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Foreign. We don't usually highlight case reports because we try to do something that has bulk of evidence. However, what we're covering today is so groundbreaking and so novel and honestly so out of the box that we've got to review this. Well, number one, because it's part of what we do. I mean, this actually just came out in the New England Journal of Medicine on February 19, 2025. Again, pretty much like a case report. It's an n of 1. Never been done before, but its implications are so intriguing and so hopeful. We gotta talk about this. Okay, now this comes out of St. Jude Children's Hospital, which is an incredible institution in Memphis, Tennessee. Thank you, Dave Thomas, for all of the. The. This, the donations, the create the. The creation of a wonderful program because Dave Thomas of Wendy's fame, Wendy's Hamb, was a big contributor to the St. Jude Children's Research Hospital. This comes out of that institution and it is a first ever in utero therapy for spinal motor neuron deficiency. In other words, the genetic basis of spinal muscular atrophy, sma. Okay, when you get into all of this and we're going to review sma, because SMA spinal muscular atrophy is one of the maternal carrier states that we're supposed to be looking for in pregnancy along with cystic fibrosis. And we covered maternal carrier screening in the past. Hemoglobinopathies, we've talked about that. Fragile X, some people throw that in there based on family history. We've talked about that. But this is a big deal because spinal muscular atrophy actually has four different types. And unfortunately, type one, which is the worst, the most affected babies, the most affected infants have. Type one is uniformly lethal. We're going to talk about type one, type two, type three, and times four. And all of those types get progressively milder the more you go down the number chain. All right, so number four is very mild. Type one is very severe. And we're gonna talk about just briefly, the genetics of this so we can remind ourselves what SMA is and how it relates to spinal motor neuron number one. I'm sorry, Survival motor neuron one. I always say spinal cause it affects the spine, but it's actually survival motor neuron gene 1. That's S M N1. S M N1. We're going to talk about that. All right, Survival motor neuron gene 1. So here's what these authors did, and I don't want to get into it because I'm still in the intro, but with an N of one at the parents discretion and suggestion. Did you all get this, guys? It wasn't like the physicians who said, hey, can we volunteer your, your pregnancy, your child for this in utero treatment? No, no. The parents brought this up to the physicians. Is that incredible or what? Good for them. So this was a parent proposal. I'm going to get into that in a minute. But the short of it is these parents who were known carriers of this already had a significant heartbreaking loss from this horrible condition. And so they're the ones who said, hey, look, why don't we. Is it possible to start treatment for this before the child is born? In utero treatment. We're going to discuss what that in utero treatment was like, because it wasn't just done one time, it was a plan. And the child, who's now nearly three years old, is still on the medication. But it's fascinating. Now, please hang in here with me because I understand it's an N of one and it worked. Okay, it's an N of one and it worked. We need a lot more data. However, here's why I'm highlighting this. Number one. Again, it's part of our plan to let you know it's hot off in print. And this was done relatively recently. We're doing this in the first week of March 2025, and this was done at the end of February 2025. So that's our commitment number two. We're supposed to be screening for this as a maternal carrier state. So if a child is found to have this confirmed, of course, by amniocentesis, we need to be able to explain what this is. Now, it is true that in utero treatment is not standard yet. However, how hopeful can this be to parents with a confirmed diagnosis that their child has this condition? How hopeful is it that we can now get on top of this problem? Now, right now there is FDA approved treatments that typically happen in infancy shortly after birth. However, these parents thinking again outside the box, saying, well, if we can start this treatment when the child is born, why don't we start it now? Meaning in the late second, early third trimester, we're gonna discuss all of that in this pregnancy. Okay? Because this medication was started at around 32 weeks gestation, it's an oral medication given to the mom which passes to the child. It's not like the child had some kind of gene splicing technology which entered in utero through cortosynthesis or something. No, no, no. It's in utero because the medication passed to the child. But not necessarily injected into the child. Right. So it's maternal administration for passage in utero, for in treatment. So we call this a breakthrough for in utero SMA therapy. Now, there's limitations, again, n of 1. But my point is, look how far science has advanced. It's amazing. And honestly, kudos to the parents who said let's start this treatment. We are, we are aware it's investigational. We're in. And as of the publication date of this publication, the child seems to be free of any kind of symptomatology. Okay, so I'm going to say that again now, when the child, when this was first published again, just about two weeks ago, up to the the current state, the child seemed to be completely asymptomatic and be doing very, very well. All right, we're going to talk about how this medication works, what medication was given. And so potentially this can be a treatment in utero for, for this affliction. All right, I think I've set it up enough. When we get into it, we're going to get into this publication that is fresh off the heels of the New England Journal of Medicine from February 19, 2025 out of St. Jude's Children's Research Hospital out of Memphis. We'll be right back. This is Clinical Pearl. On top of building this fake volcano for months, I give my daughter Smarty pants vitamins to support her brain health. So her science fair project sounds more like and less like. And while I may say it's not a competition, of course it's a f competition. Choose smarty pants vitamins to support your kid's brain health and save the science fair. Shop on Amazon, smartypantsvitamins.com or at target today. Hey, it's Ryan Reynolds here from Mint Mobile. Now I was looking for fun ways to tell you that Mint's offer of unlimited Premium Wireless for $15 a month is back. So I thought it would be fun if we made $15 bills, but it turns out that's very illegal. So there goes my big idea for the commercial. Give it a try. @mintmobile.com Upfront payment of $45 for three month plan equivalent to 15 per month required new customer offer for first three months only. Speed slow after 35 gigabytes of network's busy taxes and fees extra c mint mobile.com you know, when we went back and forth with our team about whether we're going to cover this or not, we're like, man, we don't do case reports. We, we had to do it and basically we settled with this is so encouraging because it's never been done before. Plus, what a great water cooler kind of story, right? I mean, people don't do that anymore. Go to the water cooler. I don't know, maybe they do. And discuss just some fascinating things here. Now, first of all, remember that there is no cure for sma. So I'm not saying that as far as we know, because most of the treatment begins already after the fact, after the spinal muscular atrophy has already been set in motion. Okay? This is why this is so exciting. Because even though right now there's no effective cure, as far as we know, this child, who's almost three, has no discernible evidence of sma. Okay? In other words, it seems to have worked at a time where she surely should have had some manifestations of this because she doesn't have any SMN1 protein. We're going to discuss this in just a minute. All right? So my point is, I'm not. I'm not saying that this is what kind of cure. I'm saying it is a fascinating investigational therapy done at the parent's request that seems to have worked. Because if you can get ahead of the. Of the. Of the muscular atrophy by basically forcing this protein into creation, okay? Because this is what this medication does. It kind of works to say, hey, look, neurons, pump this protein out. That's necessary for good spinal cord development and muscular innervation. Let's get this thing going. And if you do that early enough, like in utero, maybe it. Maybe it works. Okay? So I know that there's a lot of limitations here, and I'm not saying there's some kind of miracle cure for this. I'm saying it's fascinating that. So far, so good. Okay? Now once again, if we go back to the ACOG guidance on maternal carrier screening, we can go back to March 2017, which is carrier screening for genetic conditions. ACOG says that SMA is one of the things that we need to look out for because potentially it's devastating. All right? And patients need to be aware of this so that the pediatric neurologist can get on top of this so at time of birth can start medication. All right, now let's get into just briefly what SMA is again, how it relates to the survival motor neuron number one, and then the different kinds. All right, because there's type one, which is your most severe type, and then type four, which actually has its onset in adulthood. Right? So the exact opposite of type 1, which is the most severe Remember, as the numbers go up, the more mild the condition. Okay, but in general, this is an autosomal recessive issue that is characterized by degeneration of spinal cord motor neurons, which then leads to atrophy of the skeletal muscle and overall weakness. In other words, it's a central issue. Okay? Spinal cord motor neuron deficiency. They're all jacked, which then affects downstream in the periphery, the skeletal muscle. Okay, so it's not. The skeletal muscle is honestly the victim here, guys. Right? It's just. It's not getting the right signal. It's not getting the innervation from the central part of the system, from the cns, from the spine. And so that's where the issue lies. All right, so this disorder is caused by a mutation in the gene known as the survival motor neuron one that's responsible. Here it is, guys. This is key for a protein that's essential to motor neuron function. So what happens is you have SMN1, and if both of those copies are gone, if they are toast, you don't get that protein, and then that's what leads to the phenotype. Now, it is relatively rare, and it also depends on what kind of ethnicity the patient has, because, oddly enough, Hispanics tend to have one of the lower frequency carrier rates of this. So carrier frequency in Hispanics is like 1 in 115 or so. In Caucasians, who tend to have the higher frequency, it can be as high as 1 to 35. Okay, so Caucasians 1 to 35, Hispanic, about 1 in 115 to 117. Depends on who you read. African Americans is like double that of Caucasians. So it's like in 1 to 60 or 1 to 66 as a carrier frequency. All right, so Caucasians 1 to 35. African American like 1 to 66, and then Hispanic anywhere from 1 to 15 to 1 to 17, based on who you read. Okay, so the carrier frequencies do vary by ethnicity. Now, let's just quickly do the types, and we'll get into this publication. Just gonna be very, very quick, guys. Again, because it's not big protocols, there's not a lot of data here. I'm just trying to highlight the encouragement that we have that if we get to this early enough in utero through maternal ingestion, that can pass through the child seems to be promising. All right. And it's a good review of what SMA is, since we're supposed to be screening for this anyway. Okay, so the most severe form is type one. This is the one where the kids become Symptomatic at or before six months of age. Guys, that's super, super early. Now the sad part is that by around age 2, they tend to get such muscle weakness that it involves a respiratory system, so they have respiratory failure within the first two years of life. Y' all get this. So type one, not good. Okay, so type one is basically, you don't have any of this protein. It's most severe form of atrophy. Now there is another gene that's right next door called SMN2. This can produce some protein to give milder forms of the condition. But still nonetheless, you really need functioning SMN1 protein for this to work. Okay, so type 1 is the most severe. Type 2 is a little less severe, but still, still fatal. It's still not good. For this type 2 SMA variant, the phenotype as we said, is a little milder. Remember, type one typically has presentation at around six months and then by age two, almost universally lethal. Although there's a lot of variance here guys, in penetrances just in generalities. Type 2, however, typically begins symptoms at around age 2. And these children have milder versions. They are able to sit, but few are able to stand or walk without assistance. Now for these, respiratory insufficiency still seems to be the universal end here. However, they can last into adolescence. All right, so more than 80% of SMA cases are either type 1 or this milder, type 2. Again, both of which are lethal. That's the heartbreaking part, right? But type one is the worst. After type two, there's an even milder form called type three. Now this typically has a symptoms around 18 months of age or so up to that two year stage. Just like with type two, however, symptoms again become very, very variable and again much milder than even type 2. And these individuals typically can reach all major motor milestones, but it depends to what degree. Some require a wheelchair, some require a lot more assistance. So it's very, very variable. However, for this variety, type 3, here's the good news guys, they tend to typically have normal life expectancies. And then type 4, which again has normal life expectancy, tends to have its presentation in adulthood, right? So type one the worst, type four, which presents in adulthood and seems to be much more mild. Okay, now remember, this all has to do with the active gene, this survival motor neuron protein, SMN1, okay? And the way that it affects the patient is that if they have deletion of both of these SMN1 genes, then you have a severely affected child. Okay? SMN2 gene, which again, just right next door, can help alleviate some of that phenotype, but it's typically not enough like SMN1. So the good news is, is that if you have One variant of SMN1, it's. It's helpful, okay? You don't want to be missing both, because when you miss both, that's where you get a severely affected child, right? So survival motor neuron one, that's the issue here. If you have both missing, it's. It's pretty bad, okay? So the more proteins that you have, the better. So this is why we do carrier detection. It is a big deal, even though, as we've already mentioned, there is some variance here based on ethnicity. Okay? So in brief, normal is to have two copies of S&M1. If you are a carrier, that means that mom has only one copy of SNM1. And of course, if somebody has two messed up SNM1 genes and they are affected. Okay, now there is a catch here because what is being looked for with the carrier screen is, is a copy of the S&M1 gene by genetic profile. Okay? Now it is possible. Guys, listen to this very quickly. And then we're done with this whole genetics part because this is kind of boring, but nonetheless, we have to do it so we can remind ourselves of what we're looking for. It is possible to be a carrier and have a normal screening test result. It is possible. And here's how. Normally, the SM1 gene is on two separate chromosomes, right? So the stepladder, right, we all get that the DNA double helix. One's on one side and one is on the other side. It is possible for a patient to have SNM1 genes next to each other on one strand of the double helix and not on the other arm. So that if the other arm is missing that protein, they can still test a normal. They can have a normal screening result, although some genetic tests are able to tease this out. All right, so all to say, they are either completely normal on screening, which means they have two copies of SNM1 1 on each chromosome, they can be a carrier, meaning they only have one SNM1 gene. They can have a carrier, but still be a normal screening result. If both SNM1s are living next to each other on one strand of the DNA. But again, they can tease that out. And anybody who's affected means that both genes of the SNM1 are missing. Okay? Which would present with type one spinal muscular atrophy. Just a quick recap. Just a quick recap of the genetics of this thing. And if you want more information, although you pretty much covered it, it goes back to March of 2017 and ACOG's committee opinion number 691, carrier screening for genetic conditions. All right, now that we've laid that out, let me just tell you where this new publication is coming from. The Journal. I'll give you the title and then we'll take a quick break. I'll let you know what they found and then we'll call it a day. Again, relatively quick episode just to give some hope for patients who are diagnosed, truly diagnosed, not with a screening test, but the child is actually found to be affected. And this could potentially give future patients and parents some hope. Anyway, the title of this case report is Risdiliplam, and I say that different every time. R I S D I P L A M. This is one of the FDA approved oral medications, Residopam. Or is it Risdiplam? Is it Resdiplam? Look, man, I say it different every time. Sometimes I say Res. Diplam or Resdiplam. Whatever. Ristoplam for prenatal therapy of spinal muscular atrophy. Notice not infant therapy for prenatal therapy. Super fascinating. The first listed author is Richard Finkel, who is the physician and this is supported through St. Jude Children's Research Hospital out of Memphis, Tennessee. Ristoplam for prenatal therapy for spinal muscular atrophy. Let's get into that when we come back. Abercrombie denim is everything right now. Denim should feel like this. Confident, easy, like your butt has never looked better. If you didn't know, Abercrombie's Curve Love Denim went viral in 2019 for eliminating waist gap, and it's still a game changer. Between that and their classic fits with a straighter line from waist to hip, the perfect denim does exist. Shop Abercrombie Denim in the app online and in store this Labor Day at Lowe's Shop member only Doorbuster deals for a limited time. Save $50 on an ego string trimmer now $169 plus get 50% off select Holland Pavers. Not a rewards member. Sign up for free today but hurry Labor Day Doorbuster deals won't last long. Lowe's we help you Save valid through 9:1 while supplies last program subject to terms and conditions. Details@lowes.com Terms subject to change page. Hey, we're glad you're part of our podcast community. You're listening to Clinical Pearls. Yeah, this story is definitely getting some news. And it should. It was in a News brief from St. Jude Children's Research Hospital. It actually was featured in a little cover story the day after publication. So this was out on February 20, 2025 out of the journal Nature. And the title of this commentary was Rare genetic disorder treated in womb for the first time. Okay, and then the little subheading is the child who is now almost three years old. Here it is, guys. Quote, shows no signs of the often fatal motor neuron disease. End quote. This is a little girl, okay? So fascinating, fascinating. And hopefully this is something that can be replicated. And again is encouraging that even though it's rare, like 1 in 6,000 to 1 in 10,000 or 1 in 11,000, based on who you read, that there is some potential hope Here when this SNM1 gene, when both copies are knocked out. Okay, so first of all, the medication was not experimental, that was FDA approved. It's already used to treat again newborns for this condition. Wrist diploma, Wrist diploma, whatever. I mean, look it up, man. Look it up. So again, this was a parent proposal. So the parents already had suffered a child with this horrible disease. And so the patient actually brought this up and said, can I please take this medication? Started in utero to try to get ahead of this. Fascinating. So it was patient slash, mother initiated. Awesome. Good for her for doing something out of the box. Now they began therapy at around 32 weeks, which is the ideal time to get ahead of this thing because remember that the cns, the brain, these motor neurons still are developing. One of the last things to develop, of course, is the brain and the neuronal system. And so this was done starting around 32 weeks. So the patient took this from 32 weeks until 38 weeks for about six weeks. And the child was given the same medication and was continuing to take this. Is still continuing to take this up to the date of publication of this report. All right, let me just read you a little quick excerpt from this. Because while it seems to be a victory in terms of the spinal muscular atrophy expression, because kid has no phenotype of this affliction, which is amazing. I'm going to read you that in just a minute. Unfortunately, the kid does have some other kind of organo developmental issues. It was a VSD that was found. There was an optic nerve hypoplasia, a little bit of brain stent asymmetry. But this has nothing to do with the medication. I'll be very clear. So the outcome there was this other issue going on these three developmental abnormalities, VSD, optic nerve hypoplasia, and a brainstem asymmetry issue, which did not seem to have any relation to the exposure of ristablam. Okay, to be very clear, this seemed to be like, oh, by the way this happened, but it's unrelated to the SMA issue. Okay, so it'd be very clear. Yes, the child has some other conditions, but in terms of the treatment of this mom taking this medication daily from 32 weeks until delivery and the kid continuing to take it is for protection of sma, which seemed to work. Okay, so let me just read you this quick excerpt and we start wrapping this up. Quote, the parents in this case were both known carriers of SMA genetic variants and had a prior infant born with SMA Type 1 before current treatments became available. That child died at 16 months of age. Okay, so once again, they knew this game already. They're like, oh my gosh, we got to check this child out. And this child did have. So the patient did have amniocentesis and confirmed that the fetus again had no copies of survival motor neuron gene. So that along with the patient's history, they're like, we gotta do something. All right, so they were both carriers, both had a previous child who demised with this under age 2. And then this pregnancy had an amniocentesis confirming that their child had type one condition. Remember, most of these should have symptoms by six months of age. Now we're coming up to almost age three years. Okay, so it, it's, it's fantastic if this can be replicated. Okay, so it says, quote, restiplem was administered to the expectant mother during the final six weeks of pregnancy and the child continues to take this medication up to date. So it's. I know there's a lot of limit. There's a lot of things here that are like, well, are we supposed to do this to everybody? No. However, it's such a devastating issue that right now, if a child is found to have a type 1 or type 2, which are 80% of this condition, they begin treatment shortly after birth, in the first few days after birth to get on top of this. However, this opens up the door potentially for prenatal in utero therapy for this condition. Anyway, just kudos to these researchers and for the manufacturer. They actually supply this medication. Again, not a sponsor. And it's unclear if other medications would work because they weren't checked. This was, the medication that was used was only this one type, Ristiplam, which is made by Roche. Not a sponsor, but you would figure the other medications would work, but who knows? This was just what they used in this study. So anyway, I just want to let you know what was up in print at this kind of a feel good story because man, a child's almost three years old and there is no physical evidence of SMA condition in this child. Fantastic. All right. Oh, I guess I should tell you how this medicine works. So anyway, very quickly, this medication does work by actually going to the gene and saying, hey, you got to get your stuff together, all right? I know you're messed up, but you got to start cranking up this protein, right? That's in a very short choppa synopsis way. That's how this medication works. It's considered a gene targeted therapy to increase the expression of the protein that is missing. Okay. So phenomenal thinking out of the box. It's a huge win. Although we definitely need more data out there. Rare genetic disorder treated in womb for the first time. That is the title out of nature. All right, Podcast family, we're thankful for you. We hope you enjoyed this kind of feel good episode and as always, we'll see you on another episode of Clinical Pearls. Now let's take it home. Podcast family, we really are thankful for you. We hope you enjoyed this episode. We'll see you next time on Clinical Pearls.