Genetic dystonias and understanding molecular pathways • 2024 MDS Congress

And then Importantly, around 2010, we observed the broader introduction of next generation sequencing technologies, which then led to the identification of a really accumulating number of genes in which variants can cause dystonic symptoms, isolated dystonia, or combined dystonia or more complex conditions with dystonia as a prominent feature.

 So what we observed in recent years was that analysis of patients with dystonia by exome sequencing mainly, so one of the main next generation sequencing analysis techniques, led to an increasing number of different genes in different populations. And so there were nice studies from different parts of the world, from Europe also from other countries, from India, from Australia, from Asian countries, from North America. And one conclusion is that in different populations you find overlapping genes, but you always find also different genes and within populations when you increase sample sizes, you always observe new dystonia implicated genes.

So what we concluded, or what we highlighted yesterday in the talk, is that when the sample sizes increase for patients that are sequenced the number of dystonia causing genes is also increasing and this seems to increase, at least at the moment, quite linearly. So when you sequenced around 500 patients, you may find 70 different genes.

And when you sequenced around 2, 000 patients, you can find more than 200 genes, especially in patients with complex dystonic conditions. So not Isolated, it's more or less not really static, but less pronounced. But for complex dystonia conditions, it's steady increase in dystonia causing genes.

And so the question is, what can we learn from these gene discoveries and what can we do to translate the insights into better understanding of pathophysiology and patient care.

So one important point is to, to have a look at these genes which were identified. You have to catalog them, and then you have to understand what they are doing. And there are different overarching themes in dystonia pathogenesis. For example, one theme is whether it is developmental in origin or it's degenerative in origin. And there's many, Lines of evidence argue that it's developmental because it, it's, there's some neuro degeneration on MRI in many patients with dystonia. And the phenotype is not always rapidly progressive, so it's often static. So there seems to be something in the developing brain what is deficient. So first what I presented yesterday was that groups or also our group tried to see how many of the genes that were found are related to neurodevelopment. And we observed that around 70 percent of the genes in a large cohort, for example, or the one that we analyzed were related to developmental disorder related phenotypes or neurodevelopmental genes. And this indicates that developmental mechanisms play an important role.

And the next question is then on the cellular level, what kind of pathways may be involved. And here you also can try to bring different gene findings into context and try to understand how they are related to each other.

And there are some important studies from recent years and reviews from colleagues from important dystonia research centers highlighting such relationships. And so yesterday I highlighted two emerging pathways, I think, which are promising also for future research in the field, which are converging mechanisms for dystonia, or seem to be converging mechanisms.

And one is the integrated stress response and the relation to the nuclear envelope and nuclear pore complexes. There was important research about dystonia and the integrated stress response from, for example, Nicol Kalakos from the United States. And so what I highlighted yesterday was that you can bring, for example, six gene here in this context; one that was discovered by you, Sarah, the, the PRKRA gene causing DYT16 or early onset Parkinson's, dystonia parkinson's and we learned to generalize dystonia. And so this may be one starting point of this cascade. So it is a kinase involved in stress response and upon cellular stressors, this kinase is, It's activated and then it activates the integrated stress response pathway, which consists of other kinases and effector molecules, for example, the EIF2AK2 gene, which is also involved in monogenic form of dystonia.

And then the stress response acts on other sub groups of molecules in the cell, for example. And translation and transcriptional control, which is then again, a link to other monogenic forms of dystonia, such as sub one related dystonia, which is a transcription factor. And importantly, and this is a new emerging pathway, which I found very interesting is that the stress response pathway also acts on TORSIN 1A and also on nuclear pore complex function via TORSIN1A perhaps or directly or indirectly. And there was one recent paper published this year by a group from Bildauer showing that TORSIN1A is responsible for nuclear pore complex biogenesis. And during a developmental window, which again highlights the developmental aspect and Shows that when you have TORSIN1A dysfunction for, for example, in DYT1, this may be related to abnormal nuclear pore complexes and they are very central in the cell because everything which has to be exchanged between the nucleus and the cytoplasm has to go through the nuclear pore complex.

So I think this is a new molecule or complex which is interesting to study further for potentially new interventions. And so this was one pathway that was highlighted. And the other one was the endophagosomal autophagosomal pathway which is recently emerging for dystonia, which is longer known from the field of neurodegeneration and from Parkinson's but which seems to also be involved in dystonia.

And so especially with the discovery of recent dystonias related to the hops complex, so called hops complex, which is the bridge between autophagosomes, endosomes, endolysosomes. This highlights the importance of this pathway for dystonia and hops complex consists of so called VPS proteins or gene encoded proteins.

Uh, VPS16 for example, and this is one of the most and very frequent cause of early onset generalized isolated dystonia. And so this may be another pathway, which is very intriguing to study.
 

[00:07:27] Dr. Sarah Camargos:
So do you oversee how those discoveries could be translated into treatment targets?
 

[00:07:32] Prof. Michael Zech:
Yes, so I think there are several aspects to consider. First is when we speak about treatment targets so we must understand if these are already targets, known targets, or if these may be targets for development of new treatments.

And of course In clinical practice, it may be promising to use targets or molecules which are already known as targets for existing drugs, so, so called drug repurposing and, and for example in lysosomes or integrated stress response, are the targets. In other diseases with drugs which already existing, for example certain HIV drugs are effective.

And so it may be one opportunity to use existing drugs which have an approval from FDA.

Of course, this must be well designed and many considerations have to be taken into account, side effects and so on. But at least starting with cell models or animal models, try to see if this may have an effect on the dystonia related pathology.

As well, for example, HIV drugs for integrated stress response or certain drugs developed for lysosomal disorders. There's a large group called lysosomal storage disorders, where you have treatments available like Substrate reducing agents or autophagy enhancing agents, so which modulate the pathway in the context of lysosomal storage disorders, which may also be promising then to translate for dystonia related lysosomal dysfunction.
 

[00:08:50] Dr. Sarah Camargos:
So the future may present us several interesting things for treatment, and You mentioned about neurodevelopmental disorders and dystonia. Could you please share with us these two related mechanisms for these diseases?
 

[00:09:07] Prof. Michael Zech:
I think there was always evidence that developmental problems lead to dystonia later on. So already in the 1980s there are reports that when you have a lesion in the brain, for example, secondary lesion by hypoxic brain injury or trauma in childhood or in infancy, so you have a lesion where the brain does not develop properly later on, you have a predisposition to develop dystonia more immediately or later on even.

And, and so there were insights already from secondary models, for example, and then with the discovery of many new Genes or developmental genes, it becomes apparent that also here there's an overlap. So you have genes causing autism or intellectual disability or epilepsy, but the same genes may be related to dystonic disorders.

And it is interesting to see that it's a spectrum. So you may have either developmental disorder, or intellectual disability or autism, or you may have dystonia and intellectual disability related to the same gene. And so the mechanisms that are responsible for this variability need to be identified.
 

[00:10:06] Dr. Sarah Camargos:
And, the phenotypic spectrum may vary a little bit, but the, the genes are the same.
 

[00:10:17] Prof. Michael Zech:
Exactly. So even the mutations may, so the gene can have many mutations, that's clear, but even the same mutation can have these different phenotypes.
 

[00:10:25] Dr. Sarah Camargos:
So do you think also about a common pathway so we can think in one target For several dystonias, or do you think there are several dystonias over there?
 

[00:10:37] Prof. Michael Zech:
For sure, there will be several, many dystonias, but we should try at least try to understand which ones are related to see which pathway is responsible for a broader group of patients. And then we also can try to understand when these different pathways from the different types of dystonia, how they are then again related to each other, so they may have also connections within the cell.

For example, stress response and lysosomes are two pathways, but they are again interrelated because when, for example, the lysosomes are dysfunctional, then the stress response is activated. So there may be again relationships. And when we have one optimal or two or three optimal targets, maybe we can modulate a broader group, or the pathology in a broader group of patients with a new treatment.
 

[00:11:20] Dr. Sarah Camargos:
Great. Thank you so much for your willingness to talk to us. And congratulations on your excellent work and your presentation from yesterday.