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International Parkinson and Movement Disorder Society
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Special Series: Approach to patients with genetic choreas

April 22, 2024
Dr. Ruth Walker invites Prof. Emilia Gatto and Dr. Kevin Peikert onto the MDS Podcast for the second episode of the Chorea Special series. Together they discuss the general approach to patients with chorea of genetic etiology, with specific clues to diagnosis in terms of neurological and other features. They also discuss the nomenclature of neuroacanthocytosis syndromes, specific clues to the diagnosis in the clinical presentation and laboratory findings.

[00:00:00] Dr. Ruth Walker: Hello, and welcome to the MDS Podcast, the official podcast of the International Parkinson and Movement Disorder Society. I'm Professor Ruth Walker from the James J. Peters Veterans Affairs Medical Center in the Bronx and Mount Sinai School of Medicine in New York City, and I'm the guest editor for this special series on chorea.


I'm interviewing Professor Emilia Gatto from the Affiliated University of Buenos Aires, Buenos Aires, Argentina, and Dr. Kevin Peikert from the University of Rostock in Rostock in Germany. Professor Gatto will be discussing her approach to the workup of the patient with genetic choreas and Dr. Peikert will be providing some additional comments regarding the neurocanthocytosis syndromes, BPS13A disease, and XK disease.

And he will also be getting into some of the the updates in the terminology in these syndromes. So we'll start [00:01:00] with Professor Gatto. So, I wanted to start off by asking you, are there any particular situations or particular patients where you might suspect a genetic etiology of chorea rather than an acquired cause?

[00:01:16] Dr. Emilia Gatto: Thank you, Ruth, for the invitation. Oh as you well know the causes, chorea are multiples. But when we need to suspect the genetic causes, probably the first point is that in general, when we are in front of the patient with the genetic chorea, the chorea is is not usually isolated.

In general, you can observe the association of chorea with other movement disorders, such as ataxia or dystonia, in many cases. Other tips or other clues to approach this patient is to think about the Accuracy, the [00:02:00] onset of the chorea and the age of chorea onset, because it's very different when you are in front of childhood or in adult onset chorea.

Otherwise you can keep in mind that chorea could be associated to other non neurological disorder. Non movement disorder exclusively. such as seizure, pyramidal symptoms, or probably hypotonia. Moreover in certain patients could be some specific targets of this chorea and obviously it's very important to search about the family history, but be careful because at many cases.

You don't receive any information about the family. That is a big problem in the clinical practice. And [00:03:00] finally, you need to suspect a genetic chorea when other non neurological symptoms appear. For instance short stature or thyroid disorders or lung disorders or kidney impairment. All of these clues help you to suspect a genetic disorder.

[00:03:25] Dr. Ruth Walker: Great. Thank you. Some really nice points there. So maybe we could focus on, if you are seeing a child, specifically an infant or a child, are there any other specific clues you would look for in a child with chorea 

[00:03:39] Dr. Emilia Gatto: Oh yeah.

In general, globally, the most frequent causes of chorea is an acquired chorea that's mean, side on hand chorea you can think about the inheritance. That is very important, but as I mentioned before, sometimes we don't [00:04:00] have this information.

Even though if we have the suspicion of autosomal dominant chorea, we need to think probably not only in Huntington's disease, with a very, very peculiar onset at the childhood age, because it's not the classical presentation with chorea. Otherwise, in general, it's Parkinsonism or behavioral or seizure disorders, but excluded Huntington's disease, we need to think about the benign hereditary choreas

That is a very interesting topic because it's not only a childhood onset, but it could be occur also in adult onset. In this case, thyroid dysfunction, lung dysfunction, short stature, and developmental disorder could be [00:05:00] the tip or the clue for identification of this kind of chorea. At the same time, in the autosomal dominant chorea it's very interesting to think about the ADCY5 chorea that could be present as a paroxysmal chorea and also with a typical involvement of the facial area with myoclonus or with some specific targets

for instance. It's appear upon awakening patient and with the typical hypotonia and a typical unusual gait, on the other side for the autosomal recessive examples of chorea with childhood onset, we need to think about the. Phenocopies, for instance, in patients with African or [00:06:00] Asian ancestry.

And also, we need to think about the metabolic disorders. That is a very big area, very big field to keep in mind. And probably the main message to, to provide is that is very, very important to identify or to arrive to to achieve a diagnosis because many of these rare chorea could be treatable.

That is a very, very important topic. Moreover, when we think about the metabolic disorder, like uretaric acidurias, or acidemia in general, or some metabolic disorder, such as, deficiencies of aromatic acid carboxylase deficiencies. All of these cases has an specific [00:07:00] treatment able to modify the follow up on the prognosis of our patient.

That is important. 

[00:07:08] Dr. Ruth Walker: Yeah. I know this is like a huge topic and it's many, many very important aspects, which we can't. Address, address today, and there's some useful resources in the literature in terms of identifying potentially treatable causes of childhood onset, genetic metabolic disorders.

What about in the young adult are there any specific disorders you might think about in a young adult as compared to a child or else an older person? 

[00:07:36] Dr. Emilia Gatto: Yeah, in young adults onset chorea, well, we have, again, after exclude Huntington's disease and taking in our mind that At many, many instance, Huntington's disease onset is not chorea but behavioral or [00:08:00] developmental or psychiatric disorders, that is important, that excluded Huntington's disease, where we need to think about other phenocopies.

And also it's very important. to explore the ocular motility. Because sometime that is a very interesting tip to exclude, for instance ocular motor apraxia with ataxia or in some cases psychotic abnormalities that could be detected during the examination. That could be a very important topic.

Otherwise the association of these. chorea with Parkinsonism could suggest a C9 ORF72 mutation. And also, sometimes blood tests could help us during the diagnosis. Two [00:09:00] important disorder To consider specifically as differential diagnosis in Huntington disease with young adults onset is Niemann Pick type C and Wilson disease.

We need to be very careful because, again, these two disorders are now actually, or nowadays a specific treatment. So it's very, very important, and also for the family counseling. These are some examples, but, you know, there are extensive literature in the field. 

[00:09:41] Dr. Ruth Walker: Thank you. Yeah, that's a really great point about the the eye examination, which I confess is still a challenge to me, but very, very important point.

 Now, what about in the older adult someone middle aged and older, there are particular diagnoses you'd think of in [00:10:00] that age group?

[00:10:01] Dr. Emilia Gatto: In this all older adults, well, we need to think, again, to very rare disorder like Huntington's disease with intermediate mutation that in some cases the symptoms onset is during the very, very late onset, it's very late onset, as well as Friedrich's ataxia, but we need to mention chorea.

That is a very interesting topic to to consider because in many cases in general, it's a topic not so much explored. So, in some cases, this patient needs to be examined. Obviously, the diagnosis, we arrive to the diagnosis by exclusion in general. We need also the support of ancillary tests, including [00:11:00] metabolic blood.

CSF test and obviously a brain MRI that help us with the diagnosis and obviously to exclude other pharmacological or other other acquired calculations. causes of chorea in adult aging. 

[00:11:20] Dr. Ruth Walker: I mean, do you think that, senile chorea do you think these people are mainly just like very late onset Huntington's disease or C9orf72 disease?

[00:11:31] Dr. Emilia Gatto: Oh, probably it's a challenge with the differential diagnosis. It's a big, big challenge. And in general, we need in some cases, if we don't have a clear family history or a clear history in general, we need also the support of the genetic testing.

[00:11:54] Dr. Ruth Walker: Thank you. Very interesting. Okay. So I think now let's move on to [00:12:00] Kevin. So to start off with, let's just talk about the the naming, the nomenclature of the, the so called neuroacanthocytosis syndromes. Can you give us an update on this this thorny area? 

[00:12:14] Dr. Kevin Peikert: Yeah. Thank you, Ruth. So first of all, thank you for the invitation, of course.

And thank you for this question, because indeed there is some movement in this this area. I think, first of all, we have to say that the term neuroacanthocytosis refers to a family of syndrome. So it is so to say, syndromatic label. It's not referring to one special diagnosis and such as syndrome would of course include on the one hand progressive neurological symptoms, for example, chorea and also on the other hand, the presence of red blood cell acanthocytosis, meaning that we have these thorny electrocytes in the blood.

So this is. First of all, the description of this syndrome [00:13:00] and historically in the pre genetic era, neuroacanthocytosis was indeed thought to constitute one single disease entity, which was sometimes referred to as Levine-Critchley syndrome. And after several steps I say of Terminological metamorphosis, so to say, of this term, and I'm not going to.

go in any detail because this is a long story. We nowadays use this term Neuroacanthocytosis syndromes as an umbrella term for actually two distinct genetic or monogenetic disorders. And they are called on the one hand side, chorea acanthocytosis, and on the other hand side, McLeod syndrome. And actually we try to avoid, so to say the term neuroacanthocytosis when it comes to a specific diagnosis, as I said, as an umbrella term, it might be quite useful, but for several reason it is really obligatory to define the specific [00:14:00] underlying genetic cause, which is for chorea acanthocytosis mutations in VPS13A gene and McLeod syndrome in the XK gene.

Also, we think that the use of these descriptive names like chorea acanthocytosis can be quite misleading, actually, especially because a patient suffering from chorea acanthocytosis for example, may not. have chorea and may even not have acantocytes in the blood. So the phynotypic heterogeneity is extremely wide, which is why we as a community would like to suggest, as you also said in your introduction, we would like to suggest using VPS13A disease or XK disease instead of these old names which would be perfectly in line with current trends in the nomenclature of monogenetic disorders. So to make this long story short, I think nowadays, [00:15:00] neuroacanthocytosis can be still used as an umbrella term for these two monogenetic disorders that are phenotypically very similar.

And these disorders should be called XK and VPS13A disease. 

[00:15:14] Dr. Ruth Walker: Thank you for that very nice explanation, Kevin. And I just want to mention that we have historically included two other diseases under this umbrella term, Huntington's disease like 2 and pantothenic kinase associated neurodegeneration, PCAN.

And we have listed these other two disorders under this umbrella, but it's very clear now that these disorders should not be included, that, and that we are only talking about VPS 13A disease and XK disease now under this umbrella. So can you tell us, when you would suspect one of these disorders, what sort of patients and then any specific red flags for making the diagnosis?

[00:15:57] Dr. Kevin Peikert: Yeah, so, classically, [00:16:00] neuroacanthocytosis should be suspected in a patient who shows the classical Huntingtonism triad. So as Emilia said, progressive movement disorders like Chorea and Dystonia, but also cognitive and behavioral impairment, however, with normal CAG repeats in the Huntington.

gene. So if we have a patient who is looking like a Huntington's disease patient, but who is not having Huntington's disease, this one should be in this patient, we should consider the diagnosis of neuroacanthocytosis syndromes. But also, Very important as the first symptom can be for example a seizure or muscle weakness or also behavioral issues These syndromes or these diseases should be suspected in patients in specialized centers for epilepsy for neuromuscular disorders or for psychiatric diseases in case we have additional red flags and I'm coming to these red flags a little bit later, but [00:17:00] we should really should have these diagnosis in mind, for example, in a patient who had his first seizure and has mild vocal tics, for example, then we really should think also about neuroacanthocytosis

 So when we discuss the, the age of onset of these patients, there's a difference between the two diseases.

The patients can be quite young. So in their. in their twenties or thirties, and this is suggestive for VPS13A disease. But if the patient is a bit older, so in his or her forties and fifties, or even sixties, this is quite suggestive for XK disease. And also these patients are typically male patients, so XK patients are male due to the inheritance is it's an X chromosomal inheritance.

Whereas in VPS13A disease, we have both sexes. So male and female can have VPS13A disease because it is [00:18:00] autosomal recessively inherited. 

[00:18:01] Dr. Ruth Walker: Right. I mean, there are rare cases in the literature of, you know, female carriers of the XK mutation being affected that we, you know, these are,

definitely the minority and there may be some variation in the phenotype as well, but really this XK disease, McLeod syndrome, is much more a disease of middle aged and older men. Yeah. So that's just something to bear in mind. 

[00:18:25] Dr. Kevin Peikert: Yeah. And you asked me about the red flags. So as I said, this Huntingtonism triad without Huntington's disease is one of the red flags, especially if the chorea and dystonia that we see in this patients. Are predominantly in the orofacial region. So if we have predominant orofacial, chorea or dystonia, if we have tics, vocal tics, if we have severe lips, tongue and cheek biting.

Then we really should think about these diseases. And there's also one very specific thing, which is [00:19:00] called feeding dystonia, which is quite specific for, for XK and VPS13A disease. This is in the end an involuntary tongue protrusion while the patient wants to eat or to swallow, which is really quite challenging for, for these patients.

But as I said, also seizures can be a red flag, especially in combination with chorea, because Huntington's disease patients normally do not have epilepsy or okay, there can be epilepsy as a comorbidity, of course, but Huntington's disease patients do not have seizures due to Huntington's disease.

So if we have this this combination. seizures and chorea, we really should think about XK and VPS13A. The same is true for, for reflexes. If we have absent or diminished deep tendon reflexes, This is not often see in Huntington's disease. We, we see very prominent reflexes, not diminished reflexes in Huntington's disease.

But in [00:20:00] neuroacanthocytosis due to, to neuromuscular involvement, we see regularly diminished or absent deep tendon reflexes. And also CK elevation, even if we do not see muscle weakness, or even if the patient does not have any neuromuscular symptoms, we see a regularly elevated CK and transaminases in XK and BPS13A.

Also another red flag is cardiomyopathy. So, if a patient with Chorea has a severe cardiomyopathy and we do not see any reason for that, then we should think about XK disease because more than 50 percent of XK patients can have a severe cardiomyopathy. And of course, acantocytosis, as I said, is a red flag, even if this is neither necessary nor sufficient to diagnose these diseases.

[00:21:00] And in the end, the last point if we have neuroimaging, atrophy of the caudate can be a red flag, but of course this is similar to what we see in Huntington's disease and other chorea syndromes. 

[00:21:12] Dr. Ruth Walker: Yeah. That's a great point, Kevin. Yeah. Certainly the radiologist may read the, the brain MRI as being consistent with Huntington's disease in any of these patients, but really that is not, that is not diagnostic at this point.

[00:21:27] Dr. Kevin Peikert: Yeah. 

[00:21:27] Dr. Ruth Walker: Well, thank you both so much for this very interesting discussion. We could, of course, talk all day about this. 

[00:21:33] Dr. Kevin Peikert: That's true. 

[00:21:36] Dr. Ruth Walker: And thank you and enjoy the rest of your days. 

[00:21:38] Dr. Kevin Peikert: Yeah. Thank you for the invitation 

[00:21:40] Dr. Emilia Gatto: Thank you for the invitation 

[00:21:43] Dr. Ruth Walker: Thank you so much [00:22:00] 

Special thank you to:

Dr. Kevin Peikert
University of Rostock
Rostock, Germany

Prof. Emilia Gatto
Affiliated University of Buenos Aires
Buenos Aires, Argentina

Dr. Ruth Walker 

James J. Peters Veterans Affairs Medical Center in the Bronx and Mount Sinai School of Medicine

New York City, NY, USA

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