So I'm going to continue this discussion with a few case scenarios. And so what we'll talk about are some dilemmas in clinical care, in the caring of children with genetic diagnoses, and really kind of just build upon some of the things that have already been identified from our previous speakers as far as kind of challenges and treatment dilemmas. My disclosure is I am on the Speakers Bureau for Nerellis. And so objectives for me in this developing this case discussion, I want you to recognize the role of genetic testing and uncovering developmental and epileptic encephalopathies. I think that's already actually been very well established by our previous speakers. But understanding the challenges of prognostication in genetic syndromes that have a clinical spectrum. And acknowledge the importance of literature review and continual literature review when you receive variants of unknown significance. So we'll jump right in. I had a case of an eight-year-old, right-handed young lady with a history of developmental delay. And she came to me for an evaluation of cognitive issues. She has global developmental delay and has required therapies throughout her life. And had previous diagnoses of speech apraxia, motor apraxia, and sensory integration disorder. She has made gains in recent years. And there was no real clear history of regression. But she had pretty significant delays still in her speech and fine motor skills. Birth history was notable for C-section at 42 weeks. So she was a bit post-date. And she had issues with latch and feeding early on. Probably kind of speaks to again some of this kind of apraxia, longstanding. And she did have low tone when she was born. And did require physical therapy in the infantile period and continued on through school age. She had neuropsychological testing when she was six and had a full-scale IQ of 59. And then repeat testing at seven was 70. And she did have some genetic testing that was kind of vaguely kind of mentioned that was unremarkable when she was four. So I want you to just kind of think about the approach to seeing this young lady in clinic. The family is coming to kind of think about an evaluation for really not what seems to be screaming epilepsy. But more of a possible kind of encephalopathic picture with cognitive issues. But again, no clear issue of regression. So she had an EEG. And some of you might think, well why? Why get an EEG? Seizures were not her presenting issue. And I would challenge you to think about when you have scenarios of, again, of challenges in cognitive domains to think about epileptic encephalopathy as being potentially part of that diagnostic profile or in your differential diagnosis. Because there could be things that could be unrecognized like absent seizures that are kind of more harder to recognize for some. And things like spike wave stupor that again are difficult to kind of clinically recognize if you have a child who has speech issues and that kind of thing. So kind of thinking outside the box to think about even though seizures are not a presenting issue, the family has never thought this child had seizures. You know, an EEG being part of the testing to consider for her. So she had an awake EEG. And interestingly, she had spikes that were notified focal in the posterior, frontal, and temporal regions. And so based on that, we decided to go ahead and get a 24-hour EEG. And in her 24-hour EEG, she had continual sleep activation of spikes that was consistent with an electrical status epilepticus of sleep kind of on that spectrum. Her spike wave index was 93%. So definitely meeting kind of traditional criteria. And so interesting. And so she had a brain MRI that was normal. And in the context of further testing for her, she did have an epilepsy genetic panel that was notable for a GNB1 mutation. And so this was then consistent with a GNB1 encephalopathy. So just a little bit of background on how does GNB1 encephalopathy? And this is a condition that in the literature is associated with a moderate to profound developmental delay or intellectual disability. And I would remind you that this young lady's IQ was on the low end. She had a 59 score, I believe, when she was around six or so. And then when she was seven, it had gone up to 70. So she meets criteria for some intellectual disability. And then other features that can be present in infancy or childhood, one or more. So generalized hypotonia of infancy, that can evolve to hypertonia and spasticity. Now this young lady did have hypotonia in infancy, did not have evidence of hypertonicity on her current exam. Feeding disorders and difficulties with weight gain in infancy. She did have issues with feeding early on in her infancy. Now movement disorder, epilepsy, and a spectrum of clinical features with epilepsy to include generalized focal and infantile spasms. Behavioral issues, autistic spectrum disorder on that list here, macrocephaly, slow growth, vision impairment, also GI issues. And interestingly, and kind of delving into the history further with this family, she did have longstanding issues with constipation. And then also cranial facial anomalies were present. So based on the clinical criteria, she met criteria for this disorder. So I want you to kind of think about this and kind of have a talk amongst yourselves because these are some of the questions that came up with this family. So I mentioned that she was eight years old, but she had a 12-year-old brother. And the mother, and she also had a two-year-old sister. So no siblings of childbearing age, but mother was still of childbearing age. And given the concern and kind of this diagnosis, the question came up about do parental testing, implications for the siblings, and then what is the prognosis for this? And so I'd like you to kind of think about those kinds of things and kind of talk amongst yourselves. And then I can kind of give you my take on what I talked with the family about. Just take a couple of minutes. All right, so I think that in the scheme of discussion with this family, the question came up about, they were really happy to have a diagnosis. For them, they felt like something had been missed for this child was eight years old. And it gave them something to hang their hat on. This is what she has. And we were correct in that something was being missed, that they knew something else was potentially going on. Also, their relief was also centered around knowing that her developmental trajectory was, had been not, I guess what I'm trying to say is that they had been doing all the right things for her and that they had not missed out on an opportunity where they could have been doing something more, I guess, if you will. So there was relief in that as well. And so, in the context, again, of parental testing, their desires were that they wanted to get parental testing. They were interested in doing so and felt that you would inform them, again, on whether or not it's something if they were carriers for. And as far as the implications for the siblings, the question came up, well, do we need to test this, to test any of the siblings who were developmentally normal, I should mention. So the siblings were developmentally normal, had no issues. And that was a little bit more of a challenging question. My thought was, we don't need to test the siblings if they're asymptomatic at this point, particularly since there's not a known specific treatment, to my knowledge, for GNB1 encephalopathy as far as a disease-modifying therapy. But it was kind of difficult to, and because the diagnostic criteria include things that present in infancy and childhood, I felt comfortable stating that, if you're, particularly with the older siblings, the 12-year-old and that kind of thing, that the likelihood of them actually having the diagnosis certainly is very low. They certainly potentially could be carriers, but that doesn't necessarily impact treatment for them at this point. But I think that some others might have felt differently about that. The family was willing to, in agreement with that. Their other question was then, understandably, so what is the prognosis for this? What's gonna happen? Is she going to require support for the remainder of her life? Is she going to be able to, is this something that she's gonna outgrow? Because I think, to this point, they had been hoping that this is something that potentially, with enough support and services, she's gonna catch up and that kind of thing. And in this scenario, again, provided them some relief, but also kind of a challenge in that they still wanted to certainly maximize her therapies and her supports, but also recognizing that, yes, this is something that is a lifelong condition, and developmentally, she's likely to stay at the trajectory that she's at. There's not gonna be, not likely to be in regression, but she's likely on a plateau. There's not gonna be this huge step up, most likely. So those are the things that I talked about with the family. And again, just highlighting the role of EEG and genetic testing and coming to a diagnosis for this family who, at this point, had just, did not have any clear answers for understanding the challenges that their daughter was having. I don't know if anyone else wants to make any points or statements that haven't already been stated about this. I don't know if anyone's had any experience with GNB1 encephalopathy. Yes. So if the penetrance of GNB1 is estimated to be at 100%, would that inform parental testing? That's a good question. I think that, yes, particularly from the scenario if they were considering having other children, if the parents were still of childbearing age, mom was considering still kind of having other children, so. All right, so we'll move on to another case. So a nine-month-old, developmentally normal infant, little boy, presented for evaluation following a first-ever seizure episode. However, this first-ever seizure was an afebrile focal status epilepticus, so kind of a red flag, afebrile focal status. Birth history and family history were unremarkable. He had a one-hour EEG. That was normal, included wakefulness and sleep. And because he was a nine-month-old who presented again with a prolonged seizure, we did do genetic testing on him. And he ended up having a pathogenic mutation in the YWHAG gene, something I'd never heard of, had to look up. And this was actually a pretty scary finding because the spectrum of this disorder includes epileptic encephalopathy, childhood myoclonic epilepsy, and also just febrile seizures. So there's a very benign end of the spectrum, and there's a very severe end of the spectrum. And this little boy's only nine months old at this point, who's doing everything a nine-month-old should do and has a normal EEG. So what do I do with this information? So I'd like you kind of just to take some time to kind of think about how to approach this clinical discussion with a family in this currently developmentally normal infant. And just talk about that, and I'll talk about, again, my approach to this in talking with the family. All right, so in approaching my approach to this with this family was to really be frank with them, as we always should be, but to really dive into, this is what I have available to me with literature, and there's this broad spectrum that includes very relatively benign kind of outcomes as well as then pretty severe potential outcomes. And at this point, I just explained the limitations of prognosis at this point. I could state that things are very reassuring at this time. Nine month old, he's doing extremely well. EEG is normal. However, we need to keep a close eye. We need to maintain continual follow-up and be aware of the spectrum of seizures so that things that look like seizures that could potentially be subtle, because this disorder has a spectrum of seizures associated with it, myoclonic seizures or febrile seizures. And so really in discussion with the family, it was a discussion of reassuring it. Things look great right now. I'm very hopeful that in the context of seizure management and outcomes that things will continue on a great developmental trajectory. However, there is the possibility that things could evolve and there was, I did not feel that there was necessarily a role because for kind of changing medical management, this child was placed on a levotirastatam because of the prolonged seizure and the thought was that we would keep that on board for six to 12 months and just kind of see how things evolved given the normal EEG, had he had an abnormally EEG, probably a little bit different discussion. And the family was on board with that and they still had a lot of questions and we have to kind of adopt a watchful waiting approach. Sometimes we don't have, we don't have a crystal ball and so that was another interesting case in discussion. Anyone else have things to add? Yes. Yes, if you go to the mic, that'd be great. Yeah, I just want to present a very different opinion. So, and just to spark a little bit discussions, right? We want to make this colorful. So, I would argue that in the scenario you just described, the opportunities were not maxed out. And in general, an example of what I want to bring is, I would say often a literature review is not sufficient. Because if you want to do a proper literature review, you probably need to spend a month on a single gene. But who has the time for that, right? And it could be in the scenario where there's a mild and a severe version of the disease that is associated with the variant type or the variant position. And not many people have the genetic literacy or the biological literacy related to how proteins work to distinguish this. Often this information is in the research, but it's hard to tease out and you need to be an expert in biology sometimes. So, in the scenario like this, I think a literature review at the beginning is a first step. But I would definitely try to reach out to an expert if there are people who describe case theories, people who do structural biology on this space. Because there might be more prognostic value already in the literature, but it's not easy to tease out in a short literature review. And so reaching out to an expert is key in my opinion. Yeah, no, that brings up a really good point. And I think that in the context of reaching out and to colleagues and to referral centers that have genetic epilepsy programs and clinics and that kind of thing would certainly be completely appropriate. And we generally, at our institution, do have a referral pathways to other institutions. For example, Children's Hospital Philadelphia and other institutions. And so I think that, and also opening up to our genetic counseling and that kind of thing. Really, that kind of to some extent goes without saying in our kind of clinical practice as far as when we get abnormal genetic testing results, they're always, most of the time, seen by either our genetics department or they're kind of referred out if their waiting list is gonna be too long. But yes, absolutely, wanting to make sure that particularly when there are unusual genetic testing results, that reaching out to genetic areas of expertise or areas of, clinical areas of excellence or clinical centers of excellence with epilepsy genetics expertise is really important. Sir? I'd like just to mention also in common to that that the parent foundations that are represented here, by the way, so I would recommend you go by the tables and chat to them. But just reaching out to them, they have the resources to help you connect to the people that you need to, that are the experts and can also provide help for the patient to understand the potential disease that they have. Yeah, that's also a really good point that often the parent support groups or the parent advocacy groups do have lists of sometimes information about treatment centers and also can help guide prognosis discussions as well because as an individual center, you may have one or two patients, but the parents and advocacy organizations often have the numbers to be able to help families in that discussion about prognosis and what to expect and what resources to utilize when certain things arise. Actually, that gentleman took the words right out of my mouth. I just wanted to mention the Rare Epilepsy Network, which is a one-stop website that includes over 100 rare epilepsy organizations. We have a table here. Many of the leaders of those organizations are in this room and specifically a new organization this year was just founded specifically for that gene that are organizing the parents. They're putting together information, education, support. Ultimately, I think they hope to also be able to offer research grants to the community. So I hope that folks will remember that the patient advocacy organizations are both for the families to provide support, community, and information, but also highly valued partners of the clinicians as well as the researchers. Absolutely. All right. And so one last case to get through here. And so this last one was also very interesting. So a six-year-old girl who had a history of toe walking, she had been referred to our Peds Physical Medicine and Rehab Specialist, had not seen neurology. And so her examination and history was notable for a long-standing mild left hemiparesis. She had an early right-hand preference and was hyper-reflexing on the left side. She also had an additional history that was taken by the Peds Rehab Physician of sporadic left limb shaking that would last minutes but without any clear alteration of awareness. And she'd been doing this for quite some time, and so our PM&R specialist referred to neurology, thinking that, well, this is interesting. Even though she's hypertonic on that side, I wouldn't necessarily expect, this is not clonus, and so referred. She does have some cognitive issues. She has an IEP for an unspecified processing disorder. And in her birth history, and this is what parents had really kind of attributed her challenges to, but in her birth history, she had a, reportedly had a difficult and protracted labor and an emergency cesarean section. And so she had never, because of this, they had always assumed that she had some form of cerebral palsy, but she'd actually never had imaging before. And so she saw us, and we got an MRI, and she had this extensive right hemispheric polymicrogyria, which was really surprising in the context of the family had thought that this was a birth-related injury, and she actually had a cortical malformation. So we did a genetic epilepsy panel, and she had a variant on the LAMC3, a gene, and this mutation has been associated with malformations of cortical development, and particularly in the occipital lobes, and there's a described disorder called occipital cortical malformation. But this was a very interesting finding. In the context of this, for some reason, my slide is not advancing. I don't know if I hit the wrong button here. Let's see. And so in this family discussion, it was very, very interesting. Actually, this family, I believe, had been involved in some litigation, and so we ended up kind of finding a genetic etiology versus what had been previously assumed to be a perinatal insult. And in the context of this, what the family was feeling is a feeling of relief versus blame. And so it just takes some time to kind of discuss that with any of your tabletop discussions here, and then we'll come back to this. And so because we're getting close to kind of running short on time, I'm gonna move on more quickly with this one. And just, this was an interesting case that highlighted things that had been carried over from previous clinicians. This young lady had never had an MRI before, interestingly, and the family had always thought that her diagnosis of cerebral palsy was related to the labor challenges that she had. And you would argue probably in the context of that, well, she probably could have had an MRI sooner, but for some reason, she never did. And had been seen in getting physical therapy, and just kind of somehow landed in neurology from our rehab specialist, because he took a careful history and realized she's proctored, this is not clonus, this actually might be seizures. I did not put this on the slide, but her EEG was abnormal. She had right hemispheric spikes and poly spikes, not surprisingly, given that polymicrogyria. So she did have seizures, and then had, again, this finding, which really changed the family's entire kind of mindset of what was the cause of their child's developmental and physical challenges. And so, again, in the context of providing a diagnosis and a cause and an etiology, this was one that really changed the entire landscape, and from a litigation perspective, really potentially changed things as well. I didn't get involved in that part of it. But sometimes with, you find things that really do provide very useful and tangible information. So just to close, I will say that genetic testing can uncover as many questions as it answers, as we have really heard a lot about here today. We do need to recognize the clinical spectrums that are associated with some of these gene mutations, and the limitations and prognostication thereof, because there are often benign ends of the spectrum, where there may be more severe ends of the spectrum, and depending on where the child is, or the infant is in that category, you may not be able to really give a clear prognosis if things are developmentally fine at this point, but there's a possibility for change later. And thoughtful and empathetic discussions with caregivers, with emphasis on shared goals of care is really, really key. And part of that is also engaging, as we've already heard, in our community and parent advocacy organizations, kind of leveraging information sharing, and also recognizing that and letting families know that even when you find the diagnosis, that is not necessarily the end, that there may be other things that are available, referring to other centers that have epilepsy genetics expertise, just kind of maintaining that partnership with the family to know that you're gonna kind of remain engaged. And so I'll close there, and thank you.

genetic conditions

genetic testing

developmental disorders

GNB1 encephalopathy

YWHAG gene mutation

polymicrogyria