Myoclonus Series: Myoclonus dystonia: Motor & non-motor symptoms and the effect of DBS

We will discuss the topic, myoclonus dystonia, motor and non-motor symptoms, and the effect of DBS. Kathryn Peall is a professor at Cardiff University and conducts her clinical work at the University Hospital of Wales. She was trained in Cardiff and under Manju Kurian in London. I had the honor of hosting her for a fellowship in Groningen in 2013, [00:01:00] and I have since followed her career with great admiration. Her primary focus is on dystonia, particularly genetic forms and non-motor symptoms. Kathryn, thank you so much for joining me today

Dr. Kathryn Peall: Oh, you're welcome. Great to be here.

Prof. Marina de Koning-Tijssen: And let's, get started. Could you give us a short introduction what myoclonus dystonia is with both the motor and non-motor features and some aspects of the genetics?

Dr. Kathryn Peall: Yeah, so myoclonus dystonia is I guess it's still one of the rare forms of dystonia, but it's generally quite well known and quite well recognized. It's the motor characteristics that clearly mark it out from other types of dystonia. And the most common motor picture is upper body distribution.

Very much an upper body disorder that combines the myoclonic components. Obviously those brief very jerk like movements, mainly involving the trunk and the upper limbs, but [00:02:00] sometimes also their head as well. And then the dystonic component is usually in the neck and the arm, so often as writer's cramps.

When people are undertaking tasks and that's definitely the most common motor feature and the most typical age of onset is in early childhood. So starting school aged children, that's when you'll most commonly start to see some signs. There are of course variations on that and there are some children that present slightly earlier in age, but with very much lower limb dystonia.

So they'll present with difficulties with gait or keeping up with their friends or their siblings in terms of doing activities. Often those children their motor symptoms will evolve as they get a little bit older and develop more of the typical pattern that I've just described.

And then certainly from my perspective, there's a third group from the motor perspective that are maybe slightly older. And by that 9, 10, 11, just going into adolescence that have much more of an [00:03:00] upper body picture and maybe more myoclonus than you might see in some of the younger children.

But broadly speaking it's an upper body disorder that combines both the myoclonus and the dystonia. And one of the reasons that I've developed quite an interest in it is that of the non-motor symptoms, and particularly the psychiatric symptoms and the psychiatric symptoms are by a long way the most well explored of the non-motor symptoms in myoclonus dystonia.

And that came about originally I think because clinicians at the time when it was first recognized as a disorder, anecdotally were reporting that they felt that there were quite high rates of psychiatric symptoms. And then that's led to, us, your team as well. Other teams throughout the world have gone and looked at these in more detail and certainly when you compare patients with myoclonus dystonia up against either unaffected family members, unaffected people within the general population or people with other movement disorders. They definitely have a higher rate of psychiatric symptoms, and I think [00:04:00] pretty consistent across the research is that these psychiatric symptoms tend much more towards the anxiety spectrum of symptoms.

Different groups have reported slightly different things, but generally general anxiety disorder, phobias, particularly social phobias and social anxiety. And then certainly in the obsessive compulsive disorder spectrum. And even within that obsessive compulsive disorder has two components.

The obsessions, which are the ruminating thoughts, and then the compulsions, which are usually the doing things or the acting out. And these patients certainly tend more towards the obsessions rather than the compulsions. It's never black and white but usually in that, in that spectrum. I think, m oving on to the genetics, the most recognized gene is the epsilon-sarcoglycan gene so the SGCE gene. And I was looking back at the literature the other day. That was identified nearly 25 years ago now, back in 2001 so quite a long time ago. And that is by far and away the majority gene for myoclonus dystonia.

There's been a lot of [00:05:00] work on gene negative, so SGCE negative cases who have a typical myoclonus dystonia phenotype and people identifying smaller numbers of patients with mutations in other genes. So the KCTD17 with Niccolo Mencacci, that, that's another gene that's been identified. I think, I would argue in that setting, it's a slightly different phenotype from the SGCE. And then, obviously your team as well, you identified the RELN variants in the RELN gene. So I think there are a number of genes, but certainly the epsilon-sarcoglycan is the most common.

It's an interesting gene in terms of inheritance, mainly because of the imprinting. So it's a gene that's maternally imprinted and imprinting in itself, for those who are not familiar is effectively a switching off or a silencing of the gene. It's a methylation process, but the end result is that there's a switching off of the gene.

So if the mutation is inherited from the mother. Then it'll be switched off, and therefore, the offspring, the child [00:06:00] won't have the clinical phenotype. But if the mutations inherited from the father, then there's no methylation, there's no switching off, and then the individual will have the clinical phenotype.

And so that just makes it a bit trickier in clinic when you're taking the family history because you run the potential of several generations not having any at least motor symptoms that, the people would identify as having a clinical disorder. And in fact, it may go back so far that there's no immediate family history and so you might not be leaning towards genetic disorder.

And I think that obviously led to a delay in the gene identification in the first place, but also makes genetic testing in this group slightly more complicated and probably means that as a group it's under tested for. I think probably overall because of this absence of family history sometimes. 

Prof. Marina de Koning-Tijssen: That's a very clear explanation about the disorder. If I go back to these non-motor symptoms, because there is always this chicken and egg story, right? Is it [00:07:00] part of the phenotype, or is it the result of the living with the disorder that everyone can see and that makes you anxious?

Can you say something about that, Kathryn?

Dr. Kathryn Peall: Yeah, so I think, obviously there are lots of different views on this and I think it's probably not as clean cuts, that it's all part of the phenotype or that it's all secondary to having a movement disorder. I think some of the factors that, or, some of the information that suggest it's more part of the phenotype is that as much as you can rely on reporting historical recall of the sequence of events but there are certainly patients who are able to recall some psychiatric symptoms prior to onset of the motor disorder.

You've also got in the psychiatric symptoms that I've described. While anxiety clearly can be a consequence of many disorders and particularly motor disorders conditions such as obsessive compulsive disorder is not generally considered to be a psychiatric symptom that people develop as a consequence.

Of having a movement [00:08:00] disorder or having a medical condition. And so particularly there that leans much more to being part of the phenotype rather than being a secondary effect. I think if you look at anxiety levels, particularly a nd progress of those over time, so longitudinally over time, you and I did some work together looking at these patients and while their motor symptoms will often stay stable, and I should have said this earlier, that is certainly true, the motor features that people have by the time they reach their late teens, early twenties, that's probably what they're going to have for the rest of their lives.

You do see an increase in the psychiatric symptoms over time. It's not a huge fall off, but there is certainly an increase and so you'd have to assume that some of that is a secondary effect, around increasing anxiety, particularly, at critical points in life.

So late teens leaving home. Into adult working environment. People's anxiety levels do seem to go up over time. So I think it's a mixture of the two. But I think there is definitely a [00:09:00] core component that forms part of the myoclonus dystonia.

Prof. Marina de Koning-Tijssen: Yes. And as you know with medication, it's usually hard to treat these patients, right? So if they have a severe phenotype we might end up with deep brain stimulation. Could you say something about the effects of that and perhaps both on motor and non-motor symptoms?

Dr. Kathryn Peall: Yeah. So I think this is, as you said, normally when you go to treat a patient, you always think about, maybe physical therapies first, then oral medical therapies, and then you're coming to the surgical treatment when you've exhausted other options. But I think myoclonus dystonia is certainly unique in that I think once you're confident of the diagnosis, you need to really start thinking about deep brain stimulation quite early because it is such an effective treatment, and that's been reported now over multiple cohorts. And not only that, but there's sustained gain and sustained benefit for these patients over time. DBS itself, the targeting of the DBS.

That has varied between different centers. So the globus [00:10:00] pallidus internus the GPI is certainly a popular target for myoclonus dystonia. Some people use the ventral intermediate nucleus of the thalamus, of the vim, within the thalamus as an alternative. And some of the reasoning behind that is that some groups found them.

More so with the GPI target that the DBS itself led to an increase in psychiatric symptoms. As anyone who does DBS work, everyone will know that in the workup. You look a lot at psychiatric symptoms in advance. And then obviously this cohort of patients have got high levels of psychiatric symptoms anyway.

And then in some patients it does seem that the DBS has worsened those psychiatric symptoms. That's a small number. Some people moved over to the vim as a target. As a result of that, I think if you look at the data from the DBS for these patients, overall, it's the myoclonus that gains the most from the DBS, you get improvement. Certainly good improvement to both myoclonus and dystonia. But if you look at the numbers on rating scales of improvement and sustained improvement over time, the myoclonus is [00:11:00] slightly better than the dystonia. But the functional gain for patients were successful is huge.

And I think there's also been some work looking at, when you should intervene for surgery. Because if you're thinking that, it's often children that are being diagnosed with myoclonus dystonia, there's obviously some hesitancy to a young age as to whether or not you wanna go quickly to surgery or whether you want to wait a while and see how the child gets on.

There's some work to suggest that, the shorter the time from diagnosis to DBS, and the younger the patient, the better the outcome long term for the patient. I think we don't fully understand the networks that we're impacting by DBS. I don't think we can fully explain that.

But that certainly is out there. And I think is certainly something to consider. In younger patients in clinic, when you're making the diagnosis, is that dialogue around DBS relatively early in that pathway compared to what you may consider for other conditions?

Prof. Marina de Koning-Tijssen: Thank you. And Kathryn just to end with, because you have told [00:12:00] us now very well how the clinical picture is, how we should treat them, but quite recently you wrote a very exciting paper about basic studies in myoclonus dystonia. Could you shortly say something about that?

Dr. Kathryn Peall: Yeah. So I think while we've done quite a lot of, clinical work in Cardiff, one of the things that I've been quite interested in is still trying to understand the basic mechanisms that give rise to these conditions. Because, we've just commented on that DBS is good, but we don't really understand how it works.

And in terms of developing other therapies that's difficult to do without understanding. So we've been using stem cell models. So IPSC models, these are samples from patients that we then culture in cells. And while as with, most movement disorders, there's been a big focus on the basal ganglia.

What we were quite interested in is looking as to whether there were any cortical changes, because we all know in dystonia and myoclonus as well, dependent on its location. You know that there are [00:13:00] observed electrophysiological changes in the cortex. We took these stem cells and differentiated them towards cortical, excitatory neurons.

And we found that in the myoclonus to the epsilon-sarcoglycan cases or the epsilon-sarcoglycan mutation positive cases that the cells themselves were more excitable, so they were hyperexcitable compared to the wild type. No mutation in the epsilon-sarcoglycan gene. And as well these cells they had a different branching pattern.

So under the microscope, the cell bodies themselves, they had more branches and they were more complex in their branching pattern, which it then in and of itself can lead then to the hyperexcitability. And that then led us down to look more at the synapse. What changes were we seeing at the synapse?

And here we found c hanges in adhesion molecules. So these are the molecules that really bring the cells together when they form synaptic connections. And the main difference we found was in something called neuroligin 4. Where there are lower levels and its [00:14:00] partner is neurexin where there are higher levels.

And you can say, okay so what, it's not that interesting. But neuroligin 4 is also a gene that's been implicated in psychiatric disorders, particularly in childhood onset psychiatric disorders. But again, it's role and how it interacts with epsilon-sarcoglycan we are still working to try and uncover that.

But from our perspective, quite interesting and then leads potentially to other targets for therapy development. So that's an avenue of work that we have ongoing. But for anyone who works in stem cells and basic science, it's a slow labor of love.

Prof. Marina de Koning-Tijssen: Thank you so much. I think it's amazing that you do all this clinical work and also this basic work and just bridging them together. I think that gives a lot of very good insight knowledge for myoclonus dystonia. So Kathryn, again, thank you so much for joining me today. I'm looking forward to the further developments in these fields. 

Dr. Kathryn Peall: Thanks very much for having me. [00:15:00]