker 2: of detail, and yet we also know so little at
Speaker 2: the same time. Yeah, yeah, And I think a lot
Speaker 2: of that too has to do with just that we
Speaker 2: know so little about our brain. You know, our brain
Speaker 2: is still Neurocognitive disorders in general are not well understood,
Speaker 2: the mechanisms, the specific nitty gritties of it, right, We
Speaker 2: just don't have the answers yet.
Speaker 5: That of course prohibits any like good treatments from being.
Speaker 2: Exactly developed quickly. So what I'm curious about, Aaron, is
Speaker 2: how we got to this point, Like, what is Huntington's
Speaker 2: like in history, because it's been around forever. This protein
Speaker 2: is in us, so yeah, so how did we get
Speaker 2: to this point? Yeah?
Speaker 5: I will try to answer this questions right after this break.
Speaker 5: In the June thirtieth, eighteen o six edition of the
Speaker 5: Suffolk Gazette, there's a brief news communication from East Hampton
Speaker 5: describing the tragic death of a woman named Phoebe Hedges,
Speaker 5: who was believed to have walked into the sea and
Speaker 5: not looked back.
Speaker 3: Quote.
Speaker 5: This extraordinary step is attributed to her extreme dread of
Speaker 5: the disorder called Saint Vidas's Dance, with which she began
Speaker 5: to be affected and which her mother now has to
Speaker 5: a great degree. This is one of the earliest reports
Speaker 5: of what would later be described as Huntington's disease. And
Speaker 5: I apologize for starting off in such a dark way,
Speaker 5: but I think that there's a lot that we can
Speaker 5: tell from this really short description in this newspaper. First,
Speaker 5: it shows us that Saint Vidas's dance still seemed to
Speaker 5: be widely known if you remember for our Dancing plague episode.
Speaker 5: I'm going to go over that like briefly again later. Anyway,
Speaker 5: The point is it was still widely known. Also that
Speaker 5: the disease can be extremely emotionally traumatic, especially due to
Speaker 5: its familial nature, like you talked about, Aaron, And also
Speaker 5: that the exclusion or stigmatization of families where Huntington's was
Speaker 5: known to occur wasn't the rule. That in some communities,
Speaker 5: like apparently in East Hampton, these families or individuals that
Speaker 5: had Huntington's were highly respected and very much integrated into
Speaker 5: and accommodated by the community.
Speaker 2: And I mentioned this last point.
Speaker 5: Because it serves as a sharp contrast for a good
Speaker 5: chunk of the social history of Huntington's and especially some
Speaker 5: of the prejudices that were created shortly after the disease
Speaker 5: was first described, and that persisted long after that. So
Speaker 5: let's begin. Most histories of Huntington's disease start off with
Speaker 5: the man for whom the disease is named, George Huntington.
Speaker 5: But I wanted to go back a little.
Speaker 2: Further than that. Of course you did, Eric.
Speaker 5: Of course, context context, context, in case you haven't listened
Speaker 5: to our Dancing plague episode, which I think it's a
Speaker 5: pretty fun episode, so I recommend it, right.
Speaker 2: Yeah, definitely.
Speaker 5: Essentially, what happened was that in fifteen eighteen there were
Speaker 5: also other small outbreaks, but the big one happened in
Speaker 5: fifteen eighteen in Strasburg. There was this outbreak of contagious
Speaker 5: and unstoppable dancing and side notes, fifteen eighteen happened to
Speaker 5: be the year after a big sweating sickness outbreak in
Speaker 5: the area.
Speaker 2: Ooh, it's all coming together, all.
Speaker 5: Coming together, okay. And so this dancing outbreak came to
Speaker 5: be called Saint Vitas's dance or Saint Vitas's Korea Korea
Speaker 5: from the Greek for dance like choreography, et cetera. Because
Speaker 5: people would go to the shrine of Saint Vidas to
Speaker 5: be cured and although the fifteen eighteen outbreak was the largest,
Speaker 5: it was not the only one, and there were smaller
Speaker 5: outbreaks in the following years. And by the eighteen hundreds
Speaker 5: these epidemics had stopped happening pretty much entirely, but the
Speaker 5: name of the condition or the condition itself didn't fade
Speaker 5: from public memory, because other people still experienced these similar
Speaker 5: movement disorders, like, for instance, Phoebe Hedges. So I just
Speaker 5: mentioned earlier, but what Phoebe was experiencing in eighteen o
Speaker 5: six was not an outbreak of dancing plague. Of course,
Speaker 5: there was just no other name for it at the time,
Speaker 5: and Saint Vitas's dance or just korea was a sort
Speaker 5: of catch all term for any kind of movement disorder
Speaker 5: at that time. Really only starting in the eighteen hundreds
Speaker 5: is when clinicians start paying closer attention to these Koreas,
Speaker 5: especially those that happened in children, possibly because of the
Speaker 5: rise in rheumatic fever due to like population growth, cities growth.
Speaker 1: Et cetera.
Speaker 2: Yeah, and so when.
Speaker 5: Physicians started describing these cases, they may have also noticed
Speaker 5: another kind of Korea, one that was different from this
Speaker 5: childhood or Sydenham's Korea. By the time that George Huntington's
Speaker 5: description of the disease was published in eighteen seventy two,
Speaker 5: there were at least five other previous descriptions of the
Speaker 5: disease going back to the eighteen forties. But we call
Speaker 5: it Huntington's, not Water's disease or LUN's disease.
Speaker 2: Why.
Speaker 5: Yeah, Well, it might just be a matter of timing, invisibility,
Speaker 5: and chance. But another thing that made Huntington stand out
Speaker 5: was his description, which the famous doctor William Ostler said, quote,
Speaker 5: there are few instances in the history of medicine in
Speaker 5: which a disease has been more accurately, more graphically, or
Speaker 5: more briefly described.
Speaker 2: Huh So it was just like a very very good description.
Speaker 3: Yeah.
Speaker 2: So he won the best Description award.
Speaker 5: He won the Best Description award. Okay, And at the
Speaker 5: tail end of Huntington's publication, which largely focused on other
Speaker 5: forms of Korea, Huntington added a few paragraphs on what
Speaker 5: he called hereditary Korea, noting its inherited nature, particularly that
Speaker 5: it didn't skip a generation mental decline as a common occurrence,
Speaker 5: and it's typically adult onset. It was descriptive yet to
Speaker 5: the point and in the decade after it was published,
Speaker 5: the disease that would later be called Huntington's Korea for
Speaker 5: this amazing description would get a whole lot more researchers
Speaker 5: interested in it, and not always for good reason. But
Speaker 5: before we get to that, I want to talk a
Speaker 5: bit about why the disease might have only been described
Speaker 5: in the late eighteen hundreds, which seems kind of late
Speaker 5: to me. Yeah, Like, you know, Saint Vidas's Dance had
Speaker 5: been around for a long time.
Speaker 2: Three hundred years between.
Speaker 5: Yeah, yeah, and so it might just be that, like
Speaker 5: there are accounts that people can't distinguish between Saint Vidas's
Speaker 5: dance and what might have been Huntington's. I'm not sure,
Speaker 5: but one of the things that people have suggested is
Speaker 5: that low life expectancy may have contributed to the apparent
Speaker 5: invisibility of the disease. Yeah, so people were more likely
Speaker 5: to die of something else before developing any symptoms that sense,
Speaker 5: which would yeah, which would also then sort of like
Speaker 5: obscure the inheritability aspect of it. But having said that,
Speaker 5: it's not like the eighteen hundreds, Like, it's not like
Speaker 5: the year from like seventeen ninety nine to eighteen hundred
Speaker 5: came with this huge, huge boost.
Speaker 3: In life expectancy.
Speaker 5: For example, if you were born in sixteen oh one,
Speaker 5: your life expectancy was thirty eight years. Oh no, whereas
Speaker 5: if you were born in eighteen thirty one, life expectancy
Speaker 5: was forty one years. Like from birth. And there are
Speaker 5: problems with life expectancy from birth because child because infant
Speaker 5: mortality was so high, et cetera. But anyway, so other
Speaker 5: people argue that it actually wasn't the slight increase in
Speaker 5: life expectancy, but rather the reframing of heredity overall and
Speaker 5: how we thought about the inheritance of traits.
Speaker 1: What.
Speaker 5: Yeah, So there was this boom around this time in
Speaker 5: natural history research and experimentation and livestock in plant breeding
Speaker 5: that had led to people thinking critically and publishing widely
Speaker 5: about the inheritability.
Speaker 2: Of traits like Mendel.
Speaker 5: Like Mendel, like Darwin, like if you remember back to
Speaker 5: our Prions episode, like all of the people who were
Speaker 5: doing sheep breeding at that time to try to find
Speaker 5: the best merino wool.
Speaker 1: Yeah.
Speaker 5: And also in medicine, there was still no germ theory
Speaker 5: in the early eighteen hundreds, and so heredity joined miasma
Speaker 5: as this way to explain why certain diseases occurred. Right,
Speaker 5: So there's that, and finally there's the matter of George
Speaker 5: Huntington and East Hampton. So the man and the place.
Speaker 5: George's grandfather, Abel, who was also a doctor, moved to
Speaker 5: this area of Long Island, New York in the late
Speaker 5: seventeen hundreds, where he set up a medical practice, and
Speaker 5: shortly after he arrived he learned of a few families
Speaker 5: in the area who were affected by something that people
Speaker 5: generally referred to.
Speaker 2: As quote that disease.
Speaker 5: Oh, the people who had that disease and their unaffected
Speaker 5: family members were not shunned or stigmatized. They held public office,
Speaker 5: they seemed to be supported by their families and by
Speaker 5: the rest of the community. It was just sort of
Speaker 5: like the way it is. It was like, this is
Speaker 5: how we are here. And George's father also became a
Speaker 5: doctor and some of his patients were also people with
Speaker 5: what would later be called Huntington's disease, and sometimes George
Speaker 5: would go on rounds with his dad. And so when
Speaker 5: George finished medical training, he not only was equipped with
Speaker 5: the ability to observe and describe certain conditions, he had
Speaker 5: the generational knowledge of his father and grandfather, and he
Speaker 5: also happened to live in a town which had a
Speaker 5: higher prevalence than in surrounding areas, and so this set
Speaker 5: him up to write his on Korea in eighteen seventy two.
Speaker 5: It was the only article he ever published apparently wow yeah.
Speaker 5: When his paper came out, other reports of Huntington started
Speaker 5: to trickle in, and not just from the US, Germany, France, Italy, Britain, Austria, Cuba, Poland,
Speaker 5: Russia and many other places reported case descriptions of what
Speaker 5: had started in eighteen eighty seven to be called Huntington's Korea.
Speaker 5: And this research on the late eighteen hundreds filled in
Speaker 5: the details of the clinical picture that Huntington had painted. So,
Speaker 5: for instance, insanity was mentioned as a defining feature in
Speaker 5: George Huntington's description of the disease, but later physicians noted
Speaker 5: that the mental impairment due to the disorder was not
Speaker 5: always severe, or it was variable or at onset differently,
Speaker 5: And it was essentially their understanding of how cognitive function
Speaker 5: worked became more nuanced.
Speaker 2: Yeah yeah.
Speaker 5: And then the average age of onset was studied, autopsies
Speaker 5: were performed, on people who had died from Huntington's and
Speaker 5: these showed these physical changes in the brain, and there
Speaker 5: was a whole lot of compare and contrast with the
Speaker 5: other highly studied form of Korea from this time, so
Speaker 5: Sydenham's Korea. William Osler, who was super interested in all
Speaker 5: types of Korea, got in touch with Huntington to ask
Speaker 5: whether he could arrange a meeting with some people who
Speaker 5: were affected by the disease in the town, and Huntington said, no,
Speaker 5: I don't think that's a good idea. I want to
Speaker 5: respect these people of privacy and you shouldn't bother them. Wow,
Speaker 5: which like in the late eighteen hundreds, I'm shocked.
Speaker 2: By I'm totally shocked, but I know way to go. Yeah,
Speaker 2: I'm guessing Fossler didn't listen.
Speaker 5: Actually he did. Yeah, he was like okay. And then
Speaker 5: Huntington moved away to a different town and another doctor
Speaker 5: took over the practice, and Ostler asked him, and at
Speaker 5: first this new doctor Osbourne said the same thing that
Speaker 5: Huntington had said, No, it's best if you don't come here.
Speaker 5: But then he changed his mind, and it seems that
Speaker 5: he thought that maybe by having Ostler come there to
Speaker 5: do more research on the disease. It could increase awareness
Speaker 5: that could lead to more support and medical treatment and cures,
Speaker 5: But on the other hand, it could bring increased scrutiny
Speaker 5: and unwanted attention to these people without their consent. Osler
Speaker 5: never did end up visiting East Hampton. He did conduct
Speaker 5: research on Huntington's disease on other families and other places.
Speaker 5: But in the last few years of the nineteenth century
Speaker 5: and in the first several decades of the twentieth, Huntington's
Speaker 5: and Osborne's initial fears were realized as the focus on
Speaker 5: Huntington's turned to one of the defining characteristics of the
Speaker 5: disease its heritability. So, like I mentioned, general patterns of
Speaker 5: inheritance had been figured out for a while by the
Speaker 5: end of the eighteen hundreds, thanks to livestock breeders, who
Speaker 5: really could be considered like the first geneticists, even more so,
Speaker 5: I would argue than Mendel. By the time Mendel was
Speaker 5: playing with his p's in the eighteen sixties, these breeders
Speaker 5: already knew about dominant and recessive forms of inheritance. Like
Speaker 5: maybe not in that formal language, but they were incredibly knowledgeable.
Speaker 5: But interest in the field of heritability grew throughout the
Speaker 5: late eighteen hundreds and into the nineteen hundreds, especially when
Speaker 5: Mendel's work, which was published in eighteen sixty six but
Speaker 5: was sort of like lost, like no one talked about it,
Speaker 5: and it was rediscovered in like nineteen hundred. Yeah, and
Speaker 5: Mendel's work gave this like form and calculation and structure
Speaker 5: to these patterns, and the interest grew even more broadly
Speaker 5: beyond that. It wasn't just plant or livestock breeders or
Speaker 5: natural historians that had an interest in which traits were
Speaker 5: passed down, but also so called social thinkers quote unquote
Speaker 5: who began to take these biological concepts and apply them
Speaker 5: to what they saw as social problems. So begins the
Speaker 5: story of eugenics. And this is a story that I've
Speaker 5: touched on so many times in this podcast. If you
Speaker 5: remember back in any of the episodes where I talk
Speaker 5: about eugenics, especially I think the birth control episode, you
Speaker 5: may remember how the term race suicide quote unquote really
Speaker 5: gained traction in the early twentieth century in the US.
Speaker 5: It was one of Teddy Roosevelt's favorite terms. Basically white
Speaker 5: middle class Americans began to be fearful of the influx
Speaker 5: of immigrants, the growth of the lower class, their own
Speaker 5: declining birth.
Speaker 2: Rate, etc.
Speaker 5: Essentially, they were worried that they were going to become
Speaker 5: outnumbered by those they deemed to be unfit or less.
Speaker 5: Then the word degeneration itself began to take on multiple meanings.
Speaker 5: It could be used medically to describe how someone's ability
Speaker 5: to walk and talk and function normally slowly deteriorated, and
Speaker 5: to the eugenesis, it could be used to vaguely describe
Speaker 5: the gradual decline of society whatever that meant. However, they
Speaker 5: wanted it to mean eugenics, and this concept of race
Speaker 5: suicide focused particularly on who was procreating and how to
Speaker 5: control it. They wanted to encourage certain people to procreate
Speaker 5: more and prevent others from procreating at all, by force
Speaker 5: if necessary. The first few decades of the twentieth century
Speaker 5: saw the rise of eugenics from this like niche theoretical
Speaker 5: biology concept to a widespread public movement, with state laws
Speaker 5: legitimizing this way of thinking and genetic research providing a
Speaker 5: scientific basis for it. Marriage prohibition, involuntary sterilization, racist immigration laws, those.
Speaker 2: Were all like the order of the day.
Speaker 5: And I think I'm probably repeating myself from past episodes
Speaker 5: when I say that Hitler and the Nazi Party got
Speaker 5: many of their ideas from directly from the eugenics movement
Speaker 5: in the United States. It's hard to overstate how just
Speaker 5: how pervasive eugenics became and in some ways.
Speaker 2: Still is today.
Speaker 5: Anyway, as eugenics gained traction, it began to hone in
Speaker 5: on certain groups of people or individual traits or conditions
Speaker 5: that they felt were quote unfit. One of these was
Speaker 5: Huntington's disease. Huntington's disease was actually one of the first
Speaker 5: genetic diseases to be described as dominant by William Bateson
Speaker 5: and Reginald Punnett of Like Punnett Square fame who in
Speaker 5: nineteen oh seven. And you know, this is something that
Speaker 5: like I think I have to relearn every so often.
Speaker 5: But just as the twentieth century birth control movement in
Speaker 5: the US has its roots in eugenics, so does the
Speaker 5: study of genetics.
Speaker 2: Yeah, I always have to relearn that as well.
Speaker 5: If someone was a geneticist in the early nineteen hundreds,
Speaker 5: they were very likely also eugenicist. Since George Huntington first
Speaker 5: described the condition in eighteen seventy two, there had been
Speaker 5: no substantial developments in terms of treatment of the disease,
Speaker 5: and because of this, eugenesis then increasingly turned towards emphasizing prevention,
Speaker 5: either through sterilization, restricting immigration, or outlawing marriage. Enter Charles Davenport.
Speaker 5: Charles Davenport may not have started the eugenics movement in
Speaker 5: the US, but he was friends with Francis Galton, who
Speaker 5: was the father of eugenics, and he also founded the
Speaker 5: Eugenics Record Office in nineteen ten, where field workers and
Speaker 5: scientists were trained in how to collect and analyze data
Speaker 5: to push their eugenic propaganda. Osborne's fears about the increased
Speaker 5: attention to the residence of Easthampton and elsewhere with Huntington's
Speaker 5: disease were about to come true. After read about the
Speaker 5: genetic basis of Huntington's and its patterns of inheritance, he
Speaker 5: viewed it as a perfect subject for a large scale
Speaker 5: project in which he would identify the source of the
Speaker 5: disease in the US, as well as shed more light
Speaker 5: generally on heritable disease. The person responsible for carrying out
Speaker 5: much of this study was the eugenics field worker, which,
Speaker 5: like I can't believe is an actual phrase a job
Speaker 5: title eugenics field worker in the nineteen hundreds, Yes, yeah,
Speaker 5: named Elizabeth Munsey. Munsey would go around to towns in
Speaker 5: different states where families with Huntington's had been identified, both
Speaker 5: to interview them as well as constructive family tree Over
Speaker 5: her years as a field worker, she created pedigrees with
Speaker 5: over five thousand people and identified nearly one thousand people
Speaker 5: with Huntington's, about two hundred and fifty of which were
Speaker 5: still living at the time of her survey. And while
Speaker 5: I was reading about this, I just could not stop
Speaker 5: thinking about how horrifying it is that there was a
Speaker 5: eugenics records office collecting the names and locations of people
Speaker 5: with certain diseases. And we can get a taste as
Speaker 5: to what could have happened with this info in the
Speaker 5: US hypothetically by looking at what did happen in Germany
Speaker 5: in the years leading up to World War Two. People
Speaker 5: with Huntington's were among the hundreds of thousands of people
Speaker 5: forcibly sterilized in Germany. Of the three hundred and fifty
Speaker 5: thousand to four hundred thousand people sterilized in Germany during
Speaker 5: nineteen thirty three to nineteen thirty nine. Around three thousand
Speaker 5: to thirty five hundred of those people were people that
Speaker 5: had Huntingtons. And then when the war started, so did
Speaker 5: the exterminations. And we don't really have good numbers for
Speaker 5: that with regards to people with Huntingtons. Anyway, back to
Speaker 5: Munsey and.
Speaker 3: Her field work.
Speaker 5: Rather inconveniently for Charles Davenport, who held these prejudicial views
Speaker 5: that people with diseases of any kind were degenerate or
Speaker 5: feewal minded, Munsey actually gained a great deal of admiration
Speaker 5: and respect for many of the people that she interviewed.
Speaker 5: I mean, she was still eugenicist, let's not forget that. Yeah,
Speaker 5: But what she found was that there was no hard
Speaker 5: and fast rule as to who developed Korea and who
Speaker 5: didn't in terms of like, oh, this person is a scoundrel.
Speaker 5: Oh this person is like really well respected in the community.
Speaker 2: Like nothing to do with who you are or what
Speaker 2: you do for a job or anything like that.
Speaker 5: Yeah, And this went against the prevailing thought of the day,
Speaker 5: at least for the eugenicist that the disease was specific
Speaker 5: to lower classes, and that was a notion that persisted
Speaker 5: well into the nineteen sixties. In terms of Huntington's Charles
Speaker 5: Davenport and Elizabeth Munsey publish the data that months he
Speaker 5: collected in nineteen sixteen in the get this This is
Speaker 5: an actual journal, American Journal of Insanity. What, yes, I
Speaker 5: wonder when it stopped being a journal or what it
Speaker 5: turned into.
Speaker 2: I know it's gonna you probably just turned into something.
Speaker 2: Can we keep googling it?
Speaker 5: It lasted until nineteen twenty one, I think, Oh, American
Speaker 5: Journal of Psychiatry. I'm pretty sure.
Speaker 1: Yeah.
Speaker 5: So what they showed in this article was a much
Speaker 5: more varied picture than the one that George Huntington had
Speaker 5: painted a nearly forty years prior. In it, they discussed
Speaker 5: the variability of the disease, both in symptoms, severity, and
Speaker 5: age of onset in general. Though the paper was terrible statistically,
Speaker 5: and broad claims were made about the unfitness of these
Speaker 5: families and the bad care characters at the top of
Speaker 5: the family tree, this article was essentially used as this
Speaker 5: platform for his eugenic propaganda, and this way of thinking
Speaker 5: about Huntington's didn't die out with Davenport. Unfortunately, if anything,
Speaker 5: this article and that research quote unquote research added fuel
Speaker 5: to the fire. Based in part on Davenport and Munsey's publication,
Speaker 5: there's a Connecticut psychiatrist named Percy Vesi who created an
Speaker 5: origin story of Huntington's in the US as one in
Speaker 5: which witchcraft and scoundrels featured prominently from the very beginning.
Speaker 5: Come on, I mean this account was based on like
Speaker 5: horrible research and just an absence of facts. Everyone in
Speaker 5: his story was either described as a criminal or a
Speaker 5: low life of some kind, and he smeared the name
Speaker 5: of every person he listed. He then blamed Huntington's disease
Speaker 5: for their behavior, and in nineteen thirty two he used
Speaker 5: this article to sterilization His fiction of witchcraft and criminality
Speaker 5: associated with the disease was thoroughly, entirely, completely disproven, but
Speaker 5: only in the nineteen sixties.
Speaker 2: Wow.
Speaker 5: Yeah, so it was repeated and repeated and repeated, and
Speaker 5: still I saw it in some papers from like the eighties.
Speaker 5: Oh no, yeah, This story, which also I will note,
Speaker 5: has been reclaimed by some people with Huntington's as a
Speaker 5: way to sort of like show the enormous prejudice and
Speaker 5: exclusion and faced by people with the disease, and the
Speaker 5: difficulties in overcoming that. But this story created this set
Speaker 5: of stigmatizing associations that persisted in Huntington's literature for decades.
Speaker 5: I was shocked, but also not shocked to find out
Speaker 5: that in nineteen fifty one, there was an article published
Speaker 5: in the Journal of Science, like this extremely prestigious journal,
Speaker 5: in which the authors claimed that there was enormously higher
Speaker 5: fertility in men with Huntington's compared to their siblings that did.
Speaker 2: Not have the disease.
Speaker 5: They used a sample size of two two brothers. That's it,
Speaker 5: nineteen fifty one Science Vacine. These claims were refuted eight
Speaker 5: years later, eight.
Speaker 2: Years later, eight years.
Speaker 5: Yeah, after World War Two, the US's infatuation with eugenics
Speaker 5: was mostly over, and research on Huntington's turned towards treatment
Speaker 5: and molecular diagnosis. And I just want to say that
Speaker 5: I feel like I spent a lot of time on eugenics,
Speaker 5: and I do all the time in these episodes.
Speaker 2: Yeah, it's like every other episode I think these days
Speaker 2: think about it.
Speaker 5: It's a horrible and depressing topic, but I feel like
Speaker 5: it's not talked enough about in history or biology classes,
Speaker 5: at least in the ones that I took. Maybe that's
Speaker 5: different now, but I think it's really important to remember
Speaker 5: how people can misuse or misquote or straight up makeup
Speaker 5: information to push their own propaganda. By couching something in
Speaker 5: science or scientific language, you can really like cause a
Speaker 5: lot of harm if your claims are not supported or
Speaker 5: if you're pushing some sort of propaganda. And I think
Speaker 5: in the US we have this tendency to ignore the
Speaker 5: dark part of our history and pretend like we were
Speaker 5: the heroes, we were the saviors in like all of
Speaker 5: our stories. We have to acknowledge our past, our dark past.
Speaker 2: So that we can be better.
Speaker 5: Yeah, it just it has to happen. I think also
Speaker 5: a lot of the response that some people have about
Speaker 5: you know, eugenics is like, oh, well it was another time.
Speaker 5: It was you have to understand it in the context
Speaker 5: of that time. And it's like you can both understand
Speaker 5: why eugenics became popular in the context of the time
Speaker 5: and also be horrified that it became popular and.
Speaker 3: That state laws existed.
Speaker 5: Yeah, like those two things are not mutually exclusive.
Speaker 2: Not in fact, they are both true.
Speaker 5: Right, It's just like this happened to people. This actually
Speaker 5: did happen to people. How do we not have this
Speaker 5: happen again? Yeah, let's just be better. Let's try anyway,
Speaker 5: speaking of better and better things. Along with the renewed
Speaker 5: scientific interest in Huntington's, there was also the birth of
Speaker 5: several advocacy and support programs. The first was the Committee
Speaker 5: to Combat Huntington's Disease, now called the Huntington's Disease Society
Speaker 5: of America, founded by Marjorie Guthrie in nineteen sixty seven,
Speaker 5: the same year that her husband. And this is what
Speaker 5: cracks me up, Aaron, because every time I said this
Speaker 5: to you, you were like, I don't know who that is.
Speaker 2: I don't know who that is. I so I feel
Speaker 2: like you were talking about him in a completely different
Speaker 2: context recently, And I was like, Yeah, I don't know
Speaker 2: who that is. And I didn't even realize that it
Speaker 2: was Huntington's Yeah, Diddy Guthrie, Yeah, Woody Guthrie. I didn't
Speaker 2: know who that was. And then when I saw his
Speaker 2: name on the Wikipedia page, I was like, oh, I
Speaker 2: know that Aaron keeps talking about I thought you were
Speaker 2: just talking about him for other random reason. He has.
Speaker 2: He's like music.
Speaker 3: Rights, he's like music.
Speaker 5: Yeah. Woody Guthrie was an incredibly influential folk singer songwriter,
Speaker 5: so he inspired like the whole you know, folk music generation.
Speaker 5: He wrote this land is Your Land, for instance. I
Speaker 5: know that song a lot of other songs that you
Speaker 5: would recognize. His guitar said, this machine kills fascists, which
Speaker 5: is also another thing. I was thinking for a quarantine name. Ooh,
Speaker 5: that would be good anyway. So Woody Guthrie started to
Speaker 5: develop symptoms of Huntington's in like the nineteen forties and
Speaker 5: finally was diagnosed in nineteen fifty two. And Marjorie when
Speaker 5: he got his diagnosis, she was asking the doctors all
Speaker 5: these questions and the doctors were just like, well, that's it, sorry,
Speaker 5: Like there's nothing we can do. There's no advice I
Speaker 5: can give you. That's it. And she was like this, no, this,
Speaker 5: I'm not going to accept that, Like this isn't it, Like,
Speaker 5: you know, I want to talk to other people who've
Speaker 5: experienced this. I want to bring us all together so
Speaker 5: that we can get support, so we can get advice,
Speaker 5: so we can raise awareness, to get more information about
Speaker 5: this disease. And so in nineteen sixty seven, which was
Speaker 5: the same year that Woody Guthrie died of the disease.
Speaker 5: She founded this organization where other people could find information
Speaker 5: and get support, and this organization, her mission, was instrumental
Speaker 5: in shedding light on this disease, getting people to talk
Speaker 5: about their experiences and how the medical establishment was frankly
Speaker 5: failing them, and later on in navigating the very comp
Speaker 5: lloicated issues of testing, insurance, financials, genetic counseling. Because of
Speaker 5: all of these years of prejudice surrounding Huntington's and stigma
Speaker 5: and shame, there was sort of this like culture of
Speaker 5: almost like silence around the disease, so like even within families,
Speaker 5: it wasn't necessarily acknowledged. And I think that in more
Speaker 5: recent years, due in part and large part to this
Speaker 5: organization and other organizations that were founded, there's been a
Speaker 5: push to like increase awareness and to stop talking about
Speaker 5: it in these like, you know, eggshell tiptoe terms like hushed,
Speaker 5: Let's talk frankly about this disease and what we can
Speaker 5: do about it and what is you know, what are
Speaker 5: the different options, what is the research telling us, what
Speaker 5: support can be provided? And on the other side, of things.
Speaker 5: There was another organization that was founded more were on
Speaker 5: the scientific angle, on the scientific research angle, called the
Speaker 5: Hereditary Disease Foundation, started by doctor Milton Wexler, whose wife
Speaker 5: Leonora died of Huntington's. Also two of their daughters, one
Speaker 5: named Alice, is a historian, I believe, and she wrote
Speaker 5: like one of the books I read, oh wow. And
Speaker 5: another of their daughters, Nancy, is a geneticist that helped
Speaker 5: to do like a ton of Huntington's disease research. So
Speaker 5: very cool, that's great. So this foundation had a different aim.
Speaker 5: They wanted to understand the mechanism of the disease. So
Speaker 5: in the early nineteen sixties, researchers came across a large
Speaker 5: cluster of people with Huntington's disease in the Zulia region
Speaker 5: of Venezuela by the shores of Lake Maracaibo. In this
Speaker 5: group of people, Huntington's was at a particularly high prevalence,
Speaker 5: so there were even some people suspected of being homozygous
Speaker 5: for the trait, meaning they had two copies of the
Speaker 5: mutated aaliele. And this group of people was studied by
Speaker 5: the Foundation and ultimately just to sort of like long
Speaker 5: story short it in nineteen eighty three, a marker for
Speaker 5: the gene was found and its location was identified as
Speaker 5: being on the fourth chromosome, and ten years later, in
Speaker 5: nineteen ninety three, the last big point in the timeline
Speaker 5: of Huntington's disease so far, the exact gene was found,
Speaker 5: and isolating the gene for Huntington's disease was huge on
Speaker 5: the scientific front. It allowed for researchers to understand how
Speaker 5: this allele produced the effects that it did, to tried
Speaker 5: to come up with potential therapies, and from the patient's
Speaker 5: point of view, it held answers because identifying this gene
Speaker 5: meant that you could be tested for the disease.
Speaker 3: But it's not as simple.
Speaker 5: As that, of course, because with this new ability to
Speaker 5: test came a bag of ethical considerations since this was
Speaker 5: a heritable disease. So, for instance, if a parent did
Speaker 5: not want to get tested, but you did and you
Speaker 5: found out that you were positive, how do.
Speaker 2: You deal with that?
Speaker 5: And Erin, I know you're going to talk a bit
Speaker 5: more about this aspect, so I'm just going to kind
Speaker 5: of wrap it up here and say that we've come
Speaker 5: a long way in our understanding of Huntington's disease and
Speaker 5: how it works, and in reducing some of the stigma
Speaker 5: and shame that used to be so prevalent.
Speaker 3: But just like you said, in many ways.
Speaker 5: We are kind of right where we were at the beginning.
Speaker 5: So erin, I'm hoping that you'll tell me the ways
Speaker 5: that we've gotten better and maybe some hope for the future.
Speaker 2: I'll try to we'll take a quick break first, so
Speaker 2: before we talk a little more about the genetic testing bit,
Speaker 2: let's just quickly go over the numbers. Overall, the prevalence
Speaker 2: of Huntington's worldwide, on average is somewhere between four and
Speaker 2: ten per one hundred thousand people. Okay, it does vary
Speaker 2: quite a bit based on region, and we don't fully
Speaker 2: know why, like why this region is more prevalent than others,
Speaker 2: But in general, in Asia the prevalence tends to be
Speaker 2: far lower. That's where it's kind of the lowest worldwideestimated
Speaker 2: there at about zero point five per one hundred thousand
Speaker 2: people in western, Central and Eastern Europe. So all over
Speaker 2: Europe as well as the UK, prevalence estimates have varied
Speaker 2: between two and seven per one hundred thousand in Africa,
Speaker 2: where we don't have as good of estimates, they varied
Speaker 2: between one and four per one hundred thousand. In Oceania
Speaker 2: it's estimated at five per one hundred thousand, and then
Speaker 2: in North America seven per one hundred thousand. But this
Speaker 2: also varies a lot within North America, Okay, South America,
Speaker 2: outside of that region in Venezuela that you mentioned, which
Speaker 2: is much higher. We really don't have good numbers on
Speaker 2: like the rest of South America, very limited data, but
Speaker 2: so worldwide overall like five to ten per one hundred
Speaker 2: thousand people. And like I said in the biology section,
Speaker 2: the mean age of onset is around forty years, so
Speaker 2: thirty to fifty years, and then life expected see tends
Speaker 2: to be about ten to twenty maybe thirty years once
Speaker 2: symptoms appear, Okay, And that part doesn't vary based on income,
Speaker 2: based on country, based on anything. And that's largely because
Speaker 2: even though individual manifestations of this disease can vary, like,
Speaker 2: the overall course doesn't really vary. And the way that
Speaker 2: we deal with it in all these different countries, regardless
Speaker 2: of country's income doesn't really vary either. So to kind
Speaker 2: of get into both what we can do for treatment.
Speaker 2: And then also what you are mentioning Aaron about this
Speaker 2: ethical dilemmas when it comes to genetic testing. The bottom
Speaker 2: line is that right now, in terms of treatment, we
Speaker 2: have nothing that can change the course of disease. We
Speaker 2: don't have any medicines or treatments that can yes the
Speaker 2: underlying issues or the progression of disease. We have symptomatic treatments,
Speaker 2: especially for the Korea form movements, those involuntary motor movements.
Speaker 2: We have drugs that affect like dopamine pathways and some
Speaker 2: other things that can help with those involuntary movements. We
Speaker 2: also have drugs that can treat things like depression and anxiety,
Speaker 2: antipsychotics if psychotic symptoms develop, So we have those kind
Speaker 2: of psychiatric drugs, but we don't have anything specific to
Speaker 2: Huntington's and we don't have anything to address the underlying
Speaker 2: issue itself. And so in part because of that, this
Speaker 2: is not a genetic disorder like for example, cystic fibrosis
Speaker 2: or sickle cell disease that we've talked about before, where
Speaker 2: early identification can lead to vastly improved outcomes. Because of
Speaker 2: the treatment options that we have available right this is
Speaker 2: not that, and so genetic testing can tell a person
Speaker 2: that they have this gene and can tell them that
Speaker 2: they are going to develop Huntington's or not. But it
Speaker 2: has sparked quite a lot of debate about when and
Speaker 2: whether to do genetic testing, especially when it comes to children,
Speaker 2: like at what age should someone be allowed to decide
Speaker 2: that they want to get tested? Yah, But it also
Speaker 2: brings up ethics in regards to the idea that, of course, ethically,
Speaker 2: everyone has a right to know their own health status. Right.
Speaker 2: I have a right to know what's going on in
Speaker 2: my body. If there's a test that can tell me
Speaker 2: that I have a genetic disorder and I want to
Speaker 2: know it, I have a right to know that. But
Speaker 2: every person also has a right to not know. And
Speaker 2: I have a right to keep all of my information
Speaker 2: secret to me if that's what I want.
Speaker 5: Yeah.
Speaker 2: So, like you mentioned Aaron, a person getting genetic testing
Speaker 2: done for something like Huntington's that is autos almal dominant
Speaker 2: necessarily discloses information about the parents' health status, right that
Speaker 2: they may or may not have wanted disclosed. It also
Speaker 2: could release information about for example, an identical twin. Oh yes, right,
Speaker 2: and so there is a lot of kind of ethical
Speaker 2: issues surrounding this.
Speaker 5: So regarding all of these like ethical considerations and whatnot,
Speaker 5: do you know how much that happens to very country
Speaker 5: to country.
Speaker 2: Very good question.
Speaker 3: I do not.
Speaker 2: I imagine it could vary quite a lot, especially because
Speaker 2: when it comes to disease and how much people want
Speaker 2: to know culturally, that varies hugely in different countries. So
Speaker 2: in some places, like people don't want to know necessarily,
Speaker 2: especially if the outcome is going to be a right, right,
Speaker 2: And so I imagine that it varies quite quite a lot. Okay, Yeah,
Speaker 2: So there's not like it, there's not an answer to this, right.
Speaker 2: It's a very person specific and so this is the
Speaker 2: kind of thing that really has to be a discussion
Speaker 2: between an individual and their healthcare provider, yes, and genetic
Speaker 2: counselors especially. But Aaron I like to try to end
Speaker 2: these episodes on more hopeful notes. So let's talk.
Speaker 5: About the future gene therapy.
Speaker 2: Gene therapy, and really, I think that one of the
Speaker 2: things about how much we do know about Huntington's is
Speaker 2: that even if we don't know every detail about the
Speaker 2: specific mechanisms, we know a lot and we know enough
Speaker 2: to know that gene therapy is a real possibility for
Speaker 2: treatment of this disease. Yeah, and that's I think, really
Speaker 2: really incredible. So there are a lot of different possibilities,
Speaker 2: and there are people working on kind of all of
Speaker 2: these different I have links to a number of papers
Speaker 2: that go in a lot of detail on all of
Speaker 2: the different research that's being done and the different kind
Speaker 2: of ways that you could target Huntington's disease from a
Speaker 2: variety of different angles with gene therapy. So a lot
Speaker 2: of it is maybe using something like RNAi, which are
Speaker 2: little small pieces of RNA that can go in and
Speaker 2: kind of make changes. I think that the most exciting
Speaker 2: prospect is Crisper, Oh, Yeah, which we talked about in
Speaker 2: a lot more detail in the sickle Cell episode, because there,
Speaker 2: I think we're a little bit further along than we
Speaker 2: are in Huntington's. But Crisper, just for anyone who hasn't
Speaker 2: listened to that or who has forgotten, is a way
Speaker 2: by which you can go in to a cell and
Speaker 2: make very specific, targeted changes one time that persist for
Speaker 2: the life of that cell, So you can actually change
Speaker 2: the DNA very specifically and cut out that mutant Huntington
Speaker 2: gene and replace it with a non mutated like a
Speaker 2: normal type Huntington gene, and you can do so with
Speaker 2: one treatment, whereas most gene therapies that are in development
Speaker 2: would require a lot of infusions, which is especially difficult
Speaker 2: for neurodegenerative diseases where you have to be able to
Speaker 2: get that into the brain. So that requires going directly
Speaker 2: into the brain, which is very problematic or very difficult. Yeah,
Speaker 2: sounds very risky, Yeah, but there are a number of
Speaker 2: different strategies. Some gene therapies might try to reduce the
Speaker 2: expression of this mutant protein, so you might still make
Speaker 2: some of it, but you just wouldn't accumulate those toxic
Speaker 2: levels because you're making less of it, Okay. Others like
Speaker 2: I mentioned, especially Crisper, would just cut that mutated region
Speaker 2: out and replace it with a normal region. And then
Speaker 2: there are other therapies that are being developed aside from
Speaker 2: just gene therapy to try and address the downstream effects
Speaker 2: as well, like try and improve cognitive decline by addressing
Speaker 2: things like mitochondrial function, which we think is very involved
Speaker 2: in dementia and cognitive decline in general. So there's a
Speaker 2: lot of research being done. If you look at Clinicaltrials
Speaker 2: dot gov and you search for Huntington's, you can find
Speaker 2: over fifteen hundred studies that are being done. Not all
Speaker 2: of those are drug studies or treatment studies, but that
Speaker 2: is a lot. It's like on par with cystic fibrosis
Speaker 2: and things like that when you kind of just search
Speaker 2: for those studies. Okay, if you check, I'll link to
Speaker 2: a website where you can check specifically gene therapy studies.
Speaker 2: There are six studies currently listed on the gene Therapy
Speaker 2: Clinical Trial Database. Several of them are stem cell studies,
Speaker 2: because that's another possibility, is using stem cells to just
Speaker 2: like regrow the brain tissue that is damaged a whole
Speaker 2: nother mechanism, and some of those kind of addressed dementia
Speaker 2: in general, not just only Huntington's. But there are at
Speaker 2: least two gene therapy studies specifically that are in phase
Speaker 2: one and phase two trials, so human trials for kind
Speaker 2: of safety and feasibility.
Speaker 3: That's cool.
Speaker 2: Yeah, so it is on the horizon. And I'll also
Speaker 2: link to another Nature just sort of write up article,
Speaker 2: not like a peer reviewed publication, but an article about
Speaker 2: a group that's working on Crisper specifically for Huntington's. So like,
Speaker 2: there's a lot of hope, I think, and there's a
Speaker 2: lot on the horizon that that could potentially come to fruition.
Speaker 2: How quickly how many people currently living with Huntington's will
Speaker 2: be able to see those benefits, I don't know, but
Speaker 2: I believe it's possible. Yeah, Yeah, so that's Huntington's. Wow,
Speaker 2: that was a big one.
Speaker 3: It was. Yeah.
Speaker 5: So sources, sources, I want to shout out just a
Speaker 5: couple in particular. I have a bunch, but I want
Speaker 5: to shout out by Alice Wexler, the Woman who Walked
Speaker 5: into the Sea, and also a textbook by Bates, Harper
Speaker 5: and Jones called Huntington's Disease. Those had great history sections.
Speaker 5: And then I have a bunch of other additional papers.
Speaker 2: I also have a number of papers. Especially interesting, I
Speaker 2: think are the ones looking at the future targets for
Speaker 2: future clinical trials in Huntington's disease and the slowing of
Speaker 2: neurodegeneration in Parkinson's disease and Huntington's disease future therapeutic perspectives.
Speaker 2: You can find the list of all of our sources
Speaker 2: from every single episode on our website this podcast will
Speaker 2: kill You dot com under the episodes tap.
Speaker 5: Thank you again so much to Jay for providing their
Speaker 5: first hand account for this episode. We really really appreciate.
Speaker 2: It, Yeah we do. Thank you. Thank you also to
Speaker 2: Bloodmobile for providing the music for this episode and all
Speaker 2: of our episodes.
Speaker 5: And thank you to the Exactly Right Network, of whom
Speaker 5: we are very proud member.
Speaker 2: And thank you to you listeners. We really appreciate you
Speaker 2: listening to this podcast. We really like making it, even
Speaker 2: when it's a tough topic to talk about. Yeah, we
Speaker 2: really do.
Speaker 5: And we appreciate you sticking with us all this time,
Speaker 5: all this time, letting us make this podcast essentially.
Speaker 2: Yeah.
Speaker 5: Well, until next time, wash your hands you feelthy animals?
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