He is a neurologist movement disorder specialist with focus in neurogenetics in terms of research. Thanks, Kishore, for coming today to the MDS podcast.
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[00:00:45] Dr. Hugo Morales:
It's a pleasure as well. Now with the advent of whole exome sequencing molecular technologies for diagnosis, a lot of places have started to understand the proportion of patients that have a genetic basis with movement disorders such as Parkinson's disease, which is one of the most common indications for genetic testing. So tell us, is there something new in the realm of Parkinson's genetics?
[00:01:13] Dr. Kishore Kumar:
Yes. Well, there happens to be quite a lot of new and exciting developments. One development is that some new genes have been identified.
One gene is the RAB32 gene, which looks like a likely cause of autosomal dominant Parkinson's disease. So one single variant in this gene has been shown to cause Parkinson's in two major studies and it looks like a fairly typical clinical picture of Parkinson's disease. And the interesting thing is that we know from the function of this protein that it's linked with LRRK2.
So the RAB32 function is linked with LRRK2, and forms a nice molecular link with the known existing cause of Parkinson's. So right now we need to learn a lot more about RAB32, that'll be exciting.
For autosomal recessive genes, there's a gene called PSFM1, which is found in 15 families and 22 affected individuals. This is only in preprint, but this I think is a, another major discovery. And the phenotype here that varies quite markedly from Parkinson's to arthrogryposis.
So it's quite a range of clinical pictures there.
[00:02:24] Dr. Hugo Morales:
And that's still not being tested in common gene panels?
[00:02:29] Dr. Kishore Kumar:
No, all of these new genes haven't really been tested in gene panels. You're correct, yeah.
[00:02:34] Dr. Hugo Morales:
And in terms of technologies to unveil undiagnosed patients with recessive Parkinsonism, for example, the most common parkin mutations?
[00:02:46] Dr. Kishore Kumar:
Yes, well, what we know is that we often have a scenario where we only find one mutation in the Parkin gene. And this is the so called Parkin heterozygotes.
And some studies have shown that Parkin heterozygotes are more common in the Parkinson's disease group compared to controls, suggesting that something might be going on. But this finding's really uncertain. And one idea is that a person with a Parkin heterozygote may have a second mutation that's hard to find, what we call like a cryptic mutation. A recent, a really exciting study from Japan is in preprint. But it used a special technology called long read sequencing. So the sequencing we talk about is short read sequencing, where we break up the DNA into little bits.
But by taking a long read of DNA, this can give you more information and particularly show up complex changes in the genome. And one of those complex changes is an inversion. So an inversion is where the part of the DNA gets broken and turned around. And this is often missed if we just use typical sequencing technology. But with long read sequencing, we can pick up these complex changes and solve cases that have previously been unsolved.
In their study, they studied 23 Parkin heterozygotes and found a cause in six of those, found a second mutation using long read sequencing, but in none of the PNK1 cases. But it looks to be even about 25 percent of cases of heterozygotes could be solved using long read sequencing.
[00:04:23] Dr. Hugo Morales:
Is there anything similar in the areas of dystonia and dystonic syndromes?
[00:04:28] Dr. Kishore Kumar:
Yes. So dystonia, we haven't applied long read sequencing as much, but this is certainly some area of research that I'm interested in. One advantage of long read sequencing is it can find epigenetic changes. So this could be particularly important for some dystonia genes such as KMT2B.
So we're developing a approach for dystonia using long read sequencing with one of my PhD students. And hopefully we'll be able to use that to find the methylation changes that can be linked with genes like KMT2B or SGCE. And as already mentioned, it's good at detecting these complex changes in the DNA. For example, inversions. So we hope that this is one approach to improve diagnosis in dystonia.
[00:05:12] Dr. Hugo Morales:
Is there any new genes in dystonia in the last 12 months?
[00:05:16] Dr. Kishore Kumar:
Actually there is always new genes that are coming up and it's hard to keep track of all of them, but major new genes in the past, the recent times that we've found is like VPS16, I think this is a really important gene that tends to cause dystonia around the mouth or a mandibular dystonia.
And we've now found many cases of VPS 16 as a common cause of dystonia. But there are rarer forms that are coming up in the literature all the time.
[00:05:44] Dr. Hugo Morales:
I can also remember that there's a big change in the areas of ataxias, particularly in very particular genes that may be hidden to the whole exon sequencing technologies.
[00:05:57] Dr. Kishore Kumar:
Yeah. So the field of ataxia has changed dramatically in the last five years. And particularly we now understand the cause of many forms of late onset ataxia. The first big discovery was the RFC1 gene. And we know that expansions on both copies of the RFC1 gene can cause a disorder canvas.
But the more recent discovery is that FGF expansions in a gene called FGF14. When those expansion of a GAA repeat is above 250, this can also cause late onset ataxia, often linked with episodes of ataxia and downbeat nystagmus. And the very exciting thing about this is that this can respond to 4 aminopyridine treatment.
So it's a potential treatable form of ataxia.
[00:06:49] Dr. Hugo Morales:
And to request a test for FTF14 diagnosis, is it a different test that you need to use?
[00:06:55] Dr. Kishore Kumar:
Yes, so there are different ways to test and I think the best way to test is long read sequencing or nanopore sequencing but unfortunately this is not available on a clinical basis in many labs.
So you could use traditional methods like repeat prime PCR. There are only two labs that I know of in the US that are testing FGF14, but I think this is a field that's rapidly changing. Because this is a treatable disorder, I think we really do need to offer clinical testing for these cases.
[00:07:25] Dr. Hugo Morales:
A common scenario where you have a group of patients you test, trying to find any sort of genetic underpinning. And you have test them, but in this group, you don't find anything. So what is the value of keep searching, trying to find the underlying cause?
[00:07:44] Dr. Kishore Kumar:
One thing you could do is look at the data that you already have, and that's called reanalysis of genomic data. And what we know is that this can improve your diagnostic rate by roughly about 10 percent if you look at all the studies. So we've done a recent study on our whole genome sequencing dystonia cohort, and I did it with, you were a part of that study, Hugo.
Okay. Our first past first paper, we diagnosed about 13 out of 111 patients, so 11. 7 diagnostic rate. But through the work of one of the visiting scientists, Avi Felner, who's from Israel. We showed that the diagnostic rate can go up just by re looking at the data and new gene discoveries. And he showed the diagnostic rate went up to 18. 9%. So this is a really effective and actually proven cost effective way to boost your diagnostic rate.
So the first thing you could do is look at the data that you already have.
[00:08:41] Dr. Hugo Morales:
Thank you very much, Kishore, for sharing your valuable insight and update in genetics and movement disorders. And I will say to our listeners, stay tuned for our next episode. We will continue to explore the latest advancements in movement disorders. Until then, stay curious and keep learning.