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International Parkinson and Movement Disorder Society
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History of Movement Disorders: Huntington's Disease in Venezuela

January 09, 2023
Series:History of Movement Disorders
As part of the History of Movement Disorders series, Dr. Sara Schaefer and Dr. David Standaert discuss the research and humanitarian work by Nancy Wexler and team starting in the 1970s in the Venezuelan village of Barranquitas, which has the highest prevalence of Huntington's disease in the world.

[00:00:00] Dr. Sara Schaefer: Hello and welcome to the MDS Podcast, the official podcast of the International Parkinson and Movement Disorder Society. I'm Sara Schaefer from the Yale School of Medicine, and I'm here with David Standaert, the chair of the Department of Neurology at the University of Alabama at Birmingham. As part of the History of Movement Disorders series, we're going to be talking with Dr. Standaert about a village in Venezuela that may be known to some of our listeners that has a very high concentration of Huntington's disease patients and the history behind the research and humanitarian efforts in that village. Thanks for joining us today, Dr. Standaert.

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[00:00:42] Dr. David Standaert: Yes, great to be here.

[00:00:43] Dr. Sara Schaefer: So tell me a little bit about this village.

[00:00:46] Dr. David Standaert: Well, the village we're talking about is a village in Venezuela, in the really western part of Venezuela near Lake Maracaibo. And so this is actually one of several villages that are along the shore of the lake where there's a very [00:01:00] high concentration of patients with Huntington's disease, presumably from a founder effect. A gene transmitted probably from the European population quite a long time ago, but really has taken root there. And there's just really a large number of patients affected by Huntington's along the shores of Lake Maracaibo.

[00:01:18] Dr. Sara Schaefer: Yes, I read that it is somewhere along the lines of one in 10 people actually with HD in this community.

[00:01:25] Dr. David Standaert: Yes, in the villages, it probably is that high. So, you know, the history of this really dates to a conference that was held. So George Huntington described Huntington's Disease in 1872. And then in 1972 there was a congress or a conference recognizing the hundredth anniversary of his description.

And the story, at least the way I've heard it, is that there were several attendees at this conference who were surprised to hear from a physician in Venezuela that they had such a large number of Huntington patients in Venezuela, and that was really the inspiration for what became the [00:02:00] Venezuela Huntington's Disease Project spearheaded really by Nancy Wexler and involving people like Anne Young and Jack Penney and others. That has eventually turned into an annual expedition that would go to Venezuela to see these patients to collect clinical information, to collect DNA, and ultimately help with the hunt for the Huntington's disease gene.

[00:02:21] Dr. Sara Schaefer: Well, that's amazing that it took a Congress for this to be even on the radar of physicians in other parts of the world.

[00:02:29] Dr. David Standaert: Yes, I think so. Although you have to appreciate the rural nature of the area that this is in. So I had the privilege to go with the Venezuela Huntington Expedition in 1996. And so the way the expedition operated is we would go to Maracaibo. Which is one of the larger cities in Venezuela, in the province of Zulia.

 And so this is in the sort of the northern corner of the lake. And Maracaibo is a reasonably developed city. But the people affected by Huntington's are spread out along the [00:03:00] shores of the lake. So it's a good three and a half hour drive along the borders of the lake to get to some of these villages.

And these are very undeveloped areas. I mean, we're talking about really very limited access. You know, typically no running water, minimal electricity homes with tin roofs and dirt floors. And you know, this is a setting where there's really not much in the way of modern medical care at the time, and I believe there really isn't still much to this day.

[00:03:27] Dr. Sara Schaefer: So you mentioned Nancy Wexler, who's obviously very central to the whole historical experience of going to this village and studying these people and trying to help them. Why don't you tell me a little bit about Nancy Wexler.

[00:03:41] Dr. David Standaert: Well, Nancy is a really remarkable person. Her mother was affected by Huntington's Disease. And Huntington's is an autosomal dominant disorder. And I think in retrospect it's turned out that a number of members of her family were affected by Huntington's and her mother died of it, and she really made a commitment to [00:04:00] spearheading the research on Huntington's disease. She was very much the driving force in those days responsible for creating the Hereditary Disease Foundation and really for pushing the whole idea of first chasing the gene, and then chasing. The idea of, understanding the disease further and developing cures and treatments for it.

And Nancy, of course, was at risk for Huntington's because her mother had it and announced just a few years ago that she does indeed have Huntington's disease. And I think a lot of the people who know her have seen the symptoms emerge over the years. So in the end it turned out to touch not only her mother but Nancy herself.

But she really was an extraordinary person. Someone with just boundless energy and enthusiasm and total commitment to finding the gene and then ultimately finding the cure.

[00:04:47] Dr. Sara Schaefer: And what was the nature of the work that she did?

[00:04:49] Dr. David Standaert: Well in the Venezuela Huntington's project, the original motivation was to find the gene. Everyone knew this was an autosomal dominant disorder, but it actually proved quite [00:05:00] difficult to locate the gene itself. Now, this work is going on in the late 1970s and early 1980s. And of course gene sequencing technology at that time is not what we have today.

Also, turned out that this gene was near a telomere, which is a difficult area to sequence and was a triple repeat disorder, and that was a kind of pathology that was unknown at the time, and so people didn't really know what they were looking for. So the original mission in Venezuela was to locate patients and families to see these people examine the patients, examine the families, look for signs of Huntington's, essentially to build out the pedigree of affected and unaffected individuals and collect the DNA that was used to pursue the sequencing and ultimately the discovery of the gene. So when I was there in 96, the pedigree had grown to almost 20,000 patients. We had it printed out on an enormous scroll of paper that was wrapped around a hotel room in the hotel in Maracaibo, because it was a little pre-computer here in 1996 [00:06:00] or early days of computer and many things are still paper. And what we would do is go out to these villages and find the families. So for example one of the areas we would often go would be Barranquitas which is one of the larger towns at the southern tip of the lake. And in Barranquitas we would set up shop in kind of a community health building, it was a cinder block building with no air conditioning of course. And we would set up shop there and patients from the town would come to be seen by the doctors and participate in the research. They were offered a few Bolivars to participate in the study, but many of them knew about Huntington's.

They didn't call it Huntington's. And in fact, they called it El Malade San Vito, Saint Vitus Dance, which of course we would use that for Streptococcal Chorea these days. But the local name for it was El Malade San Vito. Even though in that population it's really Huntington's Disease and genetic in origin, and so they would come with their family members and somebody at the door would have a big computer print out and try and figure out which family they're actually connected to.

Of course, they don't have much in the way of[00:07:00] government identification or anything, they just have names and histories, and you would try and sort out who they were, and then the neurologist would examine them and score the Huntington symptoms, really trying to determine who was affected and who was unaffected.

We'd collect blood if we didn't have it. Sometimes have other samples and then that would all get shipped back to the U.S. to help in the pursuit for the gene. So the genetic marker was discovered in 83. That's when it was localized to chromosome four. And then it was 93 when the gene itself was actually cloned.

So when I was there, we knew actually what the Huntington gene was, but what we were interested at that point were modifiers. Why did some people have early onset? Why did some have later onset? But the work was really getting up early in the morning, driving three hours to Barranquitas, setting up shop, seeing 500 patients with Huntington's in one afternoon, collecting information about them and then getting back to the hotel late at night to get up and do it again the next morning.

So it was really quite an extraordinary experience.

[00:07:59] Dr. Sara Schaefer: [00:08:00] So clearly the early goal of the research was to find the gene, and you mentioned that in later years it was looking at environmental modifiers because as we know, the number of trinucleotide repeats only explains to a certain extent the age of onset of Huntington's. So, in what ways do you think the research changed the world of HD medicine?

Other than identifying the gene itself? What other discoveries, or did it increase interest in awareness or funding for the study of this disorder?

[00:08:37] Dr. David Standaert: Well, I think that we were interested in both genetic and environmental modifiers. At that time we didn't really know which would be more important. And actually probably some of both are important. So we were interested in the question, were there genetic modifiers? But one of the things you saw, in Venezuela was the age of onset, was often quite young.

It was not unusual to see adults with onset at 20 or 30. And obviously [00:09:00] in current day in North America that would be very unusual. But probably some of that was environmental and really nutritional. The nutritional state of these families was really quite difficult. They were, subsistence fishermen, basically.

And living along this lake and I have a very vivid memory of one morning I went out by the lake and there was a little girl sitting by the lake and we were both kind of looking at it. And my Spanish is sort of rudimentary. She spoke no English but she pointed at the lake and said, contaminado which pretty much captured it. The lake was full of oil platforms, was contaminated by oil refineries and oil drilling in the lake. And this really made it difficult to be a subsistence fisherman when you're living next to a polluted lake. The other problem they had, of course, is that the families that are touched by Huntington's there have to take care of those ill relatives.

So you know, these very poor families are now burdened with an individual who can't work and can't fish. And this drives them even further into the poverty, into the scale there. So it's really quite [00:10:00] a difficult existence that they have there. And to see that was really pretty remarkable.

I do think, we learned a tremendous amount about the background genetics of Huntington's. Most of the DNA collections that are still used today to understand Huntington's and generate animal models and things were derived ultimately from the Venezuela experience and a tremendous amount of information about natural history of the disease emerged from there. Even the understanding of the relationship of triple repeat size to age of onset really comes out of the Venezuela, Huntington experience.

[00:10:30] Dr. Sara Schaefer: And what did the experience teach you as a researcher, as a clinician, what did the experience teach you?

[00:10:37] Dr. David Standaert: Well, there are a lot of interesting different levels of that. I mean, I get a chance to work with Nancy Wexler, which was extraordinary. And Anne Young and Jack Penney were both there who are really amazing forces in this field. And so that kind of personal interaction was really interesting.

I do remember one afternoon I was in Barranquitas and we were examining a relatively young patient who was probably 15 or 16. We had a standardized [00:11:00] exam that included eye movements and tests for bradykinesia and rigidity and gait and things that would be clues to Huntington's if there was no obvious chorea.

And there were some subtle bradykinesia and some subtle eye movement abnormalities in this patient. But being a relatively young faculty member, I was not very impressed. And I remember Jack Penney saying to me, what do you think? Is this patient likely to be affected? Is this early Huntington's that you're seeing here?

Or is it just normal? And I said, well, these are minor abnormalities. It's probably nothing. And he said, well, you should look around the room because at least 50% of the people in the room have Huntington's disease. And if you start from that frame of reference and you see subtle abnormalities, the odds that it's Huntington's are actually quite good.

So maybe it's sort of the beigian experience of Huntington's in a normal clinical practice setting is quite rare. Huntington's in Venezuela is so common that if you simply guess Huntington's, you'll be right half the time. And if there's any signs at all, then that's a strong clue that this is likely early [00:12:00] Huntington's.

So that was kind of extraordinary and to see how people coped with this and lived their lives, some of them with just the chorea wasn't so bad, but when they really became debilitated, it was very difficult for the family to care for them. And we did what we could in terms of bringing things like antibiotics and, things like this for them.

But the team only went once a year. So, you come, you do what you can in a year, but we're not there year round. And it's hard for the families to manage these patients when there's really not access to good care.

[00:12:29] Dr. Sara Schaefer: What were some of the other barriers to the research? You mentioned potentially language barriers, difficulty identifying patients because of lack of paperwork and identification, those types of things. Were there other barriers in terms of the political landscape there, or barriers in terms of the villager's own stigma about Huntington's disease or about American physicians or anything of that nature?

[00:12:57] Dr. David Standaert: Well, there were a lot of practical issues, so we would stay in [00:13:00] Maracaibo, in, I guess what passes for a modern hotel. Had a bit of a third world atmosphere to it, but it was a reasonable hotel that we're staying in. But of course, the patients are out along the lake and it's really not safe to stay overnight anywhere out in these villages.

So we would have to get up early in the morning, drive down along the shore of the lake. Which to be honest, is a pretty sort of lawless territory. There was really no law enforcement, there was a fair amount of gangs and things in those areas. And you'd have to drive three hours or so often in the dark to get down to these villages and do the same coming back.

And Nancy Wexler was notorious for keeping us late. She was extremely involved. She always wanted to see one more patient, and that meant we didn't drive back till midnight. Well, that's the way it was gonna be. Nancy was in charge. So, we did have some late night encounters. Remember one time getting stopped on the highway on the way back, and we were actually concerned that maybe this was one of the gangs or something, but it turned out that the truck ahead of us had hit a crocodile and killed a crocodile in the middle of the [00:14:00] road.

But of course they didn't wanna just move the crocodile, they wanted the crocodile skin. So they were skinning the crocodile in the middle of the highway and they wouldn't let anyone pass until after they finished with this. So this is the kind of thing you ran into, but in terms of, personal safety, there were some concerns in those days and part of the project would take you near the Columbian border.

A lot of drugs were moving across the border at the time, and we did see various armed people in vehicles. I never had a personal encounter with an armed group. But others did. And so, it was a bit lawless. Of course, things got much worse later on with the change in politics in Venezuela in the early 2000s. And that was an even more unstable situation. But it was a bit unstable in the 90s even.

[00:14:40] Dr. Sara Schaefer: Were there any lasting impacts in the community itself that have gone beyond just the yearly visits. For example, I read about the Huntington's chorea home of love and faith. What is that? Have there been other efforts?

[00:14:55] Dr. David Standaert: Yeah, so that was a project that was getting started while I was there. And ultimately I [00:15:00] think was built in 1999. So they convinced the local government to tear down a bar that was really a very disreputable place and build what was called a casa hogar, it was really a home for patients and families affected by Huntington's.

And that was pretty successful. And they managed to funnel some philanthropy and support in there. Now again, Chavez rose to power in Venezuela in 2002, and that's when things really became unstable down there. And as a team, the team has not returned since now. Nancy Wexler has been back herself and she's written about returning to Venezuela since the rise of Chavez and the political turmoil there. But as an organized team and expedition, it really hasn't been possible to go back since the early 2000s. And honestly, I'm not sure what happened to that. It was a great innovation and I think it was a step forward for the people living there, but I don't know if it's been possible to sustain it after the, essentially revolution in Venezuela.

[00:15:55] Dr. Sara Schaefer: It sounded like from what I read about it, that it was a very interesting [00:16:00] setup where the people who were caring for the Huntington's patients were those who had been personally affected within their family by Huntington's disease, and therefore had a particular empathy and understanding of the disease itself. 

[00:16:14] Dr. David Standaert: Yeah, and there were local physicians involved too. So there were some physicians that lived in Venezuela that were part of the team. And, were there year round and were part of the structure. And it is remarkable when you go to a village where one in 10 peoples affected by Huntington's. You literally have people standing on the street corner with chorea. You can go into homes and find they have people affected with a range of different conditions. Another thing that was unusual in Venezuela is that cause the families knew about this disease and they knew it ran in families that generally if they were going to marry and they were from a family which had el mal.

The only people they could marry were other families with el mal. So the upshot is you actually got homozygous in the pedigree. And at the time we knew there were some 50 [00:17:00] homozygous patients in the pedigree that we'd assembled. And that means that a hundred percent of their offspring are gonna be affected with Huntington's disease.

So we had one particular family where the father was a homozygous and there were 13 children, and you knew all 13 of them were gonna have Huntington's disease and to go out and see this family. And they were, many of these families were very gracious and would bring you in and offer you what they had, which often wasn't much.

Often you're kind of in the courtyard of their house, which might just have a couple of folding beach chairs at best to sit in. And that's about it. But they would try to offer you that. And, they were really very open. I think most of them, certainly the ones who came to work with us felt we were trying to help, which we were.

I think we were limited in what we could do. And one of the things I think that has always been a point of discussion among the team was, suppose we find the cure for Huntington's. How are we ever gonna bring it back to this group of people?

And I think that's still an issue, right? I mean, if you think about the kind of treatments we're pursuing for Huntington's today, the things that are on the front burner are gene [00:18:00] therapy strategies and things like this to bring that back to Venezuela in a place where, there's not even really any running water, much less ability to do an MRI or something like this.

I don't know how you translate the therapies that are on the front burner today of actual population like that.

[00:18:16] Dr. Sara Schaefer: Absolutely. That adds a little bit of coloring of ethical controversy to the entire thing.

[00:18:22] Dr. David Standaert: We did do the best we could. We often brought vitamins with us. They were always short on vitamins and had nutritional issues, so you'd bring multivitamins, you'd bring simple antibiotics for UTIs and other things like this, and I think that was helpful to them.

But in terms of really bringing a cure for Huntington's back to Venezuela. I'm still not sure how that's ever gonna happen. If it is, it's a ways off from where we are today.

[00:18:45] Dr. Sara Schaefer: Unfortunately. Well, thank you you very much for giving us this background on this very interesting case study in Huntington's disease and in research and in finding genes for various disorders and trying to figure out what's [00:19:00] going on.

[00:19:01] Dr. David Standaert: Yes. It was an extraordinary experience and a chance to get to see something you would never see in an ordinary neurology practice. And to see how people adapted and coped with this. And to work with people like, Nancy Wexler and Anne Young and Jack Penney, who were so driven to understand the disease and find the cure.

[00:19:18] Dr. Sara Schaefer: It certainly sounds like there are a lot of unbelievable characters in this story from Nancy herself to all of the patients and families that you worked with down there.

[00:19:27] Dr. David Standaert: Yes. it was an amazing time.

Special thank you to:

Dr. David Standaert

Professor and Chairman of Neurology
University of Alabama at Birmingham 

Sara Schaefer, MD 

Yale School of Medicine

New Haven, CT, USA

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