Featured Provider: Luca Farrugia, MDChild Neurology Resident PGY4 Barrow Neurological Institute at Phoenix Children’s
This video presents a clinically grounded overview of recent advances in neurogenetics and precision-based therapies for severe childhood-onset neurological disorders, including Dravet syndrome and related epileptic encephalopathies. It focuses on the evolving understanding of disease pathophysiology at the genetic and cellular level and how this knowledge is informing novel therapeutic strategies.
The discussion highlights how single-gene mutations disrupt neuronal signaling, network stability, and neurodevelopment, resulting in complex seizure phenotypes and multisystem involvement. Limitations of traditional antiseizure and supportive therapies are acknowledged, reinforcing the need for disease-modifying approaches that address underlying genetic mechanisms rather than symptom control alone.
Emerging genetic and molecular therapies—including gene replacement, gene modulation, and RNA-based strategies—are examined with attention to biological rationale, delivery challenges within the central nervous system, safety considerations, and early clinical trial outcomes. The presentation emphasizes the importance of rigorous clinical research, standardized outcome measures, and long-term follow-up in translating these therapies responsibly into pediatric practice.
Hi. Good morning, everyone. I am Kavitha Karnik. I am the program director for the Child Neurology Residency Program, and it's my pleasure to introduce Doctor Luca Faruja as our speaker this morning. Doctor Faruja completed his undergraduate studies at Boston College and went on to earn a Master of Science at Boston University. He then completed medical school at Mayo Clinic Alex School of Medicine here in Arizona and is currently a PGY4 in our residency program. He's looking forward to pursuing a fellowship in epilepsy here at Phoenix Children's following residency graduation. And Doctor Faruja, we all look forward to your talk this morning on the recognition and management of metabolic epilepsies. All right. Well, hi, everybody. Um, thanks for that introduction, Doctor Karnik. Yeah. Like I said, PGY for here in the child neurology program. Uh, I'll be talking a little bit about, um, a couple of specific, um, you know, metabolic-related epilepsies. There's a long list of, um, you know, seizure disorders related to metabolic disorders, but um I wanted to talk about a couple that were specific that one, have, um, Um, sort of specific non-seizure medication-related treatments, um, and that for the most part are not on our, uh, on our newborn screen. So, my objectives for today, um, one, you know, identify, so, you know, talk about key features that should raise someone's suspicion for a metabolic, uh, etiology of, uh, epilepsy. You need to talk about what would be a, a practical diagnostic approach to these disorders. And then 3, describe sort of management, management strategies that are sort of specific for um these disorders and, you know, specifically in these cases that are, um, you know, not necessarily our classic seizure medications, but more um metabolic metabolically aimed. And so the ones I'll specifically be talking about today um are pyruviic dehydroitis complex deficiency and gluone deficiency. Both of those sort of paired in the fact that they have the, uh, sort of same mainstay modality of treatment. Um, and then also, uh, pyridoxin-dependent epilepsy, pyridoxamine phosphate deficiency. Boxidinase deficiency and molybdenum, uh, cofactor deficiency. With those four kind of being linked in regards to sort of, you know, uh, typically intractable, um, neonatal seizures and sort of working through the steps of those. And so, we'll have sort of a flow chart at the end to kind of walk through, uh, kind of step by step way to sort of Think about treatment and workup for those specific, that specific situation, especially before you have like a um diagnostic uh confirmation. So I'm gonna start with uh pyruva dehydrogenase complex deficiency. So this is a specifically um disorder of carbohydrate metabolism uh caused by a deficiency in sort of one of the three enzymes or main parts that make the pyruvate dehydrogenase complex. And so, specifically, um, that is sort of impairing our ability to convert pyruvate to uh acetylcho A. Um, which kind of redirects our pathway, um, of, uh, making ATP. And so if we can't go down that pathway and the Krebs cycle, which, um, I'm sure we all remember every step of. Um, then we sort of get funneled over to, uh, lactate and sort of, uh, and, and sort of again make having lactic acidosis from the Lved lactate. So, it's specifically the main um subtype of um PDCD um is in the uh PDHA1 gene. Um, that's, and it's excellent recessive, but there's also uh a couple other subtypes that are, um, uh, autoimmune recessive, um, and sort of like I said, all of which combined to form, um, parts, one of the three parts of that, uh, specific enzyme. So, they, it can, and this will be a common theme with everything that I talked about today. Um, they can have a pretty variable presentation, um, having a pretty wide spectrum of clinical presentation. And so at one end, you can see it relatively quickly, um, present after birth in a neonatal that's significantly hypotonic, that's lethargic, it's not feeding well. Um, yeah, that's tachypnic. Um, but then you can also see it progress, um, You know, in late, you know, later in, you know, the first year of life or even longer than that until its first presentation with developmental delays, seizures, ataxia, recurrent respiratory illnesses, um, movement disorders. Um, all of the sort of The ones I'm talking about today have the potential to present at, for the first time as a seizure, and that might be your first sign that something could potentially be different. And so, that's specifically why I wanted to talk about some of these today. As also that's gonna be common with all these um metabolic-related epilepsies, sort of fasting illness, even exercise can um worsen symptoms. Pretty, pretty much, um, you know, there's a lot of seizure subtypes that have been described, um, generalized tonic-clonic seizures, tonic seizures, myoclonic seizures, spasms, uh, pretty, they've seen pretty much all types of seizures. Median age of diagnosis is about 1 year of age and, um, so there's the prognosis that, you know, about 60% survived past 3 months and 10% past um 4 years of age. So the workup, um, you know, initially would be sort of your basic labs which will clue, clue you in that this patient might be acidotic, um, and including getting a lactate to show that that, um, is elevated. It's important in, um, you know, when you're thinking about, uh, PCD, um, to look at the lactate in, um, Comparison with the pyruvate because the ratio should actually be relatively normal. Um, if you, if we go back to our, our graph. Um, you know, both the pyruve and the lactate should be normal based on where our sort of problem in the chain of uh command is. So, um, that would be different in some, in some other disorders that might have an elevated um lactate, um, but a normal pyruvate. And so that can help, um, in part differentiate. Because of, um, part of the byproduct, um, we'd also have an elevated, elevated plasma and urine alanine. And then, uh, specifically looking, um, at some of the cells, you'd see a low, um, PDC enzyme activity in, um, cultured fibroblasts. Some imaging findings that can be different. Uh, it's not slam dunk every time, but some sort of specific things I've seen have been, uh, cerebral atrophy, um, asymmetric ventriculomegaly, and then also sort of more midline defects, corpus callosum, agenesis, um, and dysgenesis. And then, um, confirmatory diagnosis would be, um, looking at some of the genes that I had mentioned. It, for example, it's, um, these genes are Especially the main one, are on some of the bigger panels like the neurodevelopmental disorders panel that NVA has, as well as the comprehensive, uh, neurometabolic disorders, um, panel. And so, you know, 11 of the reasons why I'm talking about this is that the management, um, including for, uh, a lot of times for the seizures, uh, can be just the ketogenic diet. Um, the, you know, way this works, you know, is we're sort of finding a different way to get to, um, acetylchoa on the, on the pathway. So, instead of um going from pyruvi, we're going from sort of the fatty oxidation pathway. Um, You know, and, and using, you know, just this and sort of correcting the sort of error in our metabolic pathways demonstrates significant seizure control, including even seizure freedom, um, a significant improvement in developmental delays and movement disorders that are seen with these patients. And as is going to be the case with all of these. Disorders, the earlier um that intervention is started, the significantly better outcome, um, is reported. All of these patients also get, um, thiamine supplementation. Um, and there was actually a trial in Ohio, um, of adding this to the newborn screen. It's obviously, it, it's quite rare. So there are a couple, um, cases that they caught, but it, it is not on the, uh, Um, on a newborn screen, um, pretty much anywhere. Including in Arizona. Uh, the next syndrome I wanted to talk about was, uh, glut one deficiency, uh, syndrome, a glucose transporter type one deficiency syndrome. So, in this case, the problem is with the transport of a glucose into the, into the brain, to the CNS, um, because we have, um, abnormal uh glut one transmitters, um, due to, uh, mutations in, uh, a specific gene I'll talk about. And so, on a, you know, despite a normal serum glucose, Um, we have a sort of abnormally low glucose, um, in the CNS, and, um, You know, and it's specifically, primarily, uh, transported, uh, uh, sorry, expressed on the endothelial cells, um, of the blood-brain period and then the astrocytes. And so this is especially problematic in an early age because um it's a problem in areas of rapid growth in high metabolic demand, which is obviously infancy and early childhood. And so, sort of crudely put, you know this low sort of energy state is disrupting the membrane potential. Neurotransmitter cycling, which in turn leads to seizures, which in turn leads to impaired synaptogenesis, myelination, neurotransmitter synthesis, which is, you know, leading to global delays and global slowing in function. So, from a genetic standpoint, um, the primary, um, pathogenic variant is the, the SLC2A1 um gene coding for, um, the glut one. Uh, transporter. Um, there actually can be, you know, with sort of single, um, Transpositions, you know, there can be mild to moderate symptoms where I suppose the whole deletion of the gene will lead to more severe symptoms. It's an autosomal dominant inherited, um, and 90% of the time, uh, de novo, 10% inherited. Um, this is also, um, on the neurodevelopmental panels that I talked about, um, But, um, as well as the epilepsy panels, including the one that, um, Phoenix Children's, uh, offers as well. So there's a couple, um. Interesting parts of the presentations, similarly, like I talked before. Um, it can be pretty variable, so it doesn't have to include all of these things. But um, something that's commonly seen and can sometimes be the first, um, sign is these paroxysmal, um, head-eye movements, um, which are sort of characterized by multi repeated psychotic, uh, conjugate movements of the eyes that are uh that are accompanied with head movements, um, in the same direction. Um, they're interesting to look at. And there's a couple of YouTube videos. Um, I didn't dare try and import them into my PowerPoint because I know that it typically does not go great trying to put videos into these things, but it'd be interesting if you are interested to take a look at. Seizures are also common and sometimes the most common presenting symptom. Um, commonly prior to 6 months and commonly refractory to seizure medications. Similarly, we can see multiple different seizure subtypes, myoclonic seizures, atonic seizures, um, GTCs, atypical absence seizures, especially at this early age, you know, atypical to see absent seizures at this age. Another thing that can sort of clue you in that. Maybe they're, this is different than sort of some of your more run of the mill genetic epilepsy is. Um, seizure frequency tends to decrease in age regardless, um, and is, and many times uh resolves by adulthood. Other things you can see is deceleration of head growth, um, developmental delays, um, and movement disorders, especially in the older population, older children, adolescents, where you can see ataxia, dystonia, tremor, chorea. In, in a lot of these older patients. Um, and similarly, a lot of these symptoms will be worse in fasting states and stress states, um, and in illness. Workup. Um, EEG is not, uh, needed for the diagnosis, but, um, in some cases, it can be helpful, especially when you're dealing with sort of a younger patient and you're not sure if the movements are, um, epileptic or not. We had a patient, um, on service earlier in the year, um, who Um, had some sort of amor kind of staring-like spells with some facial twitching that um parents are having a hard time describing. And so we weren't even sure at that time or seizures. So, once we captured those on the EEG and proved them, and then given the clinical picture that actually pushed us to be able to kind of proceed with this workup and really, um, Besides genetic confirmation, one of the key findings for diagnosis for this is um comparing The CSF glucose to the uh serum glucose. And so, and this, in gluten one deficiency syndrome, um, you have uh hypoglycoachia, um, which is sort of low glucose in the, in the CSF compared to the serum. So, you want to get a serum glucose around the same time you're getting your tap, um, and ratios of less than 0.5 would be abnormal. It's been sort of investigated and it seems like, you know, there definitely seems like more of the severe subtypes of this disorder have lower glucose as would be expected. So, less than 40 in the CSF, um, as well as a ratio of less than 0.4 has been um associated with more of the severe subtypes of disorder. And then like I talked about, as part of the workup, getting the genetic studies as well can help you with um You know, confirming this, although obviously, it will take some time. So that you, you, you can get the lumbar puncture quicker, which then we'll Start, help you get the treatment process going more quickly, which in the same way as our first disorder is the uh ketogenic diet. It is the gold standard for treatment of glut one deficiency syndrome. In a similar way, we're sort of using um ketones to sort of bypass where our error in the sys system is. So, in this case, our problem is with getting glucose um into um the brain. And so we can bypass that by using ketones that, which then can be used to seal and then, um, go through our typical processes of creating um ATP. Similarly to our other disorders, you know, the earlier the initiation of the diet, um, it's it, the better the developmental outcomes are, the better chances of um obtaining seizure control. Um, but it has a good rate of control with, with the diet, with a good percentage of our, uh, of patients, um, achieving seizure freedom with the diet itself. OK. And now, I wanna kind of move more into some of the ones that, that especially we can see with intractable, uh, intractable epilepsy, especially in the, um, Neonatal, um, period. So, first, I have a, uh, pyridoxine dependent epilepsy, and the first one I'll be talking about specifically the ALDH7A1, um, A variant of this, the more common one, which is a disorder specifically in the lysine degradation pathway, um, that's leading to early onset intractable, um, seizures. And so, this is not specifically pyridoxine deficiency, um, but more that, um, these patients are metabolically dependent on paradoxine, so, therefore, requiring excess, um. Supplementation. And, in this, in the more common type, uh, type, there's a mutation in the antiquitin enzyme, um, that's coded by uh ALDH7A1, um, which leads to uh excess AASA, um, and as well as PC P6C. Um, and the excess activity, especially the ASA can lead to reduced enzyme activity in the CNS that sort of regulate transmission of signals between neurons as well as brain development that can lead to some of the problems that. Some of these patients have. And so, clinically, you can see seizures quite soon after birth in a, a majority of these patients. Um, and one of the more telltale signs is that they're not really responsive to the traditional, um, seizure medications that we use. And you can see multiple different subtypes of seizures, um, focal seizures, tonic seizures, generalized seizures, um, as well as spasms. And there's some suspicion that some of these patients may even be seizing in utero, um. You know, with mom, um, and that maybe their parents, uh, mom is feeling some sort of abnormal movements, um, that actually might be seizures. And a lot of times these frequently um cluster and become prolonged and, um, progress in the neonatal period into uh status epilepticus. Other, other sort of signs that you can see um in these patients are fluctuations of tone, uh, irritability, poor feeding, lethargy like we talked about, and then more further along intellectual disability and developmental uh delay in addition to the seizures. From a workup, um, standpoint. You know, there's some labs and, and some tests that you can do, um, but realistically, from a timing perspective, uh, the sort of workup is, if you're suspicious of, of this, if the patient kind of is giving a metabolic picture and we're having a hard time controlling their seizures, um, at You know, close to birth, that really the workup is trying paradoxine um supplementation and seeing if there's a clinical, um, and or uh and uh EEG um improvement once starting it. You can look at some labs, like you can look at elevated uh for um elevated plasma and urinary levels of uh AASA. And then obviously, there's, um, you know, genetic, uh, you can send up panels like the, uh, epilepsy panel panel that we have here in Evita or the treatable neurometabolic uh disorder panels, but obviously, those will Take some time to confirm. So, realistically, this is a situation where part of the workup is trying the treatment. And so, like I said, the management is a paradoxy supplementation. Um, and newborns, you're going in about 100 mgs a day, and then if it's for the maximum of 300, children and adolescents maxing out, um, at about 500. Um, they're, you know, also part of the management is. Um, reducing lysine intake in the diet, as well as arginine supplementation. So, triple therapy, um, for this disease is considered all three of these. So, uh, paradoxine supplementation, arginine supplementation, and then lysine restriction. In the diet. Um, you know, early supplementation is associated, can be associated with seizure freedom and, um, a lot of these patients. Although, kind of regardless, a lot of these patients end up having some developmental and intellectual, uh, delays despite treatment. I wanna kind of pair that with uh pyridoxamine bisphosphate deficiency, um, which is a similar clinical picture to, um, pyridoxy-dependent epilepsy. So, Also with seizures soon after birth, also with multiple seizure, um, types, um, you know, this is also, you know, refractory to seizure medications and also frequently progressed to status. Um, but the difference is that it's a, you know, a different mutation in the uh paradoxamine 5 phosphate oxidase. Um, and therefore, these patients are less responsive to pyridoxine. So, it can look very similar to these patients, um, but then you're trying pyridoxine and you're not seeing, um, success. And so, in this case, the, um, management is actually, uh, slightly different. It's trying, uh, paradoxyl 5 phosphate PLP, um, the active form of pyridoxine, and these patients should be more responsive to that. Um, and so similarly, the, you know, the World Cup is, um, In confirmatory workup is um Genetic, but, um, in the meantime, it's sort of trying the treatment if this is sort of your suspicion, but then you're noticing that the, um, they didn't fully respond or didn't necessarily respond to the, um, pyridoxine. Um, bioinase, uh, deficiency is the only, is the one I included here, um, that is actually on the newborn screen, but it's sort of part of like sort of well laid out pathway that I found. So I, I wanted to talk about it here anyway. So, it's specifically a um metabolic disorder preventing um the body from uh recycling uh biotin, vitamin B7. And so, a mutation in biotadinase leads to a depletion in biotin. And so, you know, as a part of the process of biotin being sort of used for um amino acid metabolism, fatty acid synthesis, and gluconeogenesis, um, it sort of goes through a loop. And part of that, it is, um, biotanase converts uh biocetin, um, Back into sort of the free biton um pool. And so, obviously, a deficiency in that is going to sort of run your levels of biotin um out if you're not recycling it. Similarly, there's a sort of spectrum in these cases, um, and you sort of can be characterized in sort of the profound BTD or partial BTD and profound would be less than 10% of normal, uh, activity of uh bioidinase. Um, clinical features for these, um, similarly, neonatal slash infantile seizures. Similarly, you know, multiple different types have been seen, but also some characteristic, um, Uh, non-seizure related findings including, uh, alopecia, rash, especially around the mouth and the eyes, brittle nails, um, conjunctivitis, and then eventually, um, Uh, developmental delays. Um, the workup as far the issue we have now is that it's part of the, um, newborn screen um in the US, but if there's concern that patient was either born outside of the country. or um something went wrong with their newborn screen, then you can do a botanase enzyme activity assay and then obviously genetic, uh, specifically, uh, sequencing, um, the botanase, um, Uh, gene for any, uh, any variants, um, but it's, um, I have a screenshot of our um newborn screening panel and it's um number 29 on there. Uh, and even just looking at the newborn screening, you know, we can see some other, um, disorders, even some other metabolic disorders here that are associated with seizures, um, that I won't be talking about today, but I think I wanted to specifically talk about For the most part, ones that aren't on the screen, um, and that can have very specific, um, metabolic treatments. But there's a lot more that we could talk about in regards to um metabolism and seizures. Um, I'm sure we could do a couple talks about them. And so management is a lifelong biotin supplementation, sorry, 5, 10 ms per day. Um, interestingly, um, these patients should avoid ingestion of raw eggs as the protein, um, in the Avidin, um, can bind to biotin and sort of decrease its bioavailability, which would be obviously working against their interest in these cases. Um. Apparently cook cooking the eggs deactivates this and it is not as much of a concern. You know, untreated, these patients, um, can be symptomatic early, very early on, but on average of 3 to 4 months, um, seeing, and those untreated patients will, will typically develop seizures like we talked about, but can also develop sensory neural hearing loss, optic atrophy, um, as well as some of the other clinical symptoms that I had talked about before. But these patients can have a very normal life and lifespan if treated early, um, as long as we're sort of feeling that need that, um, the, that we're not getting with our, with our cycle that they can, um, have a relatively normal life. OK. And then the last one that I wanted to talk about today was the uh molybdenum uh cofactor deficiency, MOCD, um, and this is specifically, uh, a defect in the synthesis path, pathway of, uh, the, uh, local um cofactor starting from, uh, GTP, um. And sort of there's, it's characterized into three types and sort of just depending on where along the way the um Error is. Um, and, but the end result is sort of, you know, causing, um, loss of sulfide oxidase, xanthine and dehydrotase and aldehyde oxide activities. Which will lead to a toxic sulfite uh accumulation. And so, in the chart there, you can sort of see how it's broken down based on where you are into the three types. Um, So, type A at the top with the MOCS1, um, which is a majority of the cases sort of stops at the very beginning, um, where, uh, CPMP is not formed, whereas type B with MOCS 2 and 3. Um, In sort of the mill point and then type 3 with the GPHN gene um at the sort of last stage of the um pathway. And so, all three of these will, subtypes are clinically indistinguishable, um, but at least the first type, subtype has a little bit different management strategy. And so for, in these cases, in the sort of severe cases, like all of these ones and the other ones that I've um previously described, um, there's a pretty wide spectrum, but you can see really early onset seizures, uh, hypotonia, oonis, um, uh, poor feeding, and res were compromised all in the first few days of life. Um, whereas you can, in the late-onset versions, then you'll typically have minor symptoms that are more typically exacerbated, um, by, um, you know, illness or insult and where you can see mental status changes, dystonia, um, you know, movement disorders like chorea, ataxia, and nystagmus, as well as, uh, fluctuating tone. Um. And like I said, all three of those subtypes that we talked about, A, B, and C are um Indistinguishable. So, the genetics will help you um parse through them. Um, as part of the workup, um, you can do urine dipstick for sulfite levels, which should be elevated in these cases. Um, obviously, you, you confirmed with genetics and, and their MRI's can have a characteristic pattern with, um, Diffusion restriction and T2 hyperintensities throughout the cortical ribbon, subcortical white matter, including in the basal ganglia and the brain stem as well as some gyral swelling. Um, In some of these patients. And so, for specifically type A, there's a medication, um Ulory, um, it's uh phosphonopterine, um, which early on is a daily, um, infusion and it's sort of replacing what you're missing from that, um, First step. Um, so it's a CPMP substrate replacement. But then, uh, assisting restricted diet is part of the mainstay, um, of treatment, which is sort of decreasing our downstream. Sulfite um production, which is our main issue um in this disorder. And so, you know, I found on up to-date, I think I found a pretty um useful um chart that kind of walks through uh a sort of reasonable approach to managing um Patients that you're, you know, suspicious, especially of these um last four disorders that I talked about. And so, specifically, you know, you'd start with, OK, we have a neonate that's seizing. Um, and does not seem to be really responsive to a lot of the medications that we gave. And then maybe there's some other clues based on how they're looking and behaving that, you know, this could be a metabolic, um, origin of their, uh, of their seizure disorder. And so, based on, you know, kind of playing the odds, a good first step would be like we had talked about before, just trying, um, uh, paradoxine. Um, for, you know, 3 to 5 days and then assessing for, um, A response or not. And so, if yes, then that kind of would um favor a retin deficiency or, you know, or ALD 7A1 um paradoxine deficient epilepsy. And so then you could specifically test for that and that can be confirmatory. Um, and then if your genetic testing is negative, or if you don't have an adequate response to the pyridoxine, um, trial, then you can move over to, uh, PLP, um, now thinking more, maybe is this, um, you know, PMPO deficiency. Um, and so, similarly, if you do have a, a response, then that, you would seek genetic confirmation that way. If you don't, then it considers the next step, um, leucovorin, um. These, uh, first, the PDE uh at least it used to be called like a, a folinic acid, uh, responsive epilepsy. And so that is also part of the management and seeing if they are responsive, um, to leucovorin. If no, then you're starting to move sort of further down, then, you know, your tree moves to, you know, did this patient get a newborn screen? Have we already excluded biotenase deficiency? Um, if no, then trialing biotin and similarly assessing for response. And if there is a response, then you can confirm with, um, you know, biotenase activity in the serum. Um, or genetic, um, confirmation. And then if no, um, can move towards getting a urine dipstick for, um, sulfite levels and if elevated, then that would appear more um consistent with a um molybidum uh cofactor deficiency, which, like we talked about, you can confirm with uh genetic testing. And then if that's normal as well, then I think you have to be a lot more broad in your workup, um, you know, and sort of maybe more broader genetic testing and looking at er errors of metasism and channelopathies, um. Uh, if they're not responding to sort of, sort of this first step by step trial. So kind of for me. Sort of summary standpoint, like the, you know, thing that I think. I got from this and I wanted to convey is that like, think, you know, alarms should start going off, especially if we're having neonates in infants that are having seizures that are either atypical for their age or that are refractory to typical ASMs, especially if they're going into the status and we're having a hard time controlling their seizures without really any known, uh, clear insult or, uh, or cause like infection. Um, or bleed or something like that. Um, you know, that maybe should start, and especially if, you know, they're having some other things that might key us in that this maybe is potentially metabolic, like they're, in addition to the seizures, they're lethargic, they're not feeding well. Um, the, there's sort of some fluctuation that seems in regards to illness or the patient's developmental delayed that might start making you think that, um, It maybe might be worth more looking at the metabolic route. And then, obviously, in addition to what I talked about, you know, there's many other disorders um that are on the newborn screen. But obviously, if we have patients that are presenting like this and are internationally born, um, that they had a lot less substantial or maybe without newborn screening would be um worth specifically looking into a lot of these more metabolic, uh, Epilepsies. Something I just wanted to highlight um that I think is important for families, especially with some of these more rare disorders that, um, you know, especially there are other doctors may not be as familiar familiar with this, kind of how important community can be for these patients, um, in regards to them making themselves aware in regards to research, in regards to sort of a community, um, I think it can be really helpful to connect families, um. To sort of these resources. You know, Glut One has a, uh, there's a glut one deficiency Foundation, which is a great website and a lot of really good resources for families for connecting people. Um, uh, PTCD also similarly, um, has a, a research for a cure page, which also has a lot of really great information. It is also really, um, keyed in on research and, um, you know, enroll and getting families aware, you know, of studies that they potentially could be enrolled in. And then when you get even more rare where they don't usually have dedicated websites, at least the uh National Organization for Rare Disorders can, can be helpful um for a lot of these families, both from an informational um standpoint. Um, As well as a uh As a community standpoint. Um, and that is what I had for today. I'm, so happy to, uh, talk if we, if we have any questions. Hey Luca, great job, uh, Angus here, um, really a challenging, uh, topic and, uh, diagnoses that are so critically important to make as, as soon as possible. Um, and I think you summed it up really well when you said that, you know, if a child has an atypical presentation or the seizures haven't stopped, um, you need to definitely explore. You know, why and uh understand why the child is having seizures or developmental delays or particularly developmental regressions. Fortunately, we have um the ability to order genetic testing now, which is standard practice for really virtually all epilepsies. Um, even structural epilepsies can often be associated with, uh, identified genes and Uh, with or without, uh, associated metabolic problems. So, um, really nice overview. One of the challenges, um, is just the variable presentation of some of these conditions. Like, for example, glue 1 may present in infancy with, with seizures, but may not present until adulthood with a movement disorder, and they never have seizures. So, uh, it, uh, it remains a challenge to, uh, to sort out the phenotype, and once you've identified, and then, you know, figure out, you know, identify the genotype that goes along with it. Great job, Luca. It was an excellent presentation. Thanks. Mm. I'm definitely more than happy. Oh, go ahead. Uh, I would like to build off of what Doctor Wilfong just said. So many of these metabolic conditions have such variable phenotypes and presentations. Um, I would argue that you don't have like a specific metabolic phenotype that Raises concern for metabolic disorder. There are various different phenotypes that can maybe raise concern for specific metabolic conditions, but there's so many metabolic conditions that can lead to seizures, and you've only touched on a very, very small slice of them. Um, and it, I think it's important to consider that more targeted differential rather than, oh, it can be a metabolic epilepsy. Um, and then if you go back to your molybdenum cofactor deficiency slides, you mentioned, uh, urine dipstick for, uh, urine sulfites. There is, there are no validated urine dipsticks for sulfate testing, um. The only ones you can get are off of Amazon that are actually for wine testing, and Doctor Dietzen would be very upset if we actually use those here because they can affect the laboratory's cap and class certification. Oh wow, What you can actually do is send urine sulfocysteine to Mayo, call them to make sure that it's run stat, and you can have an answer in about 3 days. Um, molybdenum cofactor deficiency when presenting in that early infantile period, it can have a lot of overlap with HIE presentations, including in neuroimaging. And the treatment, Nullibry is recommended to be started within a few days of symptom onset. So that's actually the fastest method of diagnosis that you can do. I would argue that test should be sent for anybody that presents with HIV symptoms or neonatal seizures. Um, that doesn't quite have an obvious reason to have those, um, because that's actually faster than even doing a rapid exomer genome. Thank thank you. That's actually, that's really helpful. I appreciate that. OK. Well, thanks everybody. Uh, I can give you a little bit more time of your, of your morning back.
