Chapters Transcript Neuroacanthocytosis Syndromes and Other Non-Huntington's Disease Choreas Course: Advances in Movement Disorders I'm going to talk about the sort of the rarer genetic couriers, as Betsy said, which has sort of been my niche interest for a long time now. But these, you know, these are, these tend to be rare diseases, but they're definitely out there, and it's just so rewarding for the families, for the patients to be able to put a name to whatever's been going on with them. So, I'm going to talk a little bit about, you know, the overall term neurocytosis syndromes. Then I'm going to talk about the two specific disorders, which we're trying to use the genetic terms for now. We're going to take a little historical taxonomic detour, and then I'm going to kind of whiz through some of the other genetic forms, some dominant, the dominant recessive and the extinct couriers. So, chorea, as I'm sure all of you know, is the irregularly irregular movement disorder, tends to be flitting between different body parts. It tends to, people tend to be, like, just restless and fidgety. There's this phenomenon of motor imperssistence, where they can't sustain a movement. And I think we've, you've, we've already heard about the piano playing fingers. The movements are faster and more fluid than in dystonia. There's, in dystonia, you have the abnormal sustained postures. You don't tend to get that, or you don't get that in Korea, by definition. It's not as rapid and jerky as myoclonus, although, you know, subtle generalized, you know, multifocal myoclonus can look similar to generalized chore. In general, it doesn't interfere with voluntary movements unless it's very severe. Patients will often incorporate the involuntary movements into a, you know, try and disguise it as a purposeful task. We talk about a parakinesia. So, the neurocancer cytosis syndrome. So, this has been a very confusing area to be working in, and we still get papers which are submitted to journals, you know, they come to my, my colleagues and me for review that still use this nomenclature, which has been very confusing. And I've described it as a genetically and phenotypically heterogeneous group of basal ganglia disorders. But really, over the past two decades, that's the, you know, the Definition has really narrowed down. So, in the, in the 60s, there was this entity which was called Levine- Critchley syndrome. That was kind of synonymous with neuroacanthocytosis, and that name is problematic for various ways. When we started identifying the causative genes, we discovered that there were potentially 4 different entities under this umbrella, what we called choreary anthocytosis, McLeod syndrome, panthenic kines associated neurodegeneration, one of the NBIA disorders, and Huntington's like too. And in the, in the past, I guess, 8 years now, we've thrown out pecan and Huntington's like too. We've, we're just talking about two diseases under this term of neurocancer cytosis. And so now I'm going to, in general, use the genetic terms. For, you know, the, for reat cancer cytosis is VPS 13A disease, it's, um, it's certainly easier to say, it's easier to spell, although you have now like six letters or numbers rather than like one big long hyphenated word, uh, and McLeod's syndrome, um, certainly if you are not from, you know, The the UK and English is not, you know, one of your major languages. You wonder how on earth MacLeod ends up being spelled and pronounced the way it is. Um, it's a a Gaelic, obviously, it's a Gaelic word originally, um, but we're now calling that XK disease. So, um, this is kind of the trend in genetic nomenclature these days. So, what are these famous cancer sites? Let's just talk about those for a second. So we're talking about the, the structures in the top, top panel, in your peripheral red blood smear. We're talking about contracted, irregularly spiculated red blood cells. They can, they can come and go. They may not be present. So, it's Useful if you see them. If you don't see them, don't worry about it. We're not talking about echinocytes in the lower panel, which these are not contracted. Um, these can be like an artifactual feature on, on peripheral, on peripheral red blood smear. Um, so, you know, you don't go nuts. If you suspect this diagnosis, don't go nuts trying to get your lab to do this, unless there's like a hematologist who's like, really keen on doing this, because It may or may not be meaningful. Useful if it's there, but, you know, to be interpreted with caution. OK, so, what's, so, the core disease that is um one of the main ones we talk about is VPS 13A disease. So, this is very rare. We've estimated the, you know, the incidence of about 1 in a million. So, this is kind of just a base upon the number. Of cases we, we know of, like, in the, in the US. It's a, it's a large gene. There doesn't appear to be any genotype, phenotype correlation. What does seem to be particularly interesting for our little area here of New York City, it does seem to be more common in people from Puerto Rico. It's actually kind of much better known in Puerto Rico itself, and we're trying to It's, it's not a founder mutation gene, but it's probably that there appear to be several mutations, and it's probably just more to to like, you know, people tending to marry, you know, within that, you know, social ethnic group. So, um, it's definitely kind of surprising. So definitely something to think about if you see somebody um from Puerto Rico with these disorders, with one of these disorders, well, there's specifically VPS 138. It looks like Huntington's disease in many ways. You don't have the autosomal dominant family history. It tends to present in young adulthood, in the twenties, sometimes maybe a little bit younger than that. And it can present with subtle psychiatric changes. So, you definitely might be thinking of Huntington's disease when you see somebody with some behavioral problems, some psychiatric issues, maybe tics, and then a spectrum of movement disorders, which you'll see in, in the videos. So, Typically chorea, although not always, which is one reason to throw out the name of choreic cancer cytosis. Um, often dystonia, Parkinsonism, tics, truncal spasms can be quite, um, frequent. And a lot of dysphagia, dysarthrias are often affected very, very early on. And then this almost pathenomonic feeding dystonia, which you'll see in the videos. We do know that somewhat similar to Huntington's, the movement disorder can involve evolve over the course of the, you know, the disease from being hyper to hypokinetic. So people can be Parkinsonian. And there was actually a case report a couple of years ago at the movement disorders meeting of someone who presented with in a Parkinsonian state with VPS 13A disease. So, there's certainly some phenotypic variability. So, I've mentioned, so the other features, the typical kind of basal ganglia features, frontal, frontal lobe signs, disinhibition, obsessive compulsive issues, cognitive issues. About 50% of people get seizures, which is not typical for most of our other types of movement disorders, certainly not Huntingdon's. Um, Gait impairment is often an early feature. Peripheral neuropathy and myopathy, people tend to lose their reflexes, which is, again, an informative sign. And they're often picked up by that, you know, if you do the lab tests, and this is actually much more valuable than the peripheral blood smear, is check the CK, check the transaminases, and sometimes these will even be incidental findings in a, in a younger person. They may have mild cardiac disease, there may be autonomic dysfunction, um, which we're still kind of looking at. So this is a young man. OK. Does your head always go to the side like that? It does. OK. Can you unfold your arms for me? And here. So he's got kind of this, you know, sense of continuous motion. He's got some dystonia mixed in there onusa's head tilt. He's lost a lot of weight. Another sign, center. And interestingly, you know, we heard about tardive dyskinesia, of course, and And he was presented with some psychiatric changes, was given an antipsychotic medication, of course. And when he started to develop developing some speech issues, everyone thought he had tardive dyskinesia. So, something to watch out for. It can definitely, you know, Mask the symptoms, the, you know, the regression of the movement disorder. So, this little motor impersistence. And with him, really, the behavioral issues became really a challenge. The loss, lack of insight, difficulty crossing the street, listening to music very loudly. And this this, and this sort of buckling gait, it's been called, like, the rubbery gate. Prob he's got some dysonic posturing on the left, left hand, outturned the left foot. And then there's feeding dystonia, there's not much which will do this, so the jaw pulls open, the tongue dystonia pushes the food out. So there's not much of you, if you, you know, if you see this, and obviously very, very disabling. So you just look at my, look at my finger for me. Just look at my fingers, to say, and this was actually, this is a young man with a whistling tick in front of you. And this is actually filmed, there's two siblings, this was actually filmed in New Orleans in a folk art museum for, because that's just where we end, I ended up examining them. And both like this. Good. And touch my finger. And Kyle, can you, can you try not to whistle? Can you stop it? That's his, his sister in the background. Is it hard? What happens when you, I'm sorry. Yeah. Uh, yes. So she's a little bit Parkinsonian. And uh. I tell you, I'm sorry. Um-hum. Yeah. And you can see how the, the cognitive issues and this whistling tick must have been, you know, drove the mother nuts, and very difficult. Good. And just touch my finger and touch your nose. Touch your nose, touch my finger. Touch your nose. Touch my finger. Touch your nose. And actually, the, the brother, he actually died in status. Usually the seizures can be well managed, but not in his, in his case. And I don't, I don't know what happened. I've not heard from their mother, but she was managing both of these. People, so a little bit bradykinetic. And this is someone, this is another young woman. Some Parkinsonian hands are confronting facial expression like this. Ah, OK, but in persistence, very impaired at this point. And both like this. OK. And. And this was a, a patient of Michele Tagliatti's when he was seeing people, I think actually downtown at Union Square. The patient, the diagnosis was never made genetically. The patient, unfortunately died, but the the tongue protrusion dystonia was very, yeah, absolutely consistent with that. And this is, uh, again, if you see this, this is, sorry, this is very gruesome. This is, so this lip biting, this self-mutilation is, is probably a behavioral compulsion rather than being due to the movement disorder. And this can be, it's, it's variable, but if you see it, um, or like head scratching, non-healing ulcers, finger biting, it's probably more of a behavioral issue, very difficult to manage. Um, so, imaging doesn't really help you if you send somebody for a scan and you say, Korea, you know, it'll, it'll probably be read as Huntington's. You can't tell, you can't tell the difference unless you do, you know, volumetric studies, measure the, there's some subtle changes in the size of the thallami, but that's the fairly typical sign. Um. And what do people, what do people tend to die of in this disease? Um, pneumonia, very typical for these neurodegenerative disorders. Sudden unexplained death, probably related to seizure, though we're not, you know, we're not 100% sure about that, automatic dysfunction. Some of them do appear to have a cardiac etiology. Some of the suicide is not uncommon, probably related to the, the impulsivity, as in Huntington's, and then a few other. Um, not unusual causes of death. So, we recently published a series of 7 cases, which is kind of, we were fortunate to really to bring in these brains kind of from all over, all over the world to, to look at them at the brain bank at Mount Sinai. And we see this very marked loss, I don't know if my point is next, um, of the, the head of the chordate here. And we've been very, you know, because of the function of the protein, which I'm going to get into a little bit, we became interested in lipid, um, lipid accumulation. We did some lipidomics and found some abnormalities, which I am not going to get into because I, I'm not enough of an authority to know quite what it means. But we found some significant changes, even with a very, a very small n here when we did lipidomics. Well, there could be some changes in phosphatidylserine, which might be significant. We also saw these, these, these blue staining, um, inclusions in certain parts of the brain, which we call bluey, bluey bodies, um, which, which we, they might, they might be lipid, but lipid's very hard to look at in postmortem human tissue. And then we found some other markers of um of autopay, PP 62 labeling, ubiquitin labeling inclusions. So, you know, we've got some clues here, possibly related to the underlying protein dysfunction, but we're continuing to really just like look at these brains and figure out what else might be going on. And, and also the relationship to the acanthocytes. You know, I, we think it's probably related to this, you know, dysfunctional lipid metabolism resulting in membrane abnormalities. Um, but it's more really like kind of an epipheenomenon than a direct, um, you know, pathology causing um observation. So, moving on to XK disease, McLeod's syndrome. And there's a reason these two disorders are very, very similar. There's a reason why they're, you know, they were lumped together as a neurocancer cytosis syndrome for many years. This tends, so this, this gene is on the X chromosome. It's, so it affects men, tend to be in middle age, a little bit older than VPS 13A. There's more of a variable phenotype. It tends to go a little bit slower. There can be milder, milder phenotypes, although not necessarily. Um, this is probably 10-fold rarer. So again, my estimate is 1 in 10 million, just based upon the people I know of. So there's, you know, tens of men in this country. Spectrum of movement disorders, less of the lower facial hyperkinetic disorders. Again, 50% of them have seizures, may be a presenting feature. But behavioral changes, big problem, peripheral neuropathy and myopathy, um, high CK, um, very similarly. And I know of several young men now at this point, who were diagnosed in their early 20s before the appearance of any movement disorder, anything neurological, because they, I think for one case, they were, like, being tested for, like, acne medication or something. So, they were screening for, like, you know, elevation of liver enzymes, and they were found to have, that these were, you know, abnormally elevated, and then the CK was elevated. And they kind of didn't, I think one of them may have had a liver biopsy, but they ended up going to, you know, whole genome sequencing because that's what you do if you can afford it to find out the cause. And so these young men, you know, were diagnosed with, with XK disease, like, you know, decades before, um, any clinical, you know, neurological manifestations. Um, one of them had a, a VTA arrest actually, um, and it ended up. He eventually was found to have a cardiomyopathy from, from this. But um, So they can present in in different ways. So, cardiac disease can be very common, often a presenting feature. There was actually Um, a young man, actually it was actually, it must have been 2020, it was like the first summer of the pandemic, you sound like we all fixed these things in our brains when was it related to COVID, um, from upstate New York, who presented aged like 4, 42, with an ejection fraction of like 10% percentage of cardiologist was actually known from his family to have McLeod, um. And I just heard yesterday that he has no apparent neurological symptoms, but he's probably headed for a new heart. So, very variable phenotype, we don't know why, but they can look very similar to, you know, this Huntington's-like phenotype, as you'll see in a second. But this is some, you know, a reason to diagnose these people, to monitor them over the course of their disease. And they also had these abnormal red blood cell antigens, which I'll get into in a second. And So this is a man. I'm sorry, we don't have any knives. So he's actually a volunteer up at the Bronx VA was being seen at, uh, Columbia and was actually diagnosed by our colleague Paul Green, um, for those of you who remember. Remember him. And so this, you know, some behavioral issues, this kind of shambling wide-base gait, likely not due to ataxia, but due to a peripheral sensory neuropathy, as we heard earlier. lots of, you know, kind of behavioral issues. OK, come back towards me. This sort of shambling gait we think of in, you know, disorders like Huntington's. And again, and this man, you would think he has Huntington's, this, this sort of pretty advanced situation, this generalized career, this sets of continual motion, the Buckling of the legs, truncal spasms as well, very common. So very yeah, very disabled. I mean they even fun. Great, OK, so just, uh, you just kind of sit quietly, relax. This is actually, um, kind of my, my friend, who's also on the board of the uh neuro neuroacanthocytosis advocacy group in the US. He's been diagnosed for 20 years now. Just hold both hands out in front of you, straight out in front of you like this. He's still working. Beautiful. OK. Apologize for the, the video, this was a, this was a pandemic over the, over the computer video. So a little bit of Korea. In fact, we just heard some thunder a couple of seconds ago, um. Little ticky. I ended up biking in the rain a little bit. OK. So, um, Maybe just a few more seconds of you sitting just like. And he presented with fatigue and In his 30s, was found to have these serological abnormalities. Walked normally towards and then turn around and go. It's a little bit of a feeding tick. I, so I can control. I, I don't have to push the food out. I can, I can chew with my mouth. I can chew with my mouth closed. I admit it, it does take a conscious effort. If I, if I don't make a conscious effort of keeping my mouth closed. So, so much more phenotypic variability can obviously have a much more benign course. Compared to VPS 13A. So, this was originally defined with abnormalities of um of blood types. So this was the um the, the KX and the Kel antigen system, which was discovered, actually described in the 1960s. Actually, it was Hugh McLeod was a dental student at Harvard, and they were just like screening all the new students, um, and found that he had this abnormal blood group, and for a long time, it wasn't thought to mean anything. Uh, and then eventually, like 20 years later, he started to develop some, some neuromuscular symptoms. He was much more kind of peripheral neuromuscular symptoms. Um, but these people, these men have these abnormal, um, present, they have decreased XK antigen expression and decreased K because these two proteins are linked in the surface of the, of the erythrocyte. And so, if they get, if they fall, like the first guy you. Saw the one with the shambling gait, he fell and broke his hip, and so he needed surgery. And so, if people get transfused with regular Cel positive blood, they will make antibodies. And if they need more blood, they will have a hemolytic reaction. It's like the rhesus reaction for, you know, if you, for people having babies. Um, so if you have a rhesus negative child, baby, um, to rhesus negative mother, and then. Um, I'm not, I'm not, I'm, I'm going to confuse myself, so I'm not going to explain it. But anyway, these people, these people need to, you know, in general, we recommend that these men bank their own blood in case they need a blood transfusion. Unfortunately, the New York Blood Center, which is just up the road here, they've really done most of the Defining research in this area. So, I often will work with them, and they will do the phenotyping, and they'll do the genetics. And they're very invested in, there's a whole network of blood centers that specialize in rare blood types, and they will freeze, freeze blood, in case people need it. Um, so that's a very good reason to identify these men. And sometimes they are identified even, you know, on, on blood donation in their, in their youth. OK, so sleep disorders, um, another, this is kind of like a random thing that that came out of one of our family, uh, question and answer, um, sessions. So, uh, some of them can, some of these men can have, um, periodic limb movements for sleep, can be a presenting feature. They can have a REM sleep behavior disorder, which we think of more in Parkinson's. But obviously, but can be quite violent and dangerous, and they can have sleep apnea apnea unrelated to like body size or obesity. So, these are all things which are potentially need to be treated, um, because they can contribute to other comorbidities. So, as I mentioned, cardiac issues can be a presenting feature. They have a cardiomyopathy. They can have CHF, they can have dysrhythmias. There was even one patient who was diagnosed following a heart transplant. And so, if you make the diagnosis, these men should be monitored regularly. And when we look at the causes of death in McLeod, so not surprisingly, almost half of them do die of cardiac etiologies, about a third of pneumonia, as you might expect. And then this kind of other, you know, selection of other causes. So, there's a whole spectrum of presentations. We've, you know, these people can present to epileptologists. They, when they present with a seizure, they often present to a neuromuscular person, whether it's an elevated CK or peripheral neuropathy or myopathy. They can Present to psychiatrists for the behavioral and cognitive issues. Um, they can present to cardiologists if, if they have cardiac disease. Um, so really, you know, we kind of, you know, the hematologists, if they're found to have the, the acanthocytes, um, so they can really present a whole variety, variety of disciplines. But to say, the, um, The feeding dystonia points in the direction of VPS 13A. The cardiac cardiomyopathy and sleep disorders, um, it is more correlates with XK. So you can partly tell the diagnosis depending upon the family history. Um, if it's young adults or late teenagers, VPS 13A, middle-aged men, maybe the mother has like uncles, father affected, a lot of feeding dystonia, VPS 13A, um, he has a cardiac disease, or organomegaly XK. So, this can be, these can be diagnosed by targeted gene sequencing, if you're thinking of one of them, or by a whole, whole genome sequencing. We can also do protein-based testing, if you can, and this is free. If you can get blood to, to my colleagues in Germany, they can do a Western blood, and they can look for absence of Korean VPS 13A. So none of, none of this protein is made in these people that confirms the diagnosis. And then for XK you can get blood um blood typed at the New York Blood Center. So those are two, you know, protein-based ways of making the diagnosis. So, what do these proteins do? There's been a lot of um work in, is this the, is this a pointer? Do I have a pointer? No, um, is that pointer? Because my cursor is not it. 00 shoot, you're in this. I'm on my compu yeah, it's OK, it's not a big deal. No, no, we, we got it, we got it, we got it, but, uh, OK, OK, if you could use this to point, yeah, OK, you see that, yeah, same thing, you don't have to, yeah. So, the VPS 13 family, which obviously VPS 13A is a member of. So, these have recently been found to transport lipids between subcellular organelles. So, I don't know if you can see that. This is VPS 13A, and that is localized between the endoplasmic reticulum and mitochondria, also between the ER lipid droplets. We have VPS 13C, which is a rare cause of autism or obsessive Parkinsonism. And that, that goes between the ER and I think this is a lystosome here. Um, we have VPS 13D, which is an inherited spastic ataxia, which is um between the ER and mitochondria. So, these proteins are shuttling lipids between different subcellular organelles. Um, and there does appear to be A relationship with an XK in McLeod syndrome appears to be a scramblelase. So this, we now believe that XK is sitting in the, the membrane of these subcellular organelles, and it's somehow channeling lipids into the other proteins, which is shuttling these, the lipids in between these subcellular organelles. And so, You know, this is kind of where we are. We're learning more about these proteins, kind of by, by the month. So, it's really fascinating that, you know, I, and I was, I'm, I'm very much a skeptic when it comes to science, but, you know, colleagues of mine have been saying, oh, there has to be a relationship between these proteins. I'm, uh. But it does appear that they actually may be functioning together, and there may be a really good biochemical reason for these two disorders to look so, so similar. All right, so now we take a little historical detour, it's about 1:30, which is good. So, let's just kind of review the taxonomy here. So, we started off in the 1960s with Levine and Critchley. So, one of the questions has always been, you know, we're neurologists, we love kind of this historical stuff. We love, you know, tying up all the loose ends. What did these families actually have? So, we're going to talk about Critchley's Family first. So they were in eastern Kentucky. Edmund Critchie was actually a British neurologist, and in the 60s, they used to kind of come to America for a stint, and then kind of go, go back and, you know, share the wisdom. Somehow he ended up in like Lexington, Kentucky, and I don't know why. But he did, but he found this big, identified this big kindred in eastern Kentucky. And they were described as having anthocytosis and neurological disorder without beta lipoproteinemia. It's actually should have been without a beta lipoproteinemia because there's this group of lipoprotein disorders where you don't absorb um. So it's mutations of um apolipoprotein, and you don't absorb fat from the gut, and so you have acanthocytes, um, probably again a lipid problem, and you are deficient in vitamin E because you're not absorbing the fat soluble vitamins. Um, and those are the, so that's a beta lipoproteinmia is one of those diseases. But these people, this family had acanthocytes, and they had a very different situation. It doesn't reproduce very well, but the, the pro band, um. He had biting of his lip, he had biting of the tongue, and this is a pneumoencephalogram for all of the young people, showing that dilation of the, the lateral ventricles and shrinkage of the caudate nucleus. So, um, A few years ago now, I got this incredible uh email. And this is from the nephew of the prize, the prize patient from Edmund, Edmund Cri Critch's publication. And he says, are you aware of anyone who is seeking to follow up on the family? So, that was amazing. And what we ended up doing, somehow the IRB approved this. I did everything over the phone. There was a nurse out there who was part of the family who sent us samples. But we ended up getting a whole bunch of blood samples from many of the family, um, the blue is. Is the, the new links of the family were identified, we were able to get samples from everyone with a, a bar underneath them, and lo and behold, the ones with the arrows had this mutation of VPF 13A. And so we published this. We found out the Critch's Kentucky Kindred had VPS 13A disease, and that's just a picture of the, the pro bands in happier days and then, uh, then Edmund Critchley and actually. I, I only went out later to the, you know, I happened to be in Lexington and went out to meet one of the family members, but nobody was. Then they were all heterozygous carriers, of course, so nobody was affected with any symp symptoms. All of the affected had been in one generation, and they died. Now, what about Levine's family? So they, uh, Irvin Levine was based in Boston, um And he examined this very big family based in New England. And we, we had a surname, and my colleague, Adrian Dannik, from Germany, who's very invested in this, was trying to track down this family, trying to investigate the names. If you look at the pedigree, it looks like it's also more dominant inheritance. You've got male to male transmission. Which does not fit with an an extinct disorder. So, you know, for a long time it seemed that the trail had gone cold, and then lo and behold, just a few years ago, A genetic counselor, Navinaritic from Florida, University of Southern Florida, emailed us and said she had a young woman whose father was part of the last generation of the published pedigree, and that this, you know, the, this the, the patient's father had been diagnosed with XK disease. The young woman was coming for genetic counseling because she wanted to know if she, you know, could be a carrier, and if she wanted to get pregnant, you know, she understood that she was going to have, you know, she, you know, since she had two X chromosomes, one from her father, one of these is going to be a mutant chromosome. So she wanted to look into maybe getting, you know, in vitro fertilization to avoid having that genetic disease. So, um, we, we chased that situation, and I ended up talking to a lot of people up in New England, getting saliva kits, sending them saliva kits, getting consent over the phone, mailing them consent forms. And we found out that they did in, you know, these, there were a number of women who were obligate carriers. They'd inherited the mutation on the X chromosome from their their affected fathers. And so these two women, I think it's this one was the, the one getting genetic counseling. And then, and this one, they both had mutations on, on one of their X chromosomes. So, rather beautifully, Levine's family had XK disease, McLeod's syndrome, and Critchie's family had VPS 13A, precancerocytosis, which we were very excited. And actually, Adrian Danny just told me today he's finally finished up the paper on the McLeod syndrome. So we will hopefully publish that and like to tie up those, those loose, those loose ends there. Uh, and there's this other paper which has been causing us lots of trouble. Uh, Richard Hardy, um, in London published this very classic series in 1991, which is still cited in papers. And when we went back and revisited these with genetics, he had 1919 cases, which is like an amazing number of these rare diseases. But when we went back and were actually able to do genetics on tissue, on some of these surviving. Patients, we found that some of one family had XK McLeod, one family had VPS 13A. Some of them had Pecan, which fits very nicely at a very young age of onset, which would be atypical. And some of, you know, and these are sporadic cases, which had a mixture. So, if anyone, you know, tries to write a paper on this, and they'll cite these papers from the pre-genetic era, I'm like, get rid of those. Those are, you know, those are very confusing. So, the, you know, we understand why this has been, you know, until we had genetics, this was all a very confusing situation. Obviously important for the genetic counseling of people. You know, you have to have the genetics to know what to tell people. And this is, so this is from an article that we wrote a couple of years ago, and this is just Kind of summarizing all of what I've been talking about, and here's our, here's our, our red, our red flags for these disorders. So, you, you know, these are people who you might call having as having Huntingtonism. I don't like that term. But these are signs of basal ganglia degeneration, seizures, very informative, loss of the deep tendon reflexes, which are actually often brisk in, like, Huntington's and some of the other disorders. Cardiomyopathy in some situations. Acanthocytes, nice if they're there, don't go crazy if they're not. And then the CK and the transaminase is. If you, if you email me about, you know, when you had the diagnosis, that's, I'm always going to say, you know, what's the CK? Well, the transaminases. Very informative. And then the image, you know, the imaging may be useful, but may just look like Huntington's and not useful for diagnosis. So. All right, so that was my quick whirlwind tour of the neurocytosis syndromes. Let's just kind of work through some of the other disorders in kind of order of inheritance. So, of the autosomal dominant diseases, Huntingdon's, I'm obviously not going to talk about. C9 open reading frame, 72 expansions. Any of you taking the boards will know that this is a common question, the commonest cause of front inherited frontotemporal dementia, and motor neuron disease. We've got prions labeled HDL1, HDL 2 I'm gonna talk, talk about, and the inherited ataxias, very interesting, a lot of these will have movement disorders in addition to the ataxias. Um, and then some of these other disorders, which we've heard a little bit about already, the, um, the iron, the iron accumulation, and then the calcium deposition, um, we heard about. Oh yeah. So, I'm going to talk a little bit on Huntington's Light, too, partly because this is kind of what got me into the field of the rare, the rare chores. So, this is an also more dominant disease. It's probably 1000 times less common than than Huntington's. They're probably very much underdiagnosed. In all cases to date, it appears to be people have have African ancestry. I just saw one reference somewhere of someone with Caucasian ancestry. I had didn't, was not able to look at the paper at that time, but, you know, suddenly, it appears that there's African ancestry, as far as we know, in all of these people. It's a different gene than Huntington's. It's in the junctiphone free gene. And as with Huntington's, The longer repeat size, you have the younger age of onset. Looks very similar to Huntington's down the microscope. It's a very common cause of this phenotype in black patients from South Africa, likely due to the, the, the Bantu expansion. And it's interesting, it appears to be likely a founder mutation. It's not a tendency for longer repeat size in African populations. So, we did a little paper a couple of years ago, just looking, kind of mapping all the people who've been reported. So, in the US it appears to be mainly lots in the, you know, from the, from the south, the southeast. The other areas tend to be areas where slave ships being, bringing people from Um, Africa, they, they, they were stranded on the coast, um, probably accounts for the folks in Venezuela, and also in Guerrero in Mexico, and also in, in Brazil, and there's probably a lot more folks in Brazil, just haven't been diagnosed. And this is the, the pro band who I saw during my fellowship. At Sinai. Obviously very impaired. Korea, dystonia. And this very strong family history. His mother, maternal grandmother, maternal aunts. Very affected, this very marked. Global atrophy, particularly the basal ganglia. And this is his nephew, who was actually being seen. Today is a nice day. He moved to Texas, you and do this like this, you recognize the dulcet tones of Joe Jankovic. And he's got a Parkinsonian phenotype left hand. Interestingly, not, um, not related to the size of the repeats, so that's another distinction with Huntington's. But decreased facial expression, hypokinetic, bradykinetic, loss of weight loss, stooped posture, loss, decreased arm swing. So, some phenotypic variation in this family. Um, and so if any of you do diagnose these people, um, I think I had it on an earlier slide, the group at Johns Hopkins, who identified these, this gene originally is trying to collect all cases. Um, so do let them know if you make the, make the diagnosis. Um, I know Steve, you had a patient a while ago. Um, I don't know if you still follow her, but, yeah, um, but, so, the Johns Hopkins Group is very interested in keeping track of all these families. So, just a little comment on this terrible name, the Huntington's disease-like terminology. So I said this is an adjective masquerading as a noun. It doesn't translate well into languages like, like German. HDL-1 has turned out to be a prion disease. HDL-2, I just spoke about. HDL-3, um, has never really been validated. There was a childhood onset, likely also more recessive. HDL-4 turned out to be spanoce ataxia type 17, um. So, not a, hopefully, nothing else will have that terrible name. So, CNN of 72, I've yet to diagnose anybody with this. I don't know if any of you have made the diagnosis. Julietta, yeah. Still waiting to make, hm? ALS ALS but not Korea, yeah. They're out there. It's certainly in, um, you know, non-black populations. It's a common, relatively common cause of this phenotype. The, um, it's due to a hexa hexanucleotide repeat, has variable phenotypes with the frontal frontotemporal dementia, the motor neuron disease, variable age of onset, often hyperreflexia is a big, a big clue, and then the frontal, the frontal signs. You come? I want to get better, I want to get my tongue stopped wagging. Yeah, does the tongue bother you? Yeah, sometimes. Yeah, all the time, sometimes. And this is a distinction with Huntington's, it's very much the lower facial with that tongue. Doesn't have the feeding dystonia of chorea cancer cytosis, but does have the tongue protrusion, you might think he had tardive looking at him. Little bit of care is his fingers. Nike, 8987. Yeah, so Huntington's does not have this lower facial predominance, we often talk about the forehead being involved, so a different phenotype there. And this is a guy who was actually sent up to the Bronx from the Manhattan VA, um, who was diagnosed. Oh, wait, what happened to my video? Oh, no, it's OK. I think I probably um uploaded the short version. I think, I think that's um hover over it, you click. Yeah. So, a little bit of choreo. Good. And with the left hand. There we go, OK, but predominantly atax an ataxic condition. But you can get these continual fidgety movements, that's, that's chorea. And he was diagnosed by neurogenetics here at NYU. And has this very strong family history of ataxia, which hasn't been, hadn't been diagnosed. And turned out to have kind of in a large range of repeats in trinucleotide repeats in the atrophin one gene. Now, um, can you talk for me? Can you count from one up to 20? So, so it's continual fidgetiness. OK. Thank you. Are you able to put your feet together or no? And I know um I don't know if Xavier can tell us why people with ataxia ataxias have uh have career and different types of movement disorders, but it's certainly something, certainly something we see. So, moving on fairly swiftly, the last few minutes, a couple of comments. So the also more recessive careers, we, we do have the NBIA disorders, as Julietta said. There's a couple which present in adulthood, the ACLloplasm anemia, neuroferratinopathy is also dominant, and, and phospho lipase associated neurodegeneration can present with chorea in adulthood. And I pulled up this tiger with its eyes, but you kind of have to, you have to flip it vertically to make it look like the, the pathonemonic lesion iron deposition in the basal ganglia ganglia with a little bit of edema in the, in the middle. Wilson's disease is also a a rare cause of chorea in adulthood or are recessive. You can never be faulted for looking, looking for this, even if it's pretty unusual. The also some recessive ataxias, including Friedreichs ataxia, and have a spectrum of movement disorders, um, and also the childhood onset ataxias. Um, I mentioned VPS 13 13A is under the osomal recessive list, Niemann-Pix C, and then these few other disorders. And there's recently another, another publication of Niemann-Pixie presenting with a Huntington's-like presentation. And this is also the differential of a young onset PSP typically with the eye movement abnormalities. And this is a, so this man has some Parkinsonian features. But you also saw some piano playing of his fingers, and then you'll see his sister in a second. And she has the piano playing again, Matt's face. You know, more typically an ataxic disorder, she has a wide-base gait. And then there's a small number of X-link disorders. This entity known as as Lubag, Filipino dystonia, Parkinsonism, can present with, with chorea occasionally. Lena's a pediatric disease, of course, with these boys, and they have some movement disorder, but also self-mutilation. And then XK disease, McLeod, I spoke about already already. And then you heard a little bit, again, earlier about about facts has fragile X tremor ataxia syndrome. And this has now been published as a cause of a choreic phenotype. And here, again, you'll see the bright signal in the, the middle cerebral peduncle. OK, so this was kind of my claim to fame. Maybe this is this crazy flow chart, which I started compiling a number of years ago, and every few years, I update it and present it at the Movement Disorders Society meeting, and I actually just, uh, I'm due, due for another update. And it's, you know, it's a little bit obsolete these days, because so often for the genetic careers, we're going, people are going straight to whole, you know, whole exome sequencing, whole genome sequencing. But it is a little bit of a, you know, provides some, some clues along the way, starting off with the, the mode of mode of inheritance and some other clues, especially for the non-genetic careers, um, so some of the metabolic and perineoplastic autoimmune pathways. So, if anyone wants a copy, or if anyone has any critiques of it, they want to look at it, let me know. I'll be happy to to email that on to you. All right, good. So, I'm finishing with a few minutes of questions. So, this was, um, this was actually from our meeting. So, I'm very involved with the neurocance cytosis advocacy group in the, in the USA and also in the UK. This is a meeting we had actually in Ann Arbor in 2016. And this was just like a really nice group. So, we've have our patients, we've got some patients and family members in wheelchairs at the front. And then, Um, the, the scientists and clinicians, you know, all in the back, and we were all kind of, um, socializing together and answering questions and asking patients to contribute to samples and their brains, ultimately, to, to research. I think we have this man here, had McLeod. We have his brain up at Mount Sinai. He lived in Portland, Oregon. Um, This man, he's Latino, but he lived in Boston, and we have, the VPS 13A, we have his brain at Mount Sinai. Um, she is alive and living in London. I think she's about to turn 60. She's had amazing care with VPS 13A, so she's doing, doing wonderfully under with wonderful care. Um. And, um, yeah, so, some of the, the patients who've been very involved in supporting our research, and this is, uh, this is the new, this is the website of the, actually the the UK group. So, if any of you do, you know, these patients are out there, they're probably underdiagnosed. Do let me know if you suspect the diagnosis. And we're very keen to hook them up with the, the support groups. Um, we have a newsletter, we, you know, there's a website, there's like a Facebook thing, and Um, so patients and families can talk to each other, which is, as, as you all know, very important also to get support for care for caregivers, because especially with the frontal lobe issues, it's can be very, very difficult to manage. Um, so, thank you, thank you to my longtime colleague, you know, Adrian Dannik, Gabriel Miltenberg, and Miltenni, who's the, who did the lipidomics, the patient groups, uh, colleagues out at Stony Brook who are doing a lot of the yeast, yeast work, and the basic science, and then the, the, and John Cre. Mary's lab, and the neuropathology brain bank stuff at Mount Sinai, who've really kind of done all the, all the heavy lifting here. I'm just like, I'm just like the person who sends emails and says, says, you know, send us, you know, send us your brain, and they do the, they, you know, ship, they get the brains shipped, and they do, you know, all of the hard work down the microscope. Um, so, um, yeah, if you suspect a diagnosis, please email me. Um. And also if you have any people with other unusual Parkinsonian syndromes or anything else where the patient might leave their brain for, for research and for clinical diagnosis, do let me know as well, because certainly, you know, with the brain bank team at Mount Sinai, we're very interested in in encouraging brain donation and a full neuropathological workup. So, thank you. Published October 24, 2025 Created by
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