Chapters Transcript Neurometabolism: A New Era Dawns in Child Neurology Course: Advances in Child Neurology and Genetics Sometimes the patients cannot even pronounce their own diseases. And during training, we have minimal exposure, minimal education. So sometimes, Doctors feel uneasy dealing with these patients. So, like I say, around 90% of patients with inborn errors of metabolism present with a neurological phenotype. Intellectual disability, epilepsy, ataxia, strokes, optic neuropathy, peripheral neuropathy, myopathy, depression, psychosis, and so on. Frequency of these neurological deficits is not known. So In addition to primary metabolic diseases that affect the brain, there are neurological diseases in which the primary problem is not a metabolic uh condition, but in which metabolism is also involved. Neurodegenerative diseases commonly have a metabolic component. Epilepsy, autoimmune conditions. Strokes. Brain tumors, and many physiological processes which metabolism is critically involved. Right now, that brain acts as a very hot topic in neuroscience. Biomarkers and drug development. There are around 100 distinct metabolic biomarkers that we use on a daily basis in neurology, pediatric neurology and adult neurology to diagnose, uh, prognosticate follow-up patients and about 30 to 40 metabolic, uh, based therapies. It's a brief summary of a number of treatments that we use or they're currently on clinical trials on common neurological conditions. Of course, in more errors of metabolism that affect the brain that many uh treatments with a metabolic basis, Alzheimer's, Parkinson's, ALS. In MS, um. Short chain fatty acids. All right. Pretty hard right now. Basically, they're used as immunomodulators to decrease relapses and the severity of those relapses. And here, the gut-brain axis is playing a major role. Huntington's disease, epilepsy, mostly die therapies, migraines, and other neurological conditions. Probably have seen this in the news recently. Um, the government is Recommend the leucovorin, which is folinic acids, the active form of folic acid, um, to treat autism. Um, the underlying Metabolic connection between uh folinic acid and autism, as far as I know, is, is not known and it's kind of controversial. The good thing about this medication is that um it's pretty benign in terms of side effects. So A few facts. So there is a Important education gap in neurome metabolism. Um, most US calls devote less than 20 hours in general to metabolism and little to none about, uh, metabolism in the nervous system. There's usually minimal exposure during residency. Uh, in most programs, there is a lecture a year. At most, I give one lecture per year. Um, Only programs with a neuro metabolic specialist, um, We have some exposure to these conditions, about 25% of adult neurology residencies and 60% of child neurology residences. Psychiatric programs usually uh have no exposure and there's no fellowships in neurometabolism. There is a big gap in terms of education and exposure. But nonetheless, those patients show up to the ER or our clinics and we have to deal with them. It's a Standard case, 6 year old with probably dehydrogenase deficiency due to a mutation in this gene. Presented with breakthrough seizures after being seizure-free for 2 years on ketogenic diet, thiamine, and Keppra. 4 days prior to presentation, started having some UI symptoms, reduced oral intake, went to the ER, was loaded with the Depakote for seizures, got admitted. And within 12 hours, the patient became progressive insomnolent and started vomiting. So we're not familiar with a condition like this, what do we usually do? Mostly the resin goes in, um. See the patient usually. Uh, look for sources of information currently up to date. I mean Gen reviews Ion base popmed and tragic base, right? So, let's take a look at. One of these, uh, a couple of these, um, sources. So if you have a patient like this and you haven't seen a patient with this condition, let's see what you get. In Pacman, I'm sorry, in Activate. So as you can see, you have um. The broad topics, but not a specific chapter or article about. Already heterogeneous deficiency. You have to go through a lot of texts. You have a lot of information here whether you need it or not, you have to go through this. And this is available for free at Epic. So, it's up to date if you go to June Reviews, which is another. Commonly used source for um. Looking, uh, these conditions a little bit. Sorry for the noise. So you have a chapter here. Estimate the reading time, 27 minutes. So if you have a busy morning, it's very difficult to go through the whole thing. We have a lot of texts. A lot of information here. MRI labs. At the tables, more tables. More tales, more text. So you got the point, right? So it's um. So what are the problems about these resources? So, lengthy text and it's usually dimensions, so we have, we have to go line after line after line to get um the data. So it's impractical for immediate um Clinical use, if you have a busy morning or you're in the clinic with a lot of patients, you don't have have an hour to go through. Um, um. An article like that, so it's not immediately shareable. Um, if you give it uh to a student, it will take time to go through it. It's often outdated. So the uh GDX uh paper that I showed you, the last time it was updated was in 2021. It's confined so you cannot participate or edit or provide feedback to any of these resources. Um, they're not made to educate people, it's just to provide a lot of information out there, and you can do whatever you can with it, and it's not always validated like um AI sources. So There's a big gap um in the field, so what do we do about this? How can we improve um the current situation? And the other thing is, usually it's, it's not very um visually appealing, so it's a plain um um research. So, we have created RA, um, neurometabolic disease database, something that we're building, it's not available. Revo comes um from an old um English word that means to regain function, um, to fix things, to recuperate. And the problems that we're trying to solve here are basically um the problems that all the resources have. We want to convert this lengthy text into images. So we want you to see the disease. And go through it in less than one minute. So you have a patient with a disease you haven't heard of? And you can look at the disease. Know what this is about. What to do and what not to do, um, which is also a problem. People sometimes prescribe things that they shouldn't and patients get worse. Want to make it practical. Um, We want to update this weekly, so you get the latest information. We want to make it open source so people will be able to participate, introduce data, edit product feedback. And therefore, it's educational because it's visual. Um Validated by people who um work on this on a daily basis and want to make it beautiful. And therefore attractive and engaging. So, What is the current status of the database? So we have interviews the 2000 diseases in the database. And we are in the process of validate all the information. We're also getting papers from the literature and inducing that data in. To complement what is available in our databases with the literature. And we have reviewed 7000 papers so far. It's a lot of work. Uh, most of it is manual. We're using HPO terms of the information that is in the database can be exchangeable with other databases. And we want to make it available to other people, clinicians or researchers to Provide feedback and in the future also to patients and families. So, the, uh, the platform has 3 components. We're working primarily here, so we are introducing the data ourselves. From databases and from papers, using the R programming language. That is connected to Amazon Web Services. In the future, we want uh contributors like you or invite reviewers um to um edit, um. Expand the data. So that goes into the database that every piece of information that is introduced, we review with ourselves. The database has a backup. Every 24 hours we save the data and that database is connected to the web portal, uh, which is based in China. And that's what people will see. So I want to make this simple. So simple user interface. Where, so right now, um, you can only, um, Search for a disease based on the name, based on the gene, or alternative names. OK. So you can start typing because the the names are uh complex. You type the first few letters and a list of diseases will pop up and then you can uh choose the disease that you're looking for. So when you type the name of this disease, something like this will show up. See, OK. So we want to make it very simple and it's just a screenshot. Um, so all the information I need to know about this condition, this is a Um, creatinine deficiency syndrome where the transporter, OK, the globin barrier is defective. So if you have a patient like this in the clinic, Um, Here's the information. It will take probably one minute to go through it. This is the lesion. This is the name of the disease, the prevalence, it's, it's very rare gene, the inheritance, and the group of metabolic diseases that disease belongs to. Then you have the signs and symptoms, uh, distributed based on the frequency. On the top is the most frequent, at the bottom, the least frequent into systemic and neurological um deficits when they appear across the life span, and how often they appear. So instead of having the information distributed in a uni-dimensional base, this is um in a B-dimensional base. So you have H They have aint So, these patients usually manifest autism starting uh during infancy. The delay, Tonia. Epilepsy, movement disorders, and the important thing here, many of these conditions tend to progress and certain symptoms appear later in life. So, if you have a patient at this age range. Your um history can focus on this uh neurological systemic deficits instead of just asking about everything. Things that usually appear early on and about things that will show up later in life. So everybody know what could be coming and how to intervene accordingly. So, um, minimize the surprises, right? Or unexpected problems in the future. The same for laboratory features. So in this case, we usually check creatinine, one amino acetate, and creatinine levels and how those levels are distributed across the lifespan. Brain imaging were the most common uh brain lesions. When they appear, and they Typical lesions that uh usually uh show up. And then the metabolic map, this is also very important for educational purposes. What is the underlying biochemical problem? So, you have the issue at this level in brain and muscle. So you will have a decrease in creatinine and therefore, the ratio is gonna go up, as you can see here. And also what, you know, acetate. We'll go into a different pathway, so the levels are gonna be, you know. And then you have an overview of the therapies. So what to do, OK? So it doesn't tell you exactly what, uh, for example, in case of seizures, what is the most common drug. We, we won't have that information right now. But at least you, at least it gives you like an overview of, of how you should intervene, what kind of uh treatments that are available specifically for this condition. PTOT and speech therapy, medication, supporting management, and so forth. So there is a tab there to um introduce the data if you have um You know, a paper coming out about a particular disease, you want to introduce it by yourself, you can't do it. Or if there's a, a new condition that you, we don't have it in the database that um showed up in a, another database, you can introduce that information here if you want to participate. Or if it's a paper, you can add that information in that tab specifically. And also to provide feedback. The idea is to get better and get better and improve over time. So let me give you a demo. So this is internal. You won't have access to this yet, but. Hopefully in the near future. OK. So this is the uh front page. Let's look at, oh wait, the heterogeneous. So you can see, just, just type a few words, a, a few letters and you have the list of conditions here. So we say that our patient has radio hydrogenous deficiency due to PDHA1 mutation, so that is. I think there And Diego So the, the data is distributed in different hubs, as I showed you earlier. And this is generated as we speak. So if we introduce a new patient or additional data, it will be updated automatically. So all of this is done programmatically, so you can. See the gene, how often this disease appears in the US. This is very um rare. It's X-linked. Daily treatments, as we say in the case description, ketogenida thiamine interventions to avoid valproic acid, which is the case in Generally speaking, mitochondrial diseases, um, how many papers we have reviewed so far, 11. And the number of patients that are included in the database are 23, so not many. So you can see the um signs and symptoms are distributed based on the frequency. So global developmental delay appears pretty much in 100% patients, and this is basically when um um the deficit um was reported in the literature. So you can see that most of the um deficits appear during infancy, global dement and delay, hypotonia, seizures, microcephaly, respiratory failure. Attacks are usually a little bit later. Spasticity, dystonia? Facial dysmorphism. Tremors and dysarter until later, so if the patient. Um, it's a one year old. These are the things that you should look for. And these are the things that appeared later on, tremors and disaster, mostly in the form of a um cellular deficits. Here, we have a few um symptoms um selected from other databases which we don't have the number of patients listed there. They will have the laboratory features. Liked it, and this is um. When there were reports, so lactate is elevated across the life span, but in the papers, um, they only mention during infancy or childhood, and that's the reason, um, we don't have data, for example, during, um, during that period, right? The CSF is just in the infancy and childhood but not later on. Prove it pH uh activity in the muscle is down and ketone bodies, um, is a little bit high, mostly in the context of the compensation. And imaging, one of the common um structural um lesions that you usually see in these patients, basal ganglia lesions, cerebral hyperplasia. Corpus callosum capupplasia genesis. Only Michael Ja Pyja. And Corey Gansera atrophy appears later on. So, we want to convert this heat map into the cartoon that I showed you earlier with the brain and pinpoint where the lesions are and the future to actually have a typical MRI um. Uh, patients with this condition. Oh, let's see if I can. Mm Vencephalogram. Multifo foreign discharges, no background. An EMG. Metallic pathway. It's handmade and uh, I think it's really cool. So you can see the metabolic map here and the metabolic pathways that are involved when you have a Defi in this enzyme or related to energy metabolism. Enzyme is located in the mitochondria, converts peru with acetyl cove. So when you have a blockage here, everything that is upstream will accumulate. I have lactic acidos, elevated peruvi and alanin, and everything downstream will be depleted. So you're gonna have prep cycle uh deficits, respiratory chain deficit, and, and therefore deficit in energy production and biosynthesis. Then the therapist Just a general overview of what we usually do with these patients. intervention, medication, physical occupational speech therapy, and supported, uh, treatment for Um, some of these problems. Here's the submit data tab. If you wanna submit data about. This condition Over the hydrogens, the 11. I'm sorry. So if you see that something is missing, you can actually fix it. All right, listening around it. We have the signs and symptoms. You can fix it. The, the data will come to us. We'll take a look. We have questions, we'll get back to you. Imaging findings, laboratory findings. We don't have um individual values. Basically, we convert um quantitative variables into uh semi-quantitative variables, whether it's elevated or decreased or normal, EEG results, EMG and other testing. You submit and they will uh will get the um the updates automatically. And if there is a paper you wanna introduce, OK. I'm gonna say it. Department ID science symptoms, imaging fines, or finance page results. OK. And this is the feedback tab. That's it. Pretty simple. Any questions so far? I'm good. So where do we go from here? So, um, the database submission has been completed. Um, want to validate the whole thing this month. Um, When to reach about 75% of reviewing the literature by February 2026. And merging the data from all the databases and the literature around 50% by June of 2026. And release it internally at Mount Sinai um by December. Just to start getting feedback. Is the user interface easy enough? It's fluid, it's intuitive. So it's a lot of work, um, um. That um we need to do to, to make it like really cool and really useful. And this is the team that um is involved in this project. This is an NIH funded project. Um. I am collaborating with a team of bioinformaticians at Rockefeller. Started working on this about 2 years ago. And um hopefully more years coming to release this tool so you can all access and, and enjoy it and, and the ultimate goal is basically to Improve patient care, um, increase awareness about these conditions, and um You know, and spread the word about their metabolism because it's a very important field. So thank you very much, that's all. Published November 7, 2025 Created by
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