Dr. Will Meder (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Dr. Will Meder, Associate Professor of Neurology at UAB Medicine. We're excited to bring together today a thought leader panel for you with three Northwestern Medicine Physicians as we explore the findings and implications of a recently published paper on neurologic phenotypes associated with NUS1 pathogenic variants.

Joining me in this panel are Dr. Niccolo Mencacci, he's an Assistant Professor of Neurology; Dr. Elizabeth Gerard, she's an Associate Professor of Neurology; and Dr. Sarah Brooker, she's an Assistant Professor of Neurology. Thank you all for being here, and let's jump in.

Dr. Brooker, why don't we start with an overview of the published paper in Annals of Neurology this summer titled The Spectrum of Neurologic Phenotypes Associated with NUS1 Pathogenic Variants, A Comprehensive Case Series.

Sarah Brooker, MD: Absolutely. And thanks so much for having us. In this study, we put together the largest case series to date of individuals with NUS1-related neurologic conditions. We formed a large international collaboration using this platform called the Gene Matcher Platform, which allows you to search your gene of interest and identify clinicians and researchers around the world who also have an interest in that gene as well. And through that platform, we ultimately identified 41 cases of individuals who had pathogenic variants in the NUS1 gene. And we sought to identify the clinical spectrum of phenotypes in these individuals, assessing movement disorders, epilepsy, neuroimaging, and response to medications.

Host: Yeah. And I saw it was a very large group. So, a very collaborative group, it seems.

Sarah Brooker, MD: It's actually really interesting the more and more we were working on this, more and more cases came out of the woodwork. And it grew over time as more collaborators joined the group. So, it was a really exciting collaboration across multiple continents, which was great.

Host: And Dr. Brooker, what clinical or research gaps led you to investigate NUS1 variants? And how did this study address those?

Sarah Brooker, MD: So, the study really came about because there were several individuals at Northwestern, two index cases in particular that were identified by Dr. Gerard and Dr. Mencacci who had developmental epileptic encephalopathy, and also a variety of different movement disorders. And this has been recognized more and more that there can be overlap between these developmental, epileptic encephalopathies, and movement disorder cases. But for a large proportion of these individuals, they remain undiagnosed. And so, we're wondering what proportion of these people may have NUS1-related variants causing their disorder? And what are the spectrum of phenotypes we should be looking for that would prompt us to evaluate for this as a genetic cause for similar cases?

Host: Yeah. And Dr. Mencacci, can you kind of describe the range of those clinical presentations that you've observed in your cohort of patients with NUS variants and what this means for clinical practice?

Dr. Niccolo Mencacci: Yeah, absolutely. And before I jump into that, yes, it's been a lot of work to put together all these people from all over the world. But truly, I think that in the field of rare disorders, it's really important to learn from as many people as possible around the world. Every center may have only a small number of patients. But when we put together centers from all around the world, we can reach that critical number of patients where we can really start to learn from about a specific condition.

So, very interestingly, NUS1 was known to be a gene linked to developmental and epileptic encephalopathy, so mostly developmental delay and seizures. But this all started with the observations of Dr. Gerard that recognized that some of these patients have very striking and somewhat unusual movement abnormalities. So, she reached out and we diagnosed these patients. And what we first observed in our patients from Northwestern, but then throughout the collection of the additional cases is that, actually, movement disorders are present in almost 90% of all the patients with NUS1. And actually for most of them, not all of them, but truly the majority of them, it's actually the major source of disability. And these are complex movement disorders, difficult to recognize.

I think that before our effort, people used to mostly say that these movement abnormalities were tremor and maybe downplaying their role, thinking maybe they were drug-related, because all these patients have epilepsy. Most of these patients have epilepsy in the background. And sometimes medications that are given to treat seizures may cause tremor as a side effect. But then, we recognize truly a variety of movement disorders, the most common is myoclonus. About 70-80% of the patients that we recognize with movement disorders are myoclonus, but also dystonia, abnormal postures and movements; ataxia, a very common disorder of gait, gaiting and balance and troubles with coordination, but also Parkinsonism, especially in the older patients. And the symptoms all come in different combination.

And interestingly, a subset of patients, about a significant subset of patients, about 30% had only movement disorders and no seizures whatsoever. There were also patients that had just seizures and no movement disorder. So truly, every patient was different from the others with some clinical features being most represented. Like, all of them had some degree of intellectual disability and developmental delay, usually more on the mild spectrum, where with some of these isolated cases, having a more pronounced intellectual disability phenotype.

Dr. Gerard may comment more about the seizures. But most of them had some diagnosis of epilepsy, but the movement disorder was truly interesting to describe and observe the variety of combination of movement disorders. Truly, a diverse cohort of patients.

Host: Dr. Gerard, it sounds like you had a very astute observation of these patients seeing those movement disorders and that maybe led to a lot of this work. The study highlighted an overlap between developmental and epileptic encephalopathies and movement disorders, and showing that almost 90%, as Dr. Mencacci mentioned, had a movement disorder. How should that overlap inform a neurologist's diagnostic approach in similar cases?

Dr. Elizabeth Gerard: Yeah. To just highlight the overlap in these particular patients, I think, Dr. Mencacci identified it. The patients that I saw, they had had diagnoses from epilepsy from early in life. But I saw them as adults. And as the adults, we were able to recognize that there was a more complicated movement disorder phenotype. Not just myoclonus, but also dystonia, also a parkinsonism.

And I think that's something that we are seeing in some of the developmental and epileptic encephalopathies that sometimes the seizures are the first presentation. And then, there becomes more involvement of the brain and can manifest as gait disorders or movement disorders as adults. And when we see them in an adult epilepsy genetics clinic, we may see some of the movement disorder phenotypes and need some help in classifying that from our friends.

But in terms of the diagnostic and clinical approach, I run an epilepsy genetics clinic and epilepsy genetics program. And we recognize now in epilepsy genetics the developmental and epileptic encephalopathies, so patients who have some degree of learning disabilities, intellectual disability, developmental delay, sometimes autism from early life with seizures. That group of patients with or without movement disorders is going to have a very high yield on genetic testing, at least 50%. And most of those disorders are going to be genetic. Right now, we can identify about 50% of them.

I would say that if you throw in the co-occurrence of a clear movement disorder, don't think we have clear numbers for this, but I think the likelihood of identifying a genetic cause goes up even higher. And I would speculate that for patients that may not fall into the DEE category, the developmental and epileptic encephalopathy, if you have a patient with epilepsy and a co-occurring movement disorder, you should be really thinking about a multi-brain process that is likely going to be genetic first.

And so, in terms of how does that, you know, change your framework, I think with these patients, genetic testing should become earlier and earlier in your evaluation of the patients. And these patients were both diagnosed on exome had we had done more focused testing of a panel. They had both had testing in the past, but it was only doing a current exome because this gene had been reported before that we would be able to identify the abnormality.

And I would say, in terms approach in general, agnostic to the type of movement disorders with myoclonus and epilepsy, we often now are moving more and more towards genome testing or testing that allows us to look at expansion repeats that you might not identify on an exome as well.

Host: Yeah, that's great. And Dr. Brooker, kind of building on that idea, thinking about the findings of the paper, how do you believe the findings could change how we move into diagnosing and managing NUS1-related conditions?

Sarah Brooker, MD: Yeah. And to echo what Dr. Mencacci said earlier, I think the really broad spectrum and the heterogeneity of these individuals is a really important point, because we have to think about this on our differential really broadly for people who present with myoclonus dystonia, with progressive myoclonus ataxia syndromes with and without epilepsy. There's just a huge variety of presentations that we see. And so, I think this has likely been very, very underdiagnosed in the past, and the more that clinicians start to consider it as a possibility and do whole genome, whole exome sequencing, we're going to be identifying these individuals more.

And to echo what Dr. Gerard said as well, there's a subset of cases that are fairly static in terms of the clinical course. But a significant proportion, about half, had a slowly progressive course. And the movement disorders in particular can very much evolve over time with some individuals developing parkinsonism over time or having worsening ataxia. And so in clinic, these patients need to be followed really closely, and the treatments that they may require for these different movement disorders may vary over time.

Host: And Dr. Mencacci, the paper mentions mechanisms or potential mechanisms, you know, in combination with this extensive understanding of the clinical presentation. What are the potential mechanisms by which the NUS1 variants lead to complex neurologic symptoms?

Dr. Niccolo Mencacci: Yeah. That's a very important question, and I think that we have some ideas, but a lot more needs to be done. So, I'll just start with this. So, the NUS1 gene is actually implicated in a very essential biological process, which is called N-glycosylation, which is one of the most important post-translational modifications of protein. So, an essential biological mechanism for cellular function.

And the first thing that I would like to say is that it's surprising that given the function of the gene, these patients have an exclusively neurological disorder. It's already surprising. Most of the time patients have N-glycosylation disorders. They have not just neurological involvement, but have multisystem involvement with liver dysfunction, kidney dysfunction, and so forth. These patients have just neurological symptoms, epilepsy movement disorder, intellectual disability.

Now, given the broad biological implication of the role of the gene in modulating these essential aspect of cellular biology, it's not surprising that many different areas of the brain might be affected. What's striking is the fact that each patient seems to have a different combination of symptoms, which reflects the fact that there's different brain-specific susceptibility to the same biochemical defect caused by the mutation.

So clearly, the developmental epileptic encephalopathy phenotype reflects the fact that cortical neurons are certainly affected, but I think the movement disorder aspect of this condition is telling us a lot about the fact that other parts of the brain are also implicated. Certainly, the cerebellum for sure , many of the movement disorders that we are observing might reflect dysfunction of the cerebellar circuits and the basal ganglia. We see that patients have parkinsonism and dystonia, which most commonly reflects dysfunction of the basal ganglia circuits.

So truly, we are recognizing that different brain areas might be differently affected by the same biological defect, biochemical defect caused by these NUS1 mutations. But every patient responds differently, and this is probably because different areas of the brain respond to the presence of the mutation differently and are able to compensate better or worse. And we don't know what determines this, which a gray area of a very important area for future research to understand what determines this huge variability between the patient and another makes it very fascinating for sure.

Sarah Brooker, MD: Yeah. And there's another interesting aspect to that too, which is we identified a total of 38 variants, and there were a couple instances where people had the identical variant or multiple people with whole gene deletions. And even between those with the same variant, the phenotype could be very different. And we really don't understand why that is at this point.

Host: Yeah. I thought it was interesting, 38 variants with 41 individuals. It was pretty surprising. Dr. Mencacci, to follow along that line a little bit further, thinking about moving the understanding of the mechanism into the clinical realm, how do you think understanding the mechanism might influence treatment or treatment development?

Dr. Niccolo Mencacci: Yeah. Again, it's early days, but some preliminary work, some also done in our lab, but also published by other groups seems to show that a subset of proteins that are very important for function of lysosomes seems to be particularly affected by this biochemical dysfunction that affect N-glycosylation that the NUS1 mutation is causing. So, lysosomal dysfunction could be a downstream biological mechanism, which could be targeted for future therapeutic development for these patients.

And interestingly, another observation that has been made is that when NUS1 is not working properly, cholesterol tends to accumulate within lysosomes. And this could be because there's an important protein that's called the Niemann-Pick type C2 protein, which is essential for cholesterol transport in and out of lysosomes. It might be defective when an NUS1 does not work properly. And there are some treatments that first need to be tested in preclinical model that could ameliorate the cholesterol metabolism and, hence, potentially improve the neurological function of this patient. This is totally speculative at the moment. We need to do the experiments. We need to learn more about what are the targets of NUS1 dysfunction in neurons, because a lot of what we know is deriving from non-neuron-specific system.

So, it's truly early days, but I think that this is among the rare conditions that we see, a relatively frequent one. Since the paper has been published, we had other researchers saying, "Oh, we have other cases. And it's growing." So, I think it will be very interesting to understand more about the downstream molecular mechanism of NUS dysfunction to understand more about what's at the core of neural dysfunction caused by these mutations.

Host: Thank you. And Dr. Gerard, based on the paper's findings, what recommendations would you offer for clinical management and treatment of NUS1-related conditions? And we can share this question among the others as well.

Dr. Elizabeth Gerard: Yeah, I think we'll do that. You know, I think part of what this helps us with is first recognition and recognizing the syndrome and knowing that we have others to compare to when you do find somebody within this phenotypic variability.

I think one thing that's interesting as we collected the cases was to see how the approach to evaluation and management pre-diagnosis varied based on whether or not the specialist was a movement disorder specialist or an epileptologist, right? So, my bias is obviously any patient presenting with prominent myoclonus or this type of spectrum of conditions should have an EEG to help you understand more about the myoclonus. And so, that sort of just recognition is important. And obviously, having someone knowledgeable to help characterize the different types of movement disorders is also going to be, you know, helpful in managing treatment.

From a treatment standpoint, and this is often the case in these early large papers that help you understand the condition, Dr. Brooker did a wonderful job compiling all of the treatments patients have been on, and I don't think that we have a clear winner in terms of what is, you know, the best treatment for this condition yet. I think from the epilepsy and myoclonus standpoint, we tend to use medications that can target myoclonus, which include topiramate, zonisamide, valproic acid, and benzodiazepines, clobazam. And we saw a lot of that prescribed either by epileptologists or Movement Disorders, sometimes to treat the same conditions, whether they were known to be epileptic or not.

So, I think we are starting to understand that, but we'll need much larger groups to understand what really works and what should be our go-to approaches. And of course, the hope is to develop, you know, therapies that are genetically informed or mechanistically informed for these new conditions we identify. But do you guys want to add anything to that from the movement disorder standpoint?

Sarah Brooker, MD: Yeah, I agree. In terms of treatment of movement disorders, there's such a huge variety of disorders that we saw, and a long sort of laundry list of treatments that were tried. I think compiling it is a helpful resource for people to look at and see what's already been tried, which subset of medications have at least helped for a significant proportion of people, and can then give those, you know, a try in the clinic when they're managing these patients. But I don't think we have a clear, you know, sort of winner in terms of different medications for the myoclonus dystonia, et cetera. But at least we're starting to learn more about it.

Dr. Elizabeth Gerard: And I would say that, in most of the patients that we looked over from a seizure perspective, which may be partly age-related, but if the patients didn't tend to have refractory, like convulsive seizures, they may have had refractory myoclonus. And that's been our experience with the patients we've seen. But the seizures often did come under control either with medications or with age.

Dr. Niccolo Mencacci: And just one final comment to that, I think one thing that we learned-- and I think this is especially true because most of these patients were not initially seen in movement disorder setting-- is to recognize the specific movement disorder, because every movement disorder has a different treatment. So, that's truly critical to tailor a treatment to a patient, is recognize a different pattern. And again, I'm kind of repeating myself, but each patient looks different. So, that's one of the things that to me was most exciting and important about recognizing this complexity.

Dr. Elizabeth Gerard: And I think we're seeing that as we see more and more monogenetic disorders, that it's the same gene, even maybe in some cases the same gene mechanism, but they look different, right? That varies a little.

Host: And I think that wonderfully kind of dovetails with our next question about understanding, you know, the evolution of rare neurogenetic disorders. How can neurologists collaborate across specialties, as you all have just described, to improve patient outcomes?

Dr. Elizabeth Gerard: I think I'm very lucky to have first Dr. Mencacci and now Dr. Brooker, you know, interested in the same things and sharing patients and discussing ideas. And I think that's how we move it forward, not in silos, right? And bouncing it off each other. I think more and more, there are going to be people who are interested in characterizing these rare disorders. And so, I think just collaborating either within your institution or across institutions if you don't have somebody at your institution is really important.

And I think Gene Matcher is a great way of starting to get a group if you have a particular genetic condition you're interested in. But yes, I think collaboration's essential.

Dr. Niccolo Mencacci: Yeah. I think, probably many neurologists don't know what Gene Matcher is, but it's this online platform that allows to connect clinicians that have identified patients with the same mutations, and we can then share in an anonymized fashion clinical details, genetic details about our patients. And we can learn more about what a specific genetic syndrome looks like. And truly go beyond just the few patients that we see in our clinic, but learn about all the patients that are being recognized worldwide.

And yeah, I think, a very important concept about this is that we run a clinic and we tend to be very focused on the things that we know the best, the things that we're more familiar with and the things that are-- you know, if it's movement disorders, we focus on movements. And if it's seizures, if it's epilepsy, we focus on seizure management. But we need to keep our eyes open and observe things that might fall slightly outside of our area of expertise. And there's a lot to learn from things that we may not know, but we are lucky to be in a place where we have different expertises and we share, and it's very collaborative, and this is how this came about.

Dr. Elizabeth Gerard: I love that about like becoming comfortable with the things that make you uncomfortable, right? Like when I saw that first NUS1 patient, I was like, "This is something different." But I'm going to stay on it. And it took me years to diagnose her, right? And we did testing, re-analysis. And I was like, "This is something unique and we got to keep pushing. And many people before me had tried, it was just there wasn't the knowledge out there.

And I think funny story also, if you're thinking about starting something like this at your place, I mean, my interest in genetics was burgeoning. Our chairman, Dr. Krantz, was very, very interested in rare diseases and genetic medicine. And so, we actually started really small scale with a combined movement disorder and epilepsy genetics conference, which we had monthly. Now, both of our programs are so large that we actually have our own programs that serve to educate each other and work together. But that relationship and that underpinning is still there, I think, and that's what's really important.

Sarah Brooker, MD: Yeah, I agree. As we get more and more sub-specialized, I think it's very easy to sort of focus in on one thing specifically and forget the rest of Neurology. But the more that we have these collaborative interactions between each other and have joint conferences and have podcasts like this, we can learn more from each other.

Host: It's a really special collaboration that you all have. So, moving on to just some final thoughts maybe. We can start with Dr. Brooker about, you know, what would you like to share about patients with INUS1 variants and specifically what it means for clinical practice and understanding how mechanisms inform our treatment.

Sarah Brooker, MD: Yeah, I think the biggest takeaway here is that there's such a huge variety of movement disorders and different epileptic presentations that these individuals can have. And so, we've likely just been missing these patients in terms of diagnosing them. So, keeping your eyes open, and really having a low threshold for considering going forward with genetic testing for individuals who have early onset epilepsy along with myoclonus and any other movement disorders, it's really something to not miss.

Host: And Dr. Gerard, what would you like to share to inform neurologists' diagnostic approaches in similar cases?

Dr. Elizabeth Gerard: Yeah. I think, first of all, just to say, again, recognizing it, I want to say one thing about these patients. Now, that we recognize these conditions, we can recognize them earlier and earlier and hopefully help the pediatric cohorts that are seeing them. Both of the patients I said, the thing that I took away is that both of the parents told me when they were age two, they just kept having this eye fluttering. And it was an eerie feeling when both parents told me that. So, I do think whether that's eyelid myoclonia or myoclonic absence, seizures, we're not sure. But that was in a couple patients. So, recognizing that early on.

I think, again, I'll just hark back to my little soapbox, is that I think when you see these patients think about genetic testing and involving a genetic counselor and an informed neurogeneticist or genetics person in terms of moving forward, because you'll find answers.

Host: And Dr. Mencacci, what key takeaways would you like to share with neurologists about the importance of this research as well as its implications for clinical practice?

Dr. Niccolo Mencacci: I mean, I think, one important key takeaway message is that by getting the experience of clinicians and neurologists from all around the world about conditions that are very rare, you can learn a lot about how you can treat your patients. When we first met our patients here at Northwestern-- and this started a while ago because they took some time to put together such a large cohort -- we knew very little about what the disease looks like, what's the progression, how do they respond to treatments. The patients were asking, "What are we going to expect?" Because some patients were a little older, but some are younger. And by sharing all of our observations with the teams around the world, we could really come down to some robust conclusions about what the disease looked like, what to expect, prognosis, which is very important for many patients to know what the future holds.

And I'm a physician scientist, and I run a lab. So for me, it's very exciting to learn more about the underlying biological mechanisms about what's causing epilepsy and movement disorder in these patients and to recognize those mechanisms, because I think that's what going to form future treatments. So, that's really what excites me the most about this.

Host: Well, this has been such an insightful discussion. And thank you for moving this field forward. I know it means a lot to those who are affected by these conditions. For our listeners, to refer your patient or for more information, head on over to our website at breakthroughsforphysicians.nm.org/neurosciences to get connected with one of our providers. And that wraps up this episode of Better Edge, a Northwestern Medicine Podcast for physicians.

Dr. Elizabeth Gerard: Thank you.

Dr. Niccolo Mencacci: Thank you.

Sarah Brooker, MD: Thanks much for having us.