Highlights in ataxia • 2025 MDS Congress

So thank you so much for joining us.

Dr. Jackson: Thank you so much for having me. I'm so honored to get to share with you some of the insights I've learned so far from this week, in the last year and in the world of ataxia. 

Dr. Sara Schaefer: Great. Let's dive right in. Why don't you give us an idea of some of the things that have piqued your interest in the literature over the past year. And I'm sure [00:01:00] that will flow into some of the Congress highlights as well.

Dr. Jackson: So I guess I will start just talking a little bit about some of the research that's come out in the world of Friedrich's ataxia. So, as you know, Friedrich's ataxia is the most common autosomal recessive, especially pediatric onset, form of genetic ataxia worldwide. And excitingly has one of the first FDA approved treatment, omaveloxolone, which has been out now for a couple years, and we've used as a disease modifying therapy in Friedrich's ataxia. The original study, the MOXIe study, has been the one that was used to get FDA clearance, which demonstrated improvement in the Friedrich's's ataxia rating scale at one year's outcome. And actually, one of the late-breaking abstracts they're gonna present is the four year open label extension has shown ongoing disease modification, as evidenced by a delay in the progression of the ataxia rating scale by 50% compared to [00:02:00] placebo control. So really great news there. As you know, it's a life limiting diagnosis. Patients have progression to disability and cardiomyopathy is often the leading cause of death. So, really, really important to get patients on this drug and identify and treat as soon as possible.

Hopefully we'll learn more when they present more of their data. But I was excited especially to see on their abstract that there was no progression in bulbar symptoms as well in that four years. That's amazing. So I think that is definitely something to stay tuned and listen in on.

Dr. Sara Schaefer: That sounds wonderful for that patient population and everybody that treats them. What about some other genetic ataxias? Anything else we need to know about?

Dr. Jackson: Yeah. One thing especially is very new, and I think more and more people are identifying and hearing about, is this genetic entity called SCA27B or spinocerebellar ataxia Type 27 B. We had known about it. SCA27 had been around for a while. It's a repeat [00:03:00] expansion in the FGF14 gene and can lead to cerebellar ataxia.

But this was actually just recently discovered in 2022 by the Pellerin group that essentially is a repeat expansion in the intron, so not the exon. So it hadn't been identified before. And even though we've really only known about it now for three years, it's looking to be like probably it's going to surpass SCA3 as being the most prevalent adult-onset form of genetic ataxia.

It is autosomal dominant, but patients on average present in their sixties. So actually should be on your radar when you're seeing patients with otherwise unexplained or idiopathic cerebellar ataxia. And so a lot's been published now. In the last year more and more is coming out just in terms of natural history, clinical phenotyping these patients.

One study had recently shown that of cases who had been undiagnosed, about 60% were ultimately found to have SCA27B. And I looked at my cohort actually, of my patients in ataxia clinic in the last three years. [00:04:00] Of those who ended up having a genetic diagnosis, 47% has SCA27B. Definitely something to keep on your radar, and if patients are unable to, or insurance doesn't cover genetic testing, even single-gene testing is something worth exploring.

Especially because it does seem that there are a few medication options that seems to help improve quality of life and improving ataxia symptoms, specifically Ampyra. There's been a couple of studies that have come out this year as well, which show that a majority of patients who start Ampyra, which is a potassium channel blocker, seem to have pretty significant improvement in their ataxia, as well as dizziness -type symptoms. I really think it's important to consider genetic testing. And if it's not possible, even empiric treatment is something I'm doing more and more now in my ataxia cohort. Just 'because we don't have tons of other options, as for treatment of these patients with ataxia. So yeah, definitely something to explore.

Yeah. And there is actually another late-breaking abstract on SCA27B from the Pellerin [00:05:00] group that's come out. And that actually was really interesting. Kind of, delved into the somatic instability that is associated with this population.

Just to take a step back, we know that with a lot of these repeat expansion disorders, they can be associated with somatic instability. So outside of the germline cells, all the somatic cells over the course of one's life can actually expand and contract in terms of the number of repeats. And there are certain predilections for that expansion occurring in different types of cells.

For example, in Huntington's disease, we know the striatum has a tendency to really expand over the course of one's life. And it is associated with disease severity and rapidity of progression. So Pellerin, one of their abstracts this week outlined how SCA27B also has this somatic instability and it's particularly in the cerebellar cells.

So, kind of helps further allow us to understand why these patients present with a predominant cerebellar phenotype. And I think, since that condition or this disease entity is so new, we're just learning more and [00:06:00] more about it. And one really fascinating thing to me about this condition is how wide of a spectrum, patients can present. A third can have a tremor, almost looking more like an essential tremor kind of phenotype. A lot can have vestibulopathy as well. Majority of patients often do. So I think the somatic kind of variability will likely help explain why there's so much phenotypic variability.

And hopefully that allows us to just be on track to identify them in clinic, target them for testing, and then hopefully someday will have implications for how we can treat these patients better.

Dr. Sara Schaefer: We'll, that's amazing. I guess my understanding is that genetically this was very hard to isolate or identify because of the intronic nature. And so makes you wonder how many other diseases out there we might not know about yet, and might find out more about as genetic testing gets more sophisticated.

Any other highlights over the past year or at this Congress that you feel need to be discussed?[00:07:00] 

Dr. Jackson: I think, a few things that have come out more and more as well is the advent of wearables, in terms of helping us track disease progression, particularly in ataxia conditions. I think there's a lot of advantage to that and allowing for a little more objective kind of measurements over the course of disease to help us track and, once we have more disease modifying therapies, allow for better tracking in clinical trials, et cetera. So I did see a few recent reports and here in this congress there's been some abstracts that have demonstrated, both with RFC1 gene — so that is associated with a CANVAS, another actually the most common adult onset recessive form of ataxia — as well as in Friedrich's's ataxia. Both of the abstracts I'm referring to looked at the use of wearables in tracking ataxia as relates to gait, and comparing it to the ataxia rating scale. And they validated it when compared to the ataxia rating scale.

So I think that is really exciting, [00:08:00] especially, as we're looking at, more and more, how to quantify and digitally track these patients clinically. So those were a few other things that I found, interesting from the last year in ataxia.

Dr. Sara Schaefer: Great. Thank you for this overview and for joining us today.