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Welcome, Carolyn.
[00:00:30] Prof. Carolyn Sue: Thanks very much, Francesca. It's lovely to be here.
[00:00:32] Dr. Francesca Morgante: So over the past 20 years, major advancement in the understanding of the genetics of dystonia were achieved. Can you just tell with us the main milestones in this genetic journey?
[00:00:46] Prof. Carolyn Sue: Well, I think it's all about the genetic discovery of these genes. We really have over these last few decades, discovered a lot of genes that have been the cause for dystonia. And they've provided not only improvements for our clinical care of the patients, [00:01:00] but also mechanistic understanding of this disorder as a group of movement disorders.
[00:01:05] Dr. Francesca Morgante: So let's start from the first one, torsinA, previously called DYT1. Would you like to describe to us the main phenotype?
[00:01:14] Prof. Carolyn Sue: Well, this is usually an early onset dystonia, but really has major phenotypic variability to be honest with you. And so you know, one can present with a focal dystonia or usually in the hand typically, but then it can generalize and spread to more limbs and of course involve the actual musculature.
And so it can become quite generalized in the long run. Of course it can stay very focal in some patients. And within families, this can be variable between family members. So one rule is that if you see a person with dystonia, then one should always test for DYT1 or torsinA as a general rule. And it's very, very easy to test for it as well.
[00:01:56] Dr. Francesca Morgante: And other genes that we would like to mention in [00:02:00] this milestone for dystonia. Can you just, mention them to us? For example another gene that represented a major milestone in the understanding of dystonia is THAP1 , DYT6. Do you think that the phenotype of DYT6, THAP1, can be distinguished by one of DYT1 torsinA?
[00:02:20] Prof. Carolyn Sue: Yeah, absolutely. The phenotypes can be quite separate. So fortunately with THAP1 there's usually more of an upper body involvement. And so usually it affects the oral musculature and the walking is preserved. So these different types of phenotypes can indicate which type of dystonia and the genetic cause for these dystonias that one should pursue in a clinical setting.
[00:02:43] Dr. Francesca Morgante: So with all this with all this press around genes that has been discovered, I wonder whether and when we should ask for the genetic test in a child and an adult with dystonia.
[00:02:55] Prof. Carolyn Sue: That's a great question because really I think if the patient's presenting to the [00:03:00] clinician, then usually it's our responsibility to find an answer. Key to that is the diagnosis and genetic testing is really getting to that crux of the problem. So I feel that, if someone presents with dystonia, then it is up to the clinician to really consider whether a genetic form is presenting. And this can be helpful for not only informing treatments, but also informing the family about what the risks are for presentation. So we've already talked about a DYT1, or torsinA, and THAP1 which is DYT6. Essentially if those patients were to present with the clinical phenotypes, then we can proceed with genetic testing at presentation. Assess the risk of the patient having a family member having this disease because they have autosomal dominant transmission traits. And then also think about the possibilities of response to treatment. It informs the way that you might medically manage a patient with this condition.
So genetic testing when should we consider it? I think at the time that the patient presents, whether you [00:04:00] find an answer, a positive genetic test is another story because unfortunately we haven't actually identified all of the genes that cause dystonia at this point in time.
Although there are many, many, more genes that are being discovered due to the advances in genome sequencing.
[00:04:15] Dr. Francesca Morgante: Yeah. You mentioned this advanced genome sequencing, but I think that we should also highlight that unfortunately access to advanced genetic testing is not possible in all countries. There is a huge gap between, for example, Europe and North America and Australia and the rest of the world.
So if we have to consider the basic of genetic testing in dystonia, which genes by frequency in dystonic syndrome, we should really have access to?
[00:04:45] Prof. Carolyn Sue: Yeah. This is again a very relevant question, Francesca. You know, genetic testing, not being available equitably around the globe is a real problem. Of course those countries where it's available, it is a really important addition to the tools that we [00:05:00] have in our clinical toolkit to diagnose patients.
But at the end of the day, if the genetic testing is not available, and that can be either through a clinical service laboratory or even through a research program, then, it's the responsibility of the clinician to do the best they can in terms of making a clinical judgment potentially guided by the phenotype of the patient to see whether they can have the best management plan that's available to that patient in the absence or the presence of a genetic diagnosis.
So, unfortunately we can't solve all of the world's problems and make genetic testing available everywhere. Although, we can try and work together to allow access to genetic testing for our patients across the world.
[00:05:39] Dr. Francesca Morgante: So you mentioned many times the variability of phenotypes, the same gene different phenotypes within families, and also across different families. How this happens, what is the cost for this variability? Can you just provide some hypothesis to this unsolved question?
[00:05:59] Prof. Carolyn Sue: Sure. [00:06:00] Francesca, a big question as usual. So thank you. Look, I think understanding variability is known. Some mechanisms are known. Of course, there can be genetic modifiers, typically in DYT1 torsinA. And there are mechanisms that we don't know, which are only hypothetical at the moment, but they can include not only genetic mechanisms, but also environmental influences. So precipitating causes, for example, in ATP13A2 for example, where rapid onset dystonia can occur, usually precipitated by some acute event. And so we know that those sorts of precipitants can lead to the demise or the acute or abrupt presentation of someone's clinical symptoms and signs.
So those also can contribute to modifying the clinical course. And of course within families we know that the clinical course of even familiar forms of dystonia can be variable. And I guess we just don't know all the answers yet.
And it's subject to major sort of efforts of research [00:07:00] endeavor, which I encourage everybody out there to try and contemplate or undertake.
[00:07:04] Dr. Francesca Morgante: So this is a very relevant comment about the role of environment. We have a number of studies on the epidemiology in dystonia, the risk factor for dystonia, in people with sporadic dystonia, and I think that your comment induce our field to integrate like this big cohort and study genetic modifiers in this cohort because of the environment as a big role.
And maybe in the future we will be able to counsel people that have some genetic variants about their lifestyle in order to prevent or modify the clinical course in dystonia.
[00:07:40] Prof. Carolyn Sue: Absolutely. Yeah. I mean, global collaboration, I think with these sorts of rare diseases is essential to our progressing the understanding of these disorders rapidly. And so again, if we can collaborate, build cohorts that are large enough for us to adequately power studies to find these genetic modifiers or even environmental [00:08:00] modifiers, then I think that would help to progress the care of our patients.
[00:08:05] Dr. Francesca Morgante: So last but not least, many genes and each of them are involved in different mechanisms. So do you think that now in 2023, are we able at least to summarize some fundamental mechanism associated with genes involved in different dystonic syndromes.
[00:08:26] Prof. Carolyn Sue: I wish that was so, Francesca. I think we are getting more and more information about what contributes to dystonia and why the cells function. And not only that, the location of the cells that are dysfunctioning, but as with many neurodegenerative diseases there are multiple ways to enter into that degenerative pathway, which then enter into some sort of final common degenerative pathway that leads to the dysfunction of the brain cells or the parts of the brain that are affected in dystonia.
So, this speaks to two things. First of all, that it's a complex [00:09:00] mechanistic process that occurs that underlies dystonia as a whole. And second of all, it gives us some hope and need, in fact to develop treatments that are specific to the root cause of dystonic syndromes.
We know already that some forms of dystonia are responsive to deep brain stimulation, for example, or different types of therapies. And we know that for example, myclonus dystonia, which is able to respond to alcohol, for example, or some of the benzodiazepines in some more specifically.
But others are more resistant to these forms of therapy. So it gives us insights that precise diagnosis. But hopefully with genetic diagnosis being one of the first steps is necessary for precise or precision medicine for patients with dystonia. And unfortunately, those mechanisms are all leading to a final common phenotype, which we see clinically.
[00:09:52] Dr. Francesca Morgante: Well, I think that the major advancement in our field related to genetic dystonia where you, especially over the past [00:10:00] five, six years, and I'm very confident that when we are going to repeat this podcast in another five years, Carolyn Sue will be able to tell us more and maybe we are going to be on the right avenue to deliver the precision medicine in dystonia based on the knowledge of a genetic phenotype, but also on the knowledge of lifestyle and environment that allow this phenotypes to manifest.
So it was great pleasure to host Professor Carolyn Sue and this is the end of our podcast.
[00:10:31] Prof. Carolyn Sue: Thanks Francesca, it's been a pleasure to have a chat with you about this topic. Thanks very much. [00:11:00]