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International Parkinson and Movement Disorder Society
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The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders

November 28, 2022
In this episode, Dr. Hugo Morales Briceño discusses the spectrum of phenotypes and genotypes of children with hyperkinetic movement disorders with Dr. Belén Pérez Dueñas and Prof. Manju Kurian. Read the article.

00:00:00] Dr. Hugo Morales: Welcome to another MDS podcast episode. Today we have the pleasure to have Belén Pérez Dueñas and Manju Kurian. First and senior authors of the recent research paper entitled the genetic landscape of complex childhood onset hyperkinetic movement disorders published in Movement Disorder journal. Welcome Belén and Manju and thank you for accepting the invitation to be interviewed.

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[00:00:47] Dr. Belén Pérez Dueñas: Okay. The reason was that we were both concerned about the classification of movement disorders in children' because it didn't fit in most of the phenotypes that we see in the clinic. [00:01:00] So we wanted to delineate the movement disorder phenotype in a number of monogenic conditions that we know that are not pure, are not isolated, but are combined with different movements at the same time.

And with overlapping phenotypes and also with other developmental issues like complex phenotypes that are quite different from those that begin in the adult age.

[00:01:26] Dr. Hugo Morales: And how many patients were the cohorts at the end?

[00:01:30] Dr. Belén Pérez Dueñas: Yeah, we contacted a lot of centers, like 20 something. We finally got report of 14 colleagues that were aiming to collaborate. And then altogether, I think that we recruited 140 patients. It's not too much, also because the group is genetically very heterogeneous, that was also one of our aims, but still the number of patients for each genetic defect is small.

So I say this is a [00:02:00] limitation of the study, obviously, but still it's worth trying to do a classification of the movement in such a big series.

[00:02:08] Dr. Hugo Morales: And what was the methodology doing the fundamental logical diagnosis? How this was made, because I think it's interesting for the readers to know.

[00:02:16] Dr. Belén Pérez Dueñas: Yeah. We use the current classification that is validated for children in the different types of hypergenetic movement disorders, and then we analyze the videos and by consensus it drove us to define the movement that we were seeing in the video tapes of the children.

[00:02:34] Dr. Hugo Morales: Now in regarding the number of patient and different categories and different phenomenologies, dystonia, chorea. How many patients were there? What was the main finding regarding this?

[00:02:45] Dr. Belén Pérez Dueñas: I think the main finding is that there are very few patients that have a single movement disorder. Dystonia is prominent in the majority of genes, but very frequently dystonia is associated with another movement disorder. And this is [00:03:00] different when you analyze personality conditions with dopamine homeostasis abnormalities that these children mostly have dystonia combined with kinesthetic tremor, but also are very hyperkinetic in the first years of life.

But then you have other conditions where the combination is usually more dystonia with chorea, dystonia with myoclonus, but not so frequently hypokinesia. So dystonia is usually combined with another hyper or hypo kinetic movement, and is usually generalized except for those less frequent cases that begin later.

[00:03:36] Dr. Hugo Morales: I get the sense that there is a lot of complexity and the combination of the movement disorders and sometimes in the clinical practice it's difficult to tease apart, what is the best way to approach this patient. Did you guys find any difficulty in getting the phenomenology diagnosis in particular cases? Saying that this is difficult, we should come to agreement with this.

[00:03:57] Dr. Manju Kurian: Yeah, particularly for some things like, [00:04:00] myoclonus, chorea. They can all look very similar, can't they? So it's quite difficult to differentiate between them. So that's where the consensus opinion's important, but it's really not those signs, I'd say, when it comes to, you know, kind of the phenomenology.

[00:04:12] Dr. Hugo Morales: And may I ask Manju any additional features that were important or relevant in this cohort? Part from the phenomenology diagnosis, including developmental delay.

[00:04:22] Dr. Manju Kurian: So we found that developmental delay was a major factor in determining age of onset. So, genetic conditions that are associated with developmental delay tended to present earlier, and that reached a stable significance. So that's one major finding of the study.

[00:04:35] Dr. Hugo Morales: Yeah. Now for the clinicians that are listening to the podcast, any clues in terms of how to approach these patients that they may be seen in the clinic and say, I will look for this specific sign. At least to shore down the differential diagnosis list.

[00:04:51] Dr. Belén Pérez Dueñas: Okay, many clues there. The clue is to examine the patient performing different tests. The clue is to, analyze the patient [00:05:00] with chorea walking because maybe then you can get, dystonia also, or make them right, because maybe there is a writing dystonia or maybe, different fine motor tasks in the clinic of children with suspected movement disorders.

Because otherwise it's difficult to get all the clinical phenotype. So you need to perform the examination, very standardized and to analyze kinetic movement disorders in making children do a lot of fine and gross motor tasks in the clinic to see all the phenotype. I think that's very important.

[00:05:36] Dr. Manju Kurian: And I think with that also as part of the history, there are things that families will volunteer. For example, if you suspect a dopamine response to dystonia to also ask about, you know, nocturnal events. There's lots to ask specifically about triggers.

You know, these aren't things that families will naturally give you, really, but that's the major difference between assessment of an adult and a child, that you have to have a much more holistic approach. So just like, balance says that the hyper [00:06:00] disorder has to be in a fairly kind of standardized way so that you pick up all things that require stress or other things to be brought out.

But then within the history to also consider the system, so development and intellectual state and obviously things like, you know, a systemic involve to the rest of the body, which is much more common in these complex hyperkinetic movement disorders.

[00:06:19] Dr. Hugo Morales: Are there any combinations of eye movements with a hyperkinetic movement disorder that may suggest of a certain entities.

[00:06:27] Dr. Manju Kurian: Yeah, so certainly if you see the combination of ocular dry disease with a hyperkinetic movement disorder, a neurotransmitter disorder should be high on your list.

[00:06:37] Dr. Hugo Morales: And I gather that the imaging characteristic of this patient where there is a lot of positive findings, meaning there is mostly normal and there is no major abnormalities, and that adds difficulty in diagnosing these patients because the imaging is normal.

[00:06:51] Dr. Manju Kurian: So we selected this group specifically with normal imaging and also there were groups that did not have easy biomarkers in blood or urine that would give you a [00:07:00] same metabolic diagnosis. So these were patients that exactly like you say, either had no imaging clues or no easy biomarkers, you know, so biomarkers only in CSF or more complex biomarkers that are not easy to test.

So very much reliant on clinical acumen and genetic diagnosis.

[00:07:16] Dr. Hugo Morales: And there is a sort of serum mechanisms by which the molecular abnormalities led to this great dystonic syndromes. What are the implications of knowing this in a particular patient and have this molecular diagnosis and aiming for specific treatment and management or progression, for example, and disease?

[00:07:37] Dr. Manju Kurian: Yeah, so the molecular mechanisms are really broad. You'll see from the list of genes that we found that they're involved in a broad range of cellular processes from, gene expression all the way to, dopaminergic pathway genes to quality synaptic genes. You know, that would be some of the main pathways that we've kind of elucidated in this final genetical diagnosis, especially for a young family is, priceless really. Many families want additional children [00:08:00] and it will allow pre-pregnancy counseling that will allow for the implantation diagnosis and diagnosis during the pregnancy for some families. So it has huge genetic implications. I don't think you can underestimate the value of closure for families. So many families have a long, long diagnostic odyssey and have closure with a genetic diagnosis. Very important.

And then making a genetic diagnosis really negates the need for more complex investigations that some children are subject to without diagnoses like skin, muscle, other biopsies, you know, that are much more invasive. So when it negates gets the need for that, And we are really in the age now where precision medicine is really advancing and particularly for pediatric movement disorders within the group.

And many have a precised treatment, received one related disease, and also the new gene therapy for AADC deficiencies. So knowing the genetic diagnosis has certainly a lot of hope for children with these movement disorders because there are a lot of precision gene targeted treatments in the pipeline already in trial.

[00:08:57] Dr. Belén Pérez Dueñas: Also for the symptomatic [00:09:00] treatment, it's important, for example, for DBS sometimes you have concerns when or to whom offer a DBS. And if you have the genetic condition identified, sometimes that helps in offering DBS at a specific moment of the evolution. You can offer it in a timely manner if you have the genetic condition and you know their response to the DBS so you can offer it earlier in certain conditions that are progressive and not wait until the patient is more severely effected.

So genetic diagnosis helps in the management of symptomatic treatment specifically, DBS is also important.

[00:09:41] Dr. Manju Kurian: And then also it helps prop investigation. So for the genes that are well delineated in the literature, you are able to say to families, this is what the future holds, which can be very important even if there's not a treatment.

[00:09:51] Dr. Hugo Morales: And now moving to the futures area of the research in hyperkinetic movement disorders in childhood. [00:10:00] Why is it that the study identifies the gaps of knowledge and what it aims to provide it's future guidance, where to go from here?

[00:10:09] Dr. Manju Kurian: So I think it's balance very nicely and elegantly put. This paper is a starting point that even though we have 140 cases, it's so heterogeneous, you know what we need is 10 times that to really understand the nature of each condition. So we would hope that this paper would then lead to and generate even more interest in those individual genes to really understand long term outcomes, therapeutics that work, gene specific treatments.

You know, we hope that they would catapult research into all these areas and just the general understanding that actually many, many of these childhood onset Hyperkinetic movement disorders, even with normal MRIs, can be very complex with combined features. So not to forget the non neurological features that you can see.

[00:10:50] Dr. Hugo Morales: Wonderful. Thank you again, Belén and Manju for talking about your paper, and I'll invite all listeners to go and read The Genetic [00:11:00] Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders. Recently published in Movement Disorder Journal.

Special thank you to:

Dr. Belén Pérez Dueñas and Prof. Manju Kurian

Hugo Morales Briceño, MD 

Neurology and Movement Disorders Unit, Westmead Hospital

NSW, Australia

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