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We are happy to have Dr. Christelle Nilles here to explain about this study and the main findings as well. Welcome to the podcast, Dr. Nilles.
[00:00:44] Dr. Christelle Nilles: Hello. Thank you very much for the introduction.
[00:00:47] Dr. Hugo Morales: So, Dr. Nilles I guess we could start by you describing briefly about this study design and how those patients with adult-onset Wilson's disease were [00:01:00] identified. Tell us about that.
[00:01:02] Dr. Christelle Nilles: Yes, of course. So we did this observational longitudinal study in which we included patients with Wilson's disease diagnosed after the age of 40 years old.
And it was a French study. So they they were located in different cities in France. And we decided to classify them according to their mode of diagnosis of revelation of the disease. So they were the neurological group, the hepatic group, and the screening group. So, for example, someone who would have the typical neurological symptoms, for example dystonia, tremor, parkinsonism will have the neurological phenotype, although we could have also some liver abnormalities associated to it.
And when the hepatic patients will enter the disease with liver disease so abnormalities and ultrasound or cirrhosis, for example. And when the third [00:02:00] group was diagnosed through screening, so mainly those patients were relatives of patients with Wilson Disease. So we described these patients at baseline. Demographic characteristics, clinical exam, sleep, li mp examination, brain MRI, the copper tests, and the liver ultrasound, and Fibroscan.
And we also described the same characteristics at the last follow up. And the aim of the study was to describe these forms which are not well known in the literature, and to search for some specificities or differences in comparison to the classic forms in younger patients.
[00:02:39] Dr. Hugo Morales: And from all the patients in this French registry with Wilson's Disease, how many patients with adult onset did you find? Is it rare, extremely rare, or is it something that you knew you were going to find in your registry?
[00:02:56] Dr. Christelle Nilles: We found 45 patients. And at the time of [00:03:00] the registry, because we included patients between 90, 74 and so in 2016 there were 552 patients, so that would be 8% of the registry, which it's not a lot, but maybe more than one would expect. For example, if you take the only other case series of patients with Wilson's disease with late onset form.
The study published like 10 years ago or so, which was a European study. We had also 46 patients, but at that time it represented 4% of the sample. So yeah, we found twice more. Maybe because of improvements in screening or discoveries of new mutations.
But yeah, that's interesting and important data. I think.
[00:03:47] Dr. Hugo Morales: Yeah. I wonder if in this particular cohort or sub population of this registry with more than 40 years of onset. These Wilson's patients [00:04:00] had similar presentation as those with childhood adolescent onset or they're different, or do they look very atypical? Do they have the classical imaging features or biochemical features?
Are there any differences? That's one of the questions.
[00:04:15] Dr. Christelle Nilles: Thank you for your question. So to me, the most interesting finding in the study is in the neurology group. So there were 20 patients. We divided it into two subgroups. So there were 14 patients with, I would say classic and neurological Wilson's disease with dystonia, parkinsonism, gait abnormalities. And they all had the typical hyperintensities and the brain MRI. Most of them had a Kayser–Fleischer ring and they all had abnormal copper lab tests. But for six of the patients with neurological forms, the symptoms were quite unexpected.
So two of them, and they were brothers, which is also interesting. They presented with writer's cramp. [00:05:00] So one of them for 10 years before the diagnosis was made, and he developed at that time more symptoms and the other brother in one year, only. Another patient presented with cervical dystonia, but an isolated one with no other symptom.
Another one with isolated long-standing for 10 years dysarthria. And two of them with functional movement disorders. Which is quite atypical, which has been reported in the literature in one case to my knowledge with Wilson's Disease. But like it's two out of six patients of this group.
So that was quite striking. And functional human disorders, so for one of them it was paroxysmal myoclonus, of the head and the arms. And the other one was transient and inconsistent tremor of four limbs. Which obviously led to the diagnosis several years after.
[00:05:55] Dr. Hugo Morales: Yeah. And with these patients, did you find abnormalities in the brain MRI that [00:06:00] were highly suggestive of Wilson's, or were they completely different?
[00:06:05] Dr. Christelle Nilles: Well, that's the thing we didn't find in these patients the typical hyperintensities and the T2 and flare sequences. Only one of these six patients with atypical neurological forms had a Kayser–Fleischer ring. The one thing we did notice is that four of them did have some mild atrophy of the brain, which has been reported in Wilson's disease.
But all of them had abnormal copper tests with abnormal related extensible copper. And they were genetically confirmed, these cases. Although three mutations were novel. They were considered with a high probability of pathogenicity
[00:06:48] Dr. Hugo Morales: I understand. In regarding the treatment, is there any data that suggests that these patients with a typical presentation may respond at the same [00:07:00] manner as those with typical presentation? Or are the differences, or do we expect them more difficult to treat with the conventional Wilson's treatment?
[00:07:10] Dr. Christelle Nilles: Yeah, well, most of them improved or stayed stable. So we had data in 19 of them and of the 20th baseline and 16 of them improved or stayed stable. And within the three who are worsened clinically and on MRI, one of them was one of the atypical form and he worsened because of polyneuropathy due to a copper deficiency due to the treatment, right. So it developed after 28 years, I think. After the diagnosis after 20 years of treatment. So he had several treatments at that time. D-penicillamine, trientine, and zinc salt. He did develop this ployneuropathy, which did improve after the cessation of the treatments. But he still very much bothered by [00:08:00] gait abnormalities and sensory symptoms. And this is really something to monitor. It has been reported in other patients, so it's not sure that it's very specific to this late and set form.
[00:08:12] Dr. Hugo Morales: And what was the oldest patient identified within this adult cohort just to have an idea about their range of age presentation?
[00:08:23] Dr. Christelle Nilles: So the oldest one was 64 and diagnosis. And the mean age at diagnosis was 49. But I believe in the literature, there was a report of people aged 17. We don't have the oldest ones.
[00:08:37] Dr. Hugo Morales: Yeah. And, in terms of other differences within this subgroup, so you mentioned, that you had neurological, you have hepatic presentations and the other extended screening. So is there any different trajectories or severities in these different groups?
[00:08:57] Dr. Christelle Nilles: So regarding the [00:09:00] hepatic group, so we had 13 patients and 10 patients of them at diagnosis had cirrhosis including seven with decompensated cirrhosis. And overall, seven of them needed the liver transplantation at some point. So I would say that these are quite severe forms to look for.
At last for what they mostly improved. So that's good news. And in the screening group, so we had 12 patients. One was actually diagnosed incidentally in the workup of repeated vagal malaise, so that would be very typical as well. One thing that was striking to us in the people diagnosed via screening is that three of them were not treated. There was a consensual decision not to treat these patients because they were not symptomatic. They had normal copper tests. They were doing well. And so they were not treated. They just followed a low copper diet.[00:10:00] Interestingly after two years, seventy to seven years, They didn't worsen clinically.
So that's just an interesting side story, right? The goal of the paper is not to say that we shouldn't treat Wilson's disease because obviously we do. But that's something interesting.
[00:10:16] Dr. Hugo Morales: Yeah, indeed. I agree. It's interesting that even with this classical patients with Wilson's disease, when you start treatment there's no uniformity on how the patients are gonna respond despite being well-treated and biochemically improved. You either have some residual symptoms or there's some persistent symptoms so it's not something you expect that all patients are gonna improve.
There's also something that they're still having with symptoms. And with that story that you're telling. And some patients not been treated, but not been clinically bad. That means there's something that may modifying the expression [00:11:00] of the disease. Do you think, is there any genetic modifier any possible sort of ample type or something that may be changing the trajectory Wilson's disease expression?
[00:11:11] Dr. Christelle Nilles: I don't know. Maybe, I mean, but overall with these findings, I guess this is really something to look for from now on because we don't know why these patients express the symptoms later on.
And what it does influence the treatment response and the outcome, and this is highly important because, it's a treatable genetic disease.
[00:11:35] Dr. Hugo Morales: And then just to wrap up the conversation could you give some clinical pointers or clinical pearls to clinicians about how to look for patients with Wilson's Disease that present over the age of 40?
[00:11:53] Dr. Christelle Nilles: Well I guess you should look for the classic symptoms of course, because most of our patients had the [00:12:00] classic symptoms. For most difficult cases, I guess you really should look for clues in the history. So I'm thinking of family history that sometimes patients are not completely sure or psychiatric history.
Quite a few of our patients had history of depression or psychotic events or anorexia or cytopenia, like two or three of them I think. And these are clues. I will not say red flags, but some hints that could make you think of that. And yeah, I guess you should broaden your horizons in front of functional movement disorders because we had two of them. And the lab test is not so difficult to ask for. So when we have a doubt we should ask for it.
[00:12:46] Dr. Hugo Morales: Wonderful. Thank you very much, Dr. Christelle Nilles for telling us about your story in this interesting study on Wilson's Disease, and I invite all the audience to read the paper, Diagnosis and [00:13:00] Outcomes of Late-Onset Wilson's Disease, published now in Movement Disorder Journal. Thank you again for listening, and I'll see you again in another MDS podcast episode.