Perry Disease

Today we're gonna be talking about a recent article posted in Movement Disorders Clinical Practice July 2023, entitled, "Perry Disease Expanding the Genetic Basis." 

Thank you so much for joining us today. 

[00:00:49] Dr. Zbigniew K. Wszolek : Thank you. Thank you, Dr. Schaefer for inviting me to be a part of your podcast. 

[00:00:55] Dr. Sara Schaefer: I must admit that I chose this particular article [00:01:00] because I had no idea what Perry disease was. I had never heard of it and was very interested in learning more. So can you tell us, what is Perry disease?

[00:01:11] Dr. Zbigniew K. Wszolek : Well Perry syndrome, and recently also known as a Perry disease, is a neurodegenerative inherited disorder that has been initially described by Dr. Perry and his colleagues in 1975. 

So, Dr. Perry was a pediatric neurologist who was practicing at Vancouver British Columbia, working at University of British Columbia, when he described the first kindred, and then a few years later he described another kindred, the second Canadian family. And over the next 10 years or so, maybe two or three other families have been described. I started to work on this kindred and this disease in [00:02:00] 1999, 2000, when I was upgrading one of the book chapters for the genetics of Parkinson's disease. And I had a fellow from Japan. Dr. Subo, whom I asked to help me to revise the second edition of Dr. Kohler's book and my chapter in which I mentioned that Perry syndrome is one of a very rare form of genetic parkinsonism. And he came to me about two weeks later after they assigned the first conversation and he said, I think we have a family with this disease in Japan.

So that was very interesting to me. And later I visited that family and I worked with my fellow. We decided to form ad hoc international collaboration, and we collected about 10 kindreds previously describe a nuance. And that led to gene discovery [00:03:00] mutations in dynactin-1 gene. And where to really put that disease on the map because now you could do the genetic testing and find this illness relatively easy.

And dynactin-1 mutations are actually in all panels available for genetic testing of Parkinson's disease. But the disease is still very much underdiagnosed. There are about 30-plus kindreds described so far with about 160 cases published. So still very, very rare disease, but has a global distribution where cases and families described in canada, in United States, in Turkey, in Japan, in UK, in Poland, and other countries. So it's a rare [00:04:00] disease, but is actually with global distribution. It also has been described in Colombia and in new Zealand. So as you see, rather global distribution of this illness. 

[00:04:15] Dr. Sara Schaefer: And I wonder if you can expand a bit on its mode of inheritance. I believe the case that you described did not have a genetic history. What is the mode of inheritance and how often is this seen sporadically? 

[00:04:30] Dr. Zbigniew K. Wszolek : Right. So the disease is autosomal dominant, so with rather full penetrance. But sometimes, as you know, the genetic inheritance is obscured for many reasons. And we observe that in this illness and our autosomal dominant in families that I studied and followed for other illnesses.

This case we described in your journal is indeed sporadic. We were not able [00:05:00] to find positive family history despite significant effort on our part. That could be due to the spontaneous mutation that has been described in this illness and other illnesses. But in general the patients provide positive family history, and they have other relatives that have similar clinical pattern.

[00:05:26] Dr. Sara Schaefer: So if you're a clinician seeing a patient with Parkinsonism in your clinic, especially if there's no family history — I mean, obviously if there's a family history, you're gonna be thinking about genetic Parkinson's syndromes — but if there's no family history, what are the common clinical features of this illness, and how might you differentiate a patient with this from somebody with Parkinson's disease?

Are there any diagnostic tests that can help assist, other than genetic testing?

[00:05:56] Dr. Zbigniew K. Wszolek : Well, that's actually very, very good question. So the [00:06:00] first one is age of onset. Usually these patients have earlier age of onset. In early or mid forties. 

 The other things are the associate Parkinsonian features. The Parkinsonian features are usually the first symptoms of this illness, so that's very important to differentiate that from classic Parkinson's disease of earlier onset. However, the Parkinsonism is usually of akinetic rigid type, and it's usually symmetrical. And usually is not much responsive to standard doses of levodopa. So those are the clues. Otherwise they can have other symptoms. They can have resting tremor, they can have postural instability. But those features that I mentioned earlier, earlier age of [00:07:00] onset symmetrical parkinsonism, usually are kinetic rigid at we onset, and unresponsive to standard doses of levodopa, and another feature, rapid progression. 

And the next important factors are additional clinical features. And what are those additional clinical features? Those are very important. So the patients with Perry syndrome have four cardinal features that are signs that include Parkinsonism that I mentioned a moment ago.

Depression and apathy, significant weight loss — and we're talking about 10 kilograms in two, three months. And despite having a good appetite. And the other one is central hypoventilation. Albeit, central hypoventilation usually happens [00:08:00] later in the course of an illness. So at the beginning it is very hard to distinguish this illness from classic Parkinson's disease of earlier age of onset, or the genetic Parkinsonism like PINK1 or Parkin cases that are also at similar age of onset to Perry syndrome.

[00:08:24] Dr. Sara Schaefer: It certainly seems like there's a lot of overlap with some other conditions. I wonder how many of these patients have been misdiagnosed with Parkinson's plus syndromes, MSA, PSP, or even frontotemporal dementia. We'll talk about that overlap in a little bit, but before we get there, can you speak to the pathology in Perry Syndrome? 

[00:08:46] Dr. Zbigniew K. Wszolek : I completely agree with your first point, that the disease, because of this overlap with other Parkinsonian conditions, is very much underdiagnosed.[00:09:00] 

My goal is to let the physicians know more about this illness for number of reasons.

One, it's very unique disease and there are some potential treatments that we can offer to these patients. So that is important to make the diagnosis. And also it has the consequences for the patient and the patient's family, since this is a genetic disease. So, answering the second part of your question, what is the pathology of this illness?

So it's very interesting because it's a Parkinsonian condition. We just mentioned earlier that the first symptoms are Parkinsonism in majority of cases. But the pathology is not alpha synuclein, like in classic Parkinson's disease. The pathology is of TDP-43 pathology. Albeit [00:10:00] very significant depigmentation of substantial nigra in microscopic studies. And microscopically, you see the neuronal loss and gliosis in substantial nigra. But you don't see alpha synuclein deposition. So the outer basal ganglia are also affected. So this is a form of TDP-43 proteinopathy that has all characteristic features of this illness, but with different distribution than those seen in FTD or ALS cases.

[00:10:38] Dr. Sara Schaefer: And you mentioned that there are potential therapies for these patients. Can you talk about that a bit more? 

[00:10:46] Dr. Zbigniew K. Wszolek : Yes. So, for Parkinsonian symptoms, one important thing to know is that some of these patients respond to large doses of levodopa. We're [00:11:00] talking here more than one gram, or even more than two grams of levodopa per day. So significant. So it's not the doses that we usually use for patients with classic Parkinson's disease.

Of course, some patients require such doses, but usually, you can see improvement in much lower doses. So it is important to know about this because you need to push , slowly the levodopa dose. Some patients start to respond at the dose above one gram per day. So that is a very important point.

 But also down the road, they can develop dyskinesias like patients with classic Parkinson's disease. So the second point is treatment of central hypoventilation and breathing problems, because actually about one third to half of the patients [00:12:00] die suddenly in the middle of the night because they just simply stopped breathing. I had, just recently, a patient died in the afternoon hours. He was taking a nap. His wife went to do some grocery shopping, and when she came back he was deceased. So central hypoventilation is a major problem and actually cause of death. So that treatment requires ventilation support. But ventilation support really reduces the quality of life.

I had another case who was in the nursing home for three months on a ventilator. Now, we treated this patient with diaphragmatic Pacemaking, and this patient was able to return back home, enjoy much better quality of life, not [00:13:00] frequent hospitalizations due to pneumonia. So that was very helpful. So far, because we treated only two patients with diaphragmatic pacemaker. But in both cases, quality of life was better and survival was longer. So that is very important to keep in mind, that this kind of treatment is available

[00:13:24] Dr. Sara Schaefer: Do you screen patients for that? Is it very apparent in the clinic visit? Or, I know in your particular case that you reported there was a sleep study, though it did not show central hypoventilation. So how do you approach these patients? 

[00:13:40] Dr. Zbigniew K. Wszolek : Right. In both cases treated with diaphragmatic pacemaking, the first one had very frequent visits in emergency room, because require recurrent pneumonias. And then finally they did the PSG and they found that was central hypoventilation. [00:14:00] So we have a second case I already described to you, nursing home and mechanical ventilation.

Not all have central apnea on the PSG, majority of them. This case is again, outlier. The case that we publish in your journal is an outlier because this patient had PSG done twice and didn't show central hypoventilation. So where are, you know, all differences. 

Not all patients develop central hypoventilation, but majority of them. And if they developed the central hypoventilation, then this needs to be followed carefully. 

It is also important to manage depression for these patients, because about one third of them have very severe depression leading to suicidal attempts and suicides. it's not a trivial depression, it's a very severe [00:15:00] depression. And that needs to be managed appropriately and psychiatry help needs to be also offered to this patient. So that's the management. So the first one is high doses of levodopa, above one or even two grams per day. The, the second is diaphragmatic pacemaking. The third one is, management of Depression. And the fourth one is dietician needs to be involved.

Because they have a significant weight loss. So they need to have high-calorie diet, and that needs to be supported by dieticians. 

[00:15:41] Dr. Sara Schaefer: Just a clarification question because you said that the weight loss was not related to appetite, so did they just have a much, much higher caloric need similar to Huntington's patients? 

[00:15:52] Dr. Zbigniew K. Wszolek : Yes. Despite the fact that many of them are immobile, wheelchair bound, or bed bound.

[00:15:58] Dr. Sara Schaefer: And[00:16:00] before we talk about your case, you mentioned levodopa responsive, but in terms of the other diagnostics that we typically get in the clinic, like MRI, DAT scan, how are those results in patients with Perry disease?

[00:16:14] Dr. Zbigniew K. Wszolek : Yeah, this is very good question. So the standard structural imaging usually shows, very little. There is not any structural pathology. In some cases, maybe a little bit of atrophy in vital areas. They have cognitive impairments, but usually very little. The DAT scan is abnormal and usually it's abnormal symmetrically. I told you that the Parkinsonism is usually symmetrical in this cases, and that is reflected in this. PSG is of paramount importance demonstrating central hypoventilation. so that is the gold standard. And genetic testing, of course, genetic testing to make the diagnosis. It would be helpful to [00:17:00] have some sort of biomarkers, plasma biomarkers or CSF biomarkers which could do these types of experiments in one of our large families, but still our ends are small, so we didn't come up with anything here. 

[00:17:16] Dr. Sara Schaefer: Well, I imagine as alpha-synuclein seeding assays and things come out, this would be one of those situations where a negative biomarker would be helpful. 

[00:17:25] Dr. Zbigniew K. Wszolek : Yes. Yeah. That, that could be indeed. 

[00:17:28] Dr. Sara Schaefer: So tell us about your case and how it adds to the information that we know about Perry disease.

[00:17:37] Dr. Zbigniew K. Wszolek : Well, our case that we published in your journal is of importance from several reasons. First of all, there was no positive family history like in our cases, so that was kind of unusual. The second thing was a little bit later age of onset. And the age of onset the first symptoms were not [00:18:00] Parkinsonian by rather apathy and Frontal lobe release kind of signs of frontotemporal signs. 

And so that was a little bit different. And then the genetic testing showed mutation so variant, which was labeled as a VUS, variant of uncertain significance, initially for a number of reasons. First of all, that variant was outside of CAP-glycine domain. And so far, the patients with classic Parkinson's disease have mutations in CAP-glycine domain, and exon two of this dynactin-1 gene. 

So that was a little bit different genetically. But we were able to secure autopsy when the patient died and the autopsy was of classic Perry syndrome, which we actually compared with another [00:19:00] patient with classic Perry syndrome. And when autopsy was almost identical. So based on this Information, we thought that this mutation is pathogenic , and was also predicted to be pathogenic. We thought that this is another mutation, a little bit outside of CAP-Glycine domain, which kind of expands the genetic hot spot in the gene.

So that was that importance of this, this particular case. There are about 14 mutations in CAP-glycine domain, so this one will be the 15 one a little bit outside the genetic domain. 

[00:19:47] Dr. Sara Schaefer: All right, so finally in addition to this case, this patient having been diagnosed with Parkinson's disease, what struck me, and you've mentioned this, is that they had a lot of [00:20:00] features that we might think about with FTD. They had progressive language dysfunction, repeated semi-purposeful tasks, apathy, and withdrawal.

Can you discuss the clinical pathological and genetic overlap between the TDP-43opathies? You mentioned that pathologically, the distribution is different. There's also, it seems, quite a clinical overlap. Do you view these as kind of on a spectrum or, how would you characterize these disorders?

[00:20:33] Dr. Zbigniew K. Wszolek : This overlap with other diseases like FTD or ALS may help us with treatments. We might eventually borrow the treatments with those conditions and apply to this one. And very significant overlap. The pathology is similar in morphology. It is just only different distribution.

The [00:21:00] clinical features, now with more and more families described, we are learning that some families have atypical features, like in this case. They have behavioral problems, they have personality changes. Usually memory is preserved. Some of them have compulsive behaviors. So that is definitely FTD spectral. 

Now there is also some overlap with ALS, and actually we are not the first who demonstrated the presence of mutations in dynactin-1 gene. A laboratory five or six years earlier reported family from Alabama that had mutation in dynactin-1 gene. Only if I recall, 12 or 14 amino acids different position from veneer by Perry syndrome mutation. And completely different[00:22:00] presentation. And that presentation that that Alabama family had what they call distal hereditary motor neuropathy 7B or distal spinal and bulbar muscular atrophy. These patients didn't have any parkinsonism. They had muscle atrophy in hypo phenol and phenol muscles, this study, and in vocal cords. And the age of onset was a decade later. Survival was for 20 or 30 years. As a matter of fact, with help of Dr. Orr from University of Alabama, I got access to this original family. I talked to one of the family members. It was 15 years after the paper was published, and she was still alive. And it was hard to understand her because she had significant hypophonia due to the vocal cord atrophy. But she was living a [00:23:00] very long time. We also got the autopsy on one of his cases and indeed showed TDP 43 that was not reported in the paper, because they published that gene discovery before the TDP 43 protein was known. So this is very, Very interesting overlap with all this ALS type of phenotypes. Where are some other families published with ALS type of presentation or FTD presentation or PSP, progressive supranuclear palsy presentation, they all have variants outside of this CAP-glycine domain.

So maybe this variance in this gene outside of this cap glycine domain represent a risk factor for both other diseases. So we need to learn about all of that in the future. So very fascinating, interesting, interesting things. The [00:24:00] protein is involved in retrograde axonal transport, so it's, it's a very large protein and, interacts with dynein Complex is very 

large and is responsible for retrograde axonal transport. So that's a very important connection and perhaps a drug target for the future experiements

[00:24:22] Dr. Sara Schaefer: Well, this has been a fascinating conversation. I've learned a lot and I'll certainly keep Perry syndrome in my head when I'm seeing patients going forward. And I look forward to potentially treatments, like you said, coming to light for frontotemporal dementia, and other FTD-43opathies that might be able to help these patients.

Thank you for taking the time to spend with us today. 

[00:24:46] Dr. Zbigniew K. Wszolek : Thank you, Dr. Schaefer. 

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