Well, welcome to our May lecture series. So as you all hopefully know, we have a monthly lecture series that our AA PM&R community, Peds Rehab community hosts. So it is always the second Tuesday at 1 p.m. Eastern Standard Time. And today we have Dr. Mary Lynch speaking about spinal muscular atrophy. Dr. Mary Lynch attended college at Boston College. She then received her medical degree at the Creighton University School of Medicine. She completed her physical medicine and rehabilitation and then her pediatric rehabilitation medicine fellowship at the Mayo Clinic in Rochester, Minnesota. She continues to practice at the Mayo Clinic. Her practice includes the whole breadth of rehabs. She does inpatient care, outpatient care and sees all diagnoses, including the neuromuscular clinic where she is able to see children with spinal muscular atrophy. So I will let you take it away, Dr. Lynch. Great, can you hear me okay? Cause I have multiple options for audio. I can hear you well. Okay, great. Thank you so much for having me here to talk about spinal muscular atrophy today, which again is just a very small part of my practice. So I'll start by saying disclosures. This is something I mostly looked up and looked at the current literature to teach you about. I especially hope we have some learners here. This is very fundamental to kind of what we do in peds rehab. I have no disclosures other than I'll be discussing three FDA approved treatments as well as one investigational drug for treatment of individuals with SMA. Learning objectives today, I want to talk about the pathophysiology of SMA, summarize some recent advancements in medical treatments, as well as identify some rehabilitation interventions for individuals who are living with SMA. So diving right into what is spinal muscular atrophy. To make it very simple, humans need survival motor neuron protein. And without it, we develop spinal muscular atrophy. Spinal muscular atrophy is, and I'll call it SMA from here on out, is a neuromuscular disease characterized by degeneration of the alpha motor neuron in the spinal cord. And that causes progressive muscle weakness, atrophy, and that includes muscles of feeding and breathing. So today I'll be mostly focusing on the SMN related SMAs today. There are a couple other subtypes that I'll mention. This type SMN related SMA is about approximately one in every 10,000 live births, and it affects males and females equally. This type is inherited in the autosomal recessive fashion and about one in 50 are carriers. For the presentation, it's often presents as progressive and symmetric weakness, decreased reflexes and tongue articulations. And it can present in a variety of ways. The disease itself is a motor disease. So cognition and sensation is not affected. And that's very relevant when we talk about, especially treating people into adults, into adulthood with SMA, but it's just a motor disease. About 96% of SMA is related to the mutation in the SMN1 gene. And with this mutation, the SMN1 gene is a genetic mutation that affects the brain and with this mutation, the SMN1 cannot make the survival motor neuron protein that your motor neurons need and therefore they die. So everyone with SMA for this subtype has at least one copy of SMN2, which is the paralog gene that codes for a similar protein, but it doesn't last as long, it rapidly degrades. And so you only make a small percent of that SMN protein, about 10% of what SMN1 would make. So if your SMN1 is abnormal, your SMN2 kind of come to the rescue. And the more copies you have of that SMN2, the better clinical outcome you have. So I'll say it again, if your SMN1 is abnormal, you need more SMN2 to have a more typical phenotype. So if you have less copies of SMN2, you have a more severe disease. For testing, the metabolic or biochemical testing, EMG, muscle biopsies, now those are really only performed when the diagnosis is in question, because we have very great genetic testing for this. And the newborn screen is really important for this. It'll detect if there's that deletion in SMN1, which is a majority, 96% of cases. And so you can predict that a child would have SMA and look further into it to determine what type of treatment might be appropriate for them. In this talk, I'm going to pretty closely follow our Peds Rehab textbooks. I know many of you are listening are in fellowship or studying for boards, and SMA is highlighted in this text. So this is one of our figures from there that shows about how, with the different types of SMA, the phenotype can depend on how many copies of SMN2 you have. So type one, only two copies. Type four, presenting in adulthood, maybe four to eight. I've also seen a classification of SMA type zero, referring to kids with severe congenital presentation numb. And type one is referred to as when they're presenting at two or three months. So you might see that distinction of type zero versus type one. If we kind of break it down for how common each are, about 60% have SMA type one, 30% SMA type two, 10% type three, and it's quite rare about 1% to have SMA type four presenting in that second or third decade. Talk about each type a bit more in detail. So type one, again, being the most common subtype, the weakness is evident at birth or within the few months versus that type zero that you might hear as the congenital at birth. These kids have poor head control without modern treatments. They would never sit independently. They often have sparing of facial muscles, but have vulvar weakness, and have difficulties with feeding leading to poor growth, weakness of respiratory muscles, especially their intercostal muscles. There's relative sparing of the diaphragm, but the intercostals are weak. And so that's why they get that bell-shaped chest from belly breathing, which is pictured here in this child. And the life expectancy is less than two years without our modern treatments for individuals with SMA type one. So generally when I think of a baby with SMA type one, I think of a hypotonic baby having a weak cry, maybe needing some feeding and breathing support. I chose this photo because you can see he has that characteristic bell-shaped chest, but he's also super bright and engaged. Because again, this is a motor disease, not affecting cognition or sensation. Type two with a symptom onset being between six and 18 months. Often these kids are able to sit independently, maybe achieve some supported standing, but not independent standing or walking. They often have hypoventilation in sleep, have neuromuscular scoliosis, and can live into adolescence and young adulthood. Again, that's without our modern treatments. These are kids that are in their late teens, these are kids who perhaps are presenting after they learn to sit, they're not progressing in their motor skills. They can use equipment like pictured here with the stander and maybe gate trainer as well as power mobility. So kids as young as a year can successfully use power chairs who have SMA. And I wanted to pause to emphasize that SMA is not just a disease of childhood. The next two subtypes either present into adulthood or they can live far into adulthood. And with recent history and treatment advancements, our hope is that affected children, more and more affected children are going to be living into adulthood. And again, I'm going to emphasize these patients don't have cognitive impairments. And as pediatric providers, we should be including them early on in medical decisions and their medical care and helping them advocate for themselves. And they have the potential to grow up and be independent adults. So starting those skills soon early is always better. So type three, these individuals have symptom onset after 18 months. They can often sit, stand, ambulate independently or with some supports, but do have a steady decline in ambulation skills throughout adulthood. The joint contractures and scoliosis that we'll often see in younger kids with more severe SMA are less common in this population because they can get through their growing years without being severely affected. They may have mild restrictive lung disease and can have a normal life expectancy. So again, this type three, it's kind of a big span of when they can present. Sometimes you talk about 3A before age three and 3B after age three. And then we have type four for the late onset SMA. So these individuals present into adulthood typically in the fourth decade. A majority remain ambulatory and have a normal life expectancy. So these are maybe adults presenting to an adult practice. They're having some decline in their gates. They get an EMG and those results lead to this diagnosis. A few other subtypes, the non-SMN related SMAs, X-linked infantile SMA, often with arthrogryposis. Sometimes this is referred to as X-linked infantile SMA with arthrogryposis, or some might refer to it as that type zero. This is the most rare and severe presentation at birth and have minimal movement, kind of in utero or often born with multiple joint contractures and pass away before six months if untreated. There's also SMA with progressive myoclonic epilepsy with lower extremity predominance or with respiratory distress. So I'm not really gonna be talking about treatments for these types. They're more the treatments for that 96% most common types of SMN related SMA. So in pediatrics, we like to talk about milestones. So here are some for SMA. And most of this exciting history that I'm gonna be sharing is quite recent. So first German scientist, Dr. Johann Hoffman and Austrian scientist, Dr. Guido Werdnig described SMA and discovered the generation of the anterior horn. Scientists that followed described different phenotypes, but it wasn't until a century later in the 1990s that multiple scientists mapped the gene responsible for SMA to 5q13. In 1995, Dr. Judith Melke and her team identified and determined the DNA composition of the survival motor neuron gene. And this allowed the development of targeted genetic testing for SMA. And in 1999, the splicing error in SMN2 was described and that error explains why it doesn't, it only makes about 10% of the needed protein, the survival motor neuron protein. And this error is important because the target of treatments developed is to allow, some of them are to allow more SMN2 to make functional protein. So we can target that error to then make more survival motor neuron protein. Right now, there are three FDA approved treatments for SMA, SMN related, SMA, Spinraza, Evristi and Zolgensma. So in 2016, Spinraza was approved by the FDA. In 2019, Zolgensma and 2020, Evristi. I also added here in 2018, that's when Minnesota added SMA to the newborn screen by looking for that SMN1 mutation. And I believe the majority or all of states now have this involved in their newborn screen. If anyone knows for sure, go ahead and put that in the chat. I want to say it's all, but I'm not confident. It is all, like a month or two ago, really, really recent. It just became all 50 states. Okay, great. And it's super, super important for early identification. I'll talk about kind of with our treatments because early identification means early treatment, which means better outcomes. So with these FDA approved treatments, how do they work and do they work? If there's a mutation in SMN1, so SMN1 doesn't work and we're relying on SMN2, it would be great if we could find treatments that would upregulate SMN2. And so potentially we could have better survival of motor neurons overall and more mild disease. Even better would be to replace SMN1, to totally replace function. Starting with Neusonersen-Spinraza, that first FDA approved treatment. So the mechanism is an antisense oligonucleotide, ASO. And this works by modifies pre-mRNA splicing process of the SMN2. So it leads to more expression of full length survival motor neuron protein. This one specifically does not cross the blood brain barrier. So for delivery, it needs to be intrathecal every four months after four loading doses. For monitoring, we have to monitor for coagulation abnormalities, thrombocytopenia, renal toxicity, and again, the complications of having a lumbar puncture every four months. For this treatment, it doesn't actually replace the missing SMN1. That's just improved expression of more full length protein using SMN2. So does it work? One of the major studies is the NURTURE study. There's several studies for each of these drugs. So I'm just going to highlight a couple that we should be familiar with. In this study, it was ongoing, still ongoing for follow-up, phase two, open label, single arm, multinational study to evaluate the long-term safety and efficacy. And so they started with 25 children with either two or three copies of SMN2. So they kind of parse out results too by if they have two or three copies of SMN2. These children were treated at less than six weeks of age. And at time of this initial analysis, they were an average age of about 35 months. And so at 35 months, all 25 of these kids with either two or three copies of SMN2 were alive and they could sit independently and none required ventilation support. So recall that untreated, but we're talking about SMN1 with two copies, have a median time of death or ventilator support of about 13.5 months. So this was at three years of age. The chart here I have on the right is for independent walking. And it's separated out by if they have two or three copies of SMN2. And you can see that all of the individuals with three copies of SMN2 achieved this and a majority of those with SMN are with two copies as well. I remember many of the kids with SMN2 aren't really even expected to sit by themselves or have good head control, but many of them here were walking at the typical age with the Spinraza treatment initiated before six weeks of age. There's a couple other studies, CHERISH for later onset and INDEAR for infantile onset that results pointed towards a better outcome with earlier treatment for infants with SMA. Again, this doesn't reverse that motor neuron death, so that's why that earlier treatment is important. Now there is a five-year update for the same population. At the time of this analysis, the average age was about five years old, so we have five-year data on these individuals with two or three copies of SMN2. So of the original 25 participants, again all were alive, none required permanent ventilation support, and they continued to progress in their motor development. So there's dramatically less respiratory support and interventions than the natural history that would be for these individuals. For the individuals with two copies of SMN2, all of them sat independently. 14 out of 15 walked with support, and 13 of those 15 walked alone. So that's really dramatic. We don't expect these children to be standing by themselves or be really alive at five years or even two years, and here they are continuing to make progress throughout those five years of treatment. For the individuals with SMN, three copies of SMN2, all of them achieved the WHO motor milestones with all but one milestone in one children, so almost exclusively within that normal developmental time frame. And the charts on the right here, sorry I got a little blurry, on top is two copies of SMN2, on the bottom is three, and the shaded area is that kind of normal time frame expected and change in motor function as measured by the Hammersmith Functional Motor Scale Expanded. So we can see that Spinraza continues to work for at least five years, which is very exciting and keeps kids alive. So I'm not going to play these today, so these are advertisements essentially for these drugs, but they're really impactful stories. This one reminds me that Spinraza is not just a drug for children, it came out when a lot of adults were living with SMA. This is a story about a gentleman named Ian who was diagnosed at 14 and now in his 30s who's getting Spinraza injections. I just think it's nice to hear the voices of our patients that we're talking about. I don't really trust my skills to navigate multiple screens and sound, so I just hope you'll find some time on your own to watch these on the drug websites. I found them very meaningful. All right, moving on to our next treatment of RISD, RISDiplam. So the mechanism for this is an SMN2 splicing modifier, allowing the body to make more functional survivor motor neuron protein. The delivery for this drug is enteral and it's a daily medication, and so you don't have to do the every four months intrathecal injection, you have to take medication daily. This one does cross the blood-brain barrier, which is why it doesn't have to be by intrathecal injection. For monitoring, we want to avoid this in hepatic disease and not recommend it for pregnant women. Some adverse reactions for later on to SMA include fever, diarrhea, rash, and for the infantile, more respiratory tract infections, pneumonia, constipation, vomiting. So this one works by binding to the SMN2's premature mRNA molecule and preventing the removal of the exon 7 from subsequent mature mRNA. And so since it's correcting the gene splicing, the therapy has the potential to restore more function of the SMN throughout the body. Several clinical trials on this medication as well. In the top right, you can kind of see by which type of SMA for each clinical trial. I just chose to highlight a couple here. So the first one is this Firefish Part 1, the really early on treatment. They were looking at 21 individuals. 81% of them were alive at 28 months. One of those individuals passed away from unrelated causes to their SMA. And these were kids who were already symptomatic at the time of their treatment, between two and seven months old. The Type 2 and Type 3 treatments or the trial for individuals with Type 2 and Type 3 is that Funfish. They showed motor skills here on the bottom right graph. Placebo being the gray line and at RISD treated individuals being the blue line between eight and 12 months, you can see that there was a lot of ground lost in individuals with the placebo. But between that eight and 24 months function was fairly well maintained for the individuals who are being treated with RISD. And again, that's for Type 2 and 3. The Rainbowfish study is underway right now for treating pre-symptomatic individuals who are diagnosed genetically before they have symptoms. And so with the hope that the earlier treatment before an individual have symptoms, the better response and outcome eventually that they will have. This is a bit about an update from that Firefish, now Firefish Part 2. Again, this is individuals with Type 1 SMA who were symptomatic at the time of their treatment. So these these treatments don't reverse symptoms. So we're starting from a symptomatic standpoint. I couldn't find a paper on this one, but there was a press release from Genentech in June of 2023. So the individuals with SMA Type 1 who were symptomatic at the time of their treatment, 91% of them were still alive at 48 months at four years, and 95% of them maintained the ability to swallow. Between that follow-up time between two years and four years, motor function was either maintained or improved. Again, I don't have the details for that, but that was in the press release. Two additional infants gained ability to sit. So that brought it up to 64% of the entire cohort. And three gained the ability to stand, and one infant actually gained the ability to walk. So they were continuing to make gains even in that two to four year follow-up time period. And again, 91% were alive and 95% maintain the ability to swallow. They didn't really say that they take all their nutrition by mouth, but they maintained ability to swallow. Promising results. This is in that Rainbow Fish trial, so the trial for getting the medication prior to having symptoms for kids who are genetically diagnosed. Again, highlighting the importance of the newborn screen. This had 26 infants who were pre-symptomatic who had SMA, age birth to six weeks in their first treatment, and they had two or more copies of SMN2. Again, I don't have a paper to reference. If anyone does, send it my way, but I have a press release from October of 2023. 80% of the babies were sitting without support for at least five seconds after one year, and all babies were able to swallow and feed orally and none required permanent ventilation. Moving on to our third FDA-approved treatment, Zolgensma. The gene therapy, very exciting. This does replace the function of the SMN1 gene using a vector adeno-associated virus 9AV9. It is a one-time IV infusion over 60 minutes. Monitoring that needs to be in place includes liver toxicity. It's given with steroids, and there's regular liver testing required, as well as side effects of thrombocytopenia and infections. Unlike Spironraza and Ebristi, this treatment is currently for kids less than two years old. I'm highlighting a couple studies here, one being the START study and one being the SPRINT study. Distinguishing them is the START study is 15 individuals with symptomatic SMA type 1, so they already have symptoms of SMA, versus the SPRINT study is pre-symptomatic infants. And they parse it out between having two or three copies of SMN2 in their results. So for the START study, they had 15 infants already symptomatic, SMA type 1, they were treated with low-dose and 12 were treated with high-dose. 100% of the individuals in the high-dose cohort were alive without permanent ventilation at two years post-infusion, and 9 of the 12 of those could sit without support for at least 20 seconds at that two year. And again, 0% of kids would be expected to be doing this by natural history, to be sitting without support, and again, even alive at two years. For the SPRINT study, I'm highlighting the results from those 14 infants who had two copies of SMN2, so we'd expect them to have, you know, type 1 SMA, and these were treated pre-symptomatically. That gray area of the graph is what normal development age for achieving milestones would be, and then each colored line is an individual. So 64% achieved motor milestones in those first 18 months in the normal range, and 93% had fine motor skills, similar to the unaffected children of the same age. So showing that treating pre-symptomatic with Selgentva, or even for individuals who would be expected to have that really severe phenotype, can achieve motor milestones within the normal range for at least the first 18 month study. So earlier treatment, better outcomes, which was that call for universal newborn screening, which apparently was answered within the last month, which is excellent. These are some results from that SPRINT study with the individuals who have three copies of SMN2, so we'd expect them to have a less severe phenotype. All 10 of these individuals for the pre-symptomatic infants with three copies are essentially achieving motor milestones within those first two years, with just barely a couple exceptions. That gray shading being the normal expected range, and each color being one of those 15 individuals. There's an extension now, report out for that START trial. So again, symptomatic infants who had two copies of SMN2, which we would expect to have that severe SMA type 1, 13 of the 15 were followed for five years, two of them declined to follow up. We don't know why, but of those 13, three of them were the low-dose treatment, and 10 of them were the high-dose treatment. So 100% of the high-dose cohort were alive without need for permanent ventilation, and 100% of the high-dose cohort maintained motor milestones within those five years, telling us that the effect of Zolgensma, not only can we see effects in the first year, it's durable for at least five years of maintaining the motor milestones. Two individuals within this cohort gained the ability to stand without assistance during this time. They did report a fairly high rate of adverse events, you know, within this population. They still have respiratory and other medical complications, but none resulted in study discontinuation or death. These adverse events include the acute respiratory failure, pneumonia, dehydration, respiratory distress, and bronchiolitis. So these individuals, despite, I think this highlights having really good motor outcomes, can still have respiratory complications. Were these kids allowed to be getting concurrent treatments at the same time, or were they only allowed to get Zolgensma? You know, I think a handful of these individuals also got Spenraza. I meant to put that in my notes, because I anticipated that, and I forgot exactly what the details were. But yeah, that's okay. Just a lot of our patients get, like, they get Zolgensma, and then they're continued on either Arisdi or Spenraza, kind of long-term. And so I always wonder from, like, the research if they allow that or not allow that. Yeah, I think this was a kind of a separate long-term follow-up that they could opt into when there was no expectation that they wouldn't seek additional treatments like Spenraza. So I do believe a handful of them got both. I imagine the paper has more results looking at the two groups, but I can't recall details. This is another story. Again, I won't play it, but I encourage you to go watch it. Stella, this child here, has SMA type 1, diagnosed at one month. So she was symptomatic, received Zolgensma at 1.5 months. And recall in natural history would be that she would never have had control or sit independently and likely pass away before age two. But the video that they have on the website here is her at 18 months. It shows her sitting, reaching for toys, and propelling that little chair here, pictured here. And so it's a very powerful testimonial about how the drug can help that motor outcome. And you hear from the parents as well, which I always think is really a powerful thing to hear. So I encourage you to go watch those. So what else is in development targeting the myostatin pathway? So, so far we've discussed treatments that either prevent further degradation of the motor neuron, but they don't address the actual impairment such as muscle loss from previous motor neurons generation. So myostatin could, targeting myostatin could prevent that muscle breakdown. Myostatin is a negative regulator of muscle mass and strength. And so myostatin induction is associated with muscle wasting. In animal muscles or models, I have a photo here, myostatin inhibition increases that muscle mass and function. You can see on one side, muscle mass is much greater. And in humans, the myostatin related muscle hypertrophy causes excessive muscle mass at a young age. So this can be a disease state in humans as well. So a medication that could possibly use this pathway to, to help our patients is an investigational drug, apiticromab. I don't know if I'm saying that right. That's how I say it. It's an investigational, fully human monoclonal antibody and inhibits activation of myostatin, which is again, that negative regulator of muscle mass and strength. This is given by IV infusion every 28 days. Side effects include headache, fever, upper respiratory tract infection, cough, nasal pharyngitis. There were no, have been no deaths or serious adverse reactions reported. So this trial, this phase two trial, is the TOPAS study on epidechromab. This is for patients with spinal muscular atrophy types two and three. I put the different cohorts on here just to be extra clear. So there's three different cohorts for this study. The first one is ambulatory patients, ages five to 21. And some of these patients were getting Spinraza, some of them were not. The second cohort is non-ambulatory patients, ages five to 21. And then the third, and they, I'm forgetting now, I believe these individuals are also getting Spinraza. Yes, so the type, the cohort, second cohort also has Spinraza. The first cohort, some do, some don't. For the third cohort, these are non-ambulatory patients who are much younger. They were also getting Spinraza. And they tested two different doses of this medication, two milligrams per kilogram versus 20 milligrams per kilogram to look at kind of the dose effect of this medication. So they covered lots of different study, you know, phenotypes in this study, and many of them were also receiving Spinraza. I'll summarize the results as in, they had some promising, but not super dramatic results. They did report that the incidence and severity of the adverse events were pretty consistent with the underlying population and getting the Spinraza injections as well. So it seems safe. And they noticed that the magnitude of the effect of the monoclonal antibody was greater in the younger children. So the younger treatment, the better, which is kind of the theme for treatment of SMA in general. This figure here is showing the cohort three. So individuals who were younger were also having Spinraza, but got two different doses of this medication. And they showed that the change of kind of baseline, from baseline motor scores, was greater in individuals who got the higher dose. So potentially demonstrating that the higher dose is more beneficial and the non-ambulatory for like the younger patients. So in summary, I would say for the treatments, all of these studies are having long-term follow-up and ongoing treatment comparisons are going to be important, but there's a lot of promising results out there and we're seeing it in our patients and we can see it in those patient testimonials that are on the drug websites. And these aren't a complete cure for SMA and we don't have the long, long-term data yet, and they're not always accessible to everyone, these treatments. And so this leads me to kind of some of my more concluding thoughts about rehabilitation considerations and something that this group is obviously very good at, but I want to highlight a few things for SMA specifically. We're left with mostly supportive and kind of non-pharm treatments. I wanted to highlight this two-part series published in 2018, which was an update to the 2007 guidelines as an attempt to standardize the care for individuals with SMA. It's a really nice resource if you find yourself caring for someone with SMA. So if you leave with nothing else today, I want people to realize, you know, there's this new treatment coming down the way potentially targeting myostatin and that there are guidelines here, two-part series to help, especially if you don't see these individuals super often, or you just want to brush up what would a comprehensive rehab program look like. I like the figure that they have in this paper, so I've highlighted it here. Reminder to keep the patient kind of at the center of this multidisciplinary care. And we need to keep all these things in mind as we transition from adult to, excuse me, from pediatric to adult care as well. They've highlighted the pulmonary acute care, other organ involvement, medications, nutritional, GI, bone health, orthopedic, and that neuromuscular rehabilitation needs to be coordinated between the patient and the family, patient with SMA and the family. The paper itself is kind of broken out into non-sitters, sitters, and ambulant patients with SMA. And these lists that they have kind of show what to assess, like positions, musculoskeletal deformities, functions, different interventions, other care considerations when working with these different populations. So it gives you a nice guideline to go from if you find yourself caring for this population. I'll highlight just a couple musculoskeletal complications to keep in mind, especially in the more severely affected children who are skeletally immature and not done growing when they're affected. Scoliosis is almost certainly going to develop in any individual who sits the majority of the time before skeletal maturity. So that's definitely applies to the SMA population here. Contractures, either congenital, you know, arthrogryposis, those most severe children at presentation or acquired over a lifetime. Chest deformity, scoliosis, and hip subluxation are also common. Interventions that we need to think about, static splinting, dynamic splinting, maintaining range of motion through different therapies, equipment, positioning, sometimes surgical consultation is going to be necessary for improving function or comfort for this population as well. I pulled out this example of one algorithm to consider for that spinal deformity management. This is from that care guideline paper. There's going to be slight deviations in different practices, but in general, they recommend kind of the monitoring between 15 and 20 degrees. Bracing, if greater than that, you know, bracing doesn't have the best outcomes in the neuromuscular population in general, but some still attempt it. And then greater than 50, disgusting surgery, especially if it's affecting comfort, a respiratory function, et cetera. There's different options for if children are skeletally mature or not for fusions in terms of, or for spine intervention in terms of, you know, a solid fusion versus growing rods or magnetic bars and things like that. In terms of mobility and equipment, how to promote mobility is really important in how to promote independent mobility in this population. Early mobility is super important. So you don't need to walk to have independent mobility. You can use a chair, a power chair, especially in this population. Again, as young as age one, there are many benefits to the early independent mobility in this population, especially visual, spatial, cognitive, and social development. Older individuals with SMA may also use power mobility. A manual chair is hard because of the proximal weakness. And it's just a very common tool that this population would utilize in certain settings. I wanted to touch that, you know, humans have evolved to be upright. There's lots of benefits to standing. So using a standing up device can be important in this population. That can be a sit to stand, a supine stander, prone stander, mobile stander. There's benefits for social interactions, for promoting bone health, preventing contractures, improving breathing, bowel and bladder function, as well as skin protection to be in different positions. A few words on respiratory care. Again, I have kind of an algorithm taken from that guideline paper. If you remember nothing else, just order a palm consultation at the time of the diagnosis. They're going to need lifelong following. For kids with, or individuals with more severe disease, they may need 24 hour mechanical ventilation. They're at high risk for sleep disordered breathing. That weak cough means poor airway clearance and increased risk for pneumonia. So there's oftentimes, you know, aggressive airway clearance techniques for these kids, that mechanical insufflation, exhalation, assistive cough techniques, as well as having routine chest physiotherapy. And again, I have referenced some guidelines here for one of the algorithms to consider. Exercise. So historically there's been some hesitation to recommend exercise in the neuromuscular populations, and there's no formal guidelines for kids that have SMA. But the limited literature that does exist kind of concludes that progressive resistance training and aerobic exercise is safe and effective in improving function. And there should be integrated into overall SMA care plan with submaximal principles. I believe there's some evidence in mice that this actually improves survival as well. And we all know that exercise has benefits for mood, opportunity to participate, bone strengthening, pulmonary function, GI function, and should really not be feared. Swimming is a great exercise, especially for the SMA population. The support. Getting the diagnosis of SMA is something that can cause grief, no matter how old or young the patient is. And having a chronic, potentially life-limiting motor illness is a lot to navigate. And so I'd like to like make my final points about the importance of engaging support services for resources and decision-making. I'm going to circle back to the figure that they had in the Mercury Guideline paper from 2018. And I might propose a couple additions that includes palliative care, psychology, and social work. This population faces a lot of challenges and they need assistance with finding community resources, finding treatment, where can they get it, what should they choose, having a gastrostomy tube, a tracheostomy, ventilation support, symptom management, and kind of making a treatment plan for acute illnesses and sometimes looking at what an end of life look like. They really need a whole, and these families need a whole team around them. And it's really our privilege as rehab providers to be parts of this team. Which leads me to my final point about really believing that this population is best served with a multidisciplinary clinic. For us at Mayo, this is led by neurology, but might look different at different institutions. If you're wanting to start this at your institution, I'd be willing to share more about our model and I imagine others either on the call or in this practice would as well, because collaborating so we don't have to reinvent what this could look like at each institution is something that we do really well in Pete's PM&R. On that note, I'd be happy to take any questions or comments from the audience, and thank you for your attention. Thank you. Thank you, that was great. This is such an exciting topic for rehab providers. One question was, do you know if any of these treatments are approved in pregnancy? I'm thinking of this question two ways. I don't think there's a medication for individuals who are pregnant with a child with SMA. I'm not sure if that was the question. If someone who is pregnant has SMA, if that's the question of if they can continue to get treatments, I think the answer is no, but I'm not sure, because I can think of examples where treatment had to be paused and one of the medications actually lists pregnancy as contraindication, and I suppose we don't have the data, kids with SELGENSIMA are children still. So I'm not sure, but I am leaning towards no. If anyone else knows the answer, that would be great. We'd love to hear from you. I do not know the answer, but as a somewhat recently pregnant person, I would guess we don't know and don't have the data, since we barely know if we can take Tylenol during pregnancy, basically. One question I have that I've seen some variability in practice on is, are you seeing your spine teams typically have these patients wear TLSOs? In my experience, no. In my experience, kind of in our neuromuscular population in general, no. If there's a TLSO to help sit comfortably to improve function, certainly that's a different question than is it preventing their scoliosis from progressing, but I have not seen a lot of bracing in this population. So I thought it was interesting that the guidelines recommended that. I'd be curious, yeah, what other people's experiences are too, but I'm not seeing a lot of that. Yeah, Emily, you know the person I'm talking about. We typically do brace, typically our kids will be in TLSOs, and I think the team kind of feels that they might be able, especially the kids with really, really severe scoliosis, is maybe prolong the time to go to surgery, right? If they're really, really little, if they're two or three and their scoliosis is crazy, then can we prevent it from getting so worse that we have to urgently go into the OR and put in throwing rods? Can we push them back to be four or five versus two or three? And I think that's typically when they're attempting to use it is more for the little kids with pretty significant scoliosis when we default the progression to get them to be a little bit better from a nutrition standpoint and a little bit older and have a little bit more fat on their body because if they're too little, then those growing rods poke right through the skin. And so then they're just like a lot of complications related to taking them when they're malnourished and really anybody. Now that you say that, I can maybe think of an example, maybe even casting that I've seen as well. Yeah, we don't cast for that at Boston Children's. We have had a patient come in a cast before, but since a lot of these kids also have G-tubes in respiratory when they're sick, having them in a cast is just really hard. So being able to take it out, take them out of their brace to do cough assist or to do chest vest or do other things from a respiratory standpoint, we find to be a little bit better, but it's also compliance with TLSOs is just really poor. So, sorry, I had to jump off for another call. Did you answer my question about what we can give pregnant patients? The answer was, I don't know, but I was leaning towards, I think you have to pause your treatments. Yeah, I have a patient who has one kid and has not been on treatment and then was like on the fence and was about to start a residency and then got pregnant with her second. And so she's like, nope, no treatment yet. And she's just seen like decline. So it's definitely, I think from a rehab perspective, I know we're all pediatric, but a lot of our patients don't transition to adults, right? I think that's, I don't need to mention that, but what can we do from a rehab perspective with our patients that are pregnant, that are living? Like who do we get them into to help them care for their children? And like, that's also an important part of SMA treatment now that kids are becoming adults and are surviving, which is so fun. Okay, I have more questions. I'm obviously in this clinic. Sorry, I'm not on video. I'm commuting. Have you, anybody else here, have you guys been, I know that like Zolgensmo is so new, but like what is the thought in the community about contractures and scoliosis? Do we think that these kids are still going to have kind of long-term MSK side effects? Because I think we're seeing a lot of these kids still with like, even though they're ambulatory, they're having various deformities and their femurs. And it's something that's not really documented because these kids didn't walk before. So it didn't really matter. Right. And I think that interesting from our perspective is like, what's changing in terms of what these kids look like long-term when they're getting treatments before they're symptomatic or even when they're mildly symptomatic. Yeah, I think that's a great point. It's hard to know. I imagine they're still going to have orthopedic needs, but maybe again, yeah, like you mentioned, if we can delay the scoliosis progression to a size, to an age that's better for ultimate treatment with fusions, if that's even necessary, maybe we can control it so well. Maybe this population will be better responding to braces if they have a less severe phenotype. I think you're right. That's kind of unknown, but exciting. You know, that'll happen. And within our careers, I think that we'll learn more and more about that. Yeah. And I think, I mean, another thing to think about is I have a personal experience with a child of a friend's child who has SMA that was actually postnatally diagnosed. So it was a de novo mutation. And, you know, we're all at academic centers, most of us who are at least in training or working at academic centers. And I think we get so used to our roles and it's been really interesting to just hear how this child is sometimes treated because I think not everybody realizes, I mean, I hope people know about all the treatments, but maybe they don't realize how actually available they are. And just that the phenotype you used to hear of with SMA, especially one, two is just not the phenotype anymore, which is incredible. But it's really interesting to realize how some people in the community don't quite realize how much this disease, SMA specifically has changed, which is amazing. But it's also, I think, a bit of an interesting challenge for the families. And hopefully we're going to catch more and more of it through our newborn screen too. Did you hear about, there was like in People Magazine about the twins in some state that were denied SMA treatment. Did you hear about that? It was literally on People Magazine. And like the mom freaked out, like, look it up, say like refusal SMA treatment People Magazine within like the last month. It was like a big news story, literally on Instagram, I kid you not. And it was about somebody who like genetically was diagnosed with SMA and they refused treatment. And they refused, the insurance company refused to pay for it. And like, as Emily said, like, this is like what, what from the, it's hard because we have this great treatment, but that means that we need to be able to give it, right. And so like, I remember when I was training as a resident and I, the entire PEDS day was like an ethical discussion of who do we give Spinoraza to because it's so expensive, right. And that's obviously changed a lot, but I think it's still prevalent that like our, what's happening from like the insurance perspective, right. Like how are we making sure these kids are getting their treatment? One other thing just to mention is something that we really struggle with is there aren't adult neurologists that feel comfortable providing these treatments. And there are adult physical therapists who can follow and do the testing required in order to continue to get insurance approval. So a lot of these kids are not able to transition to adult care and are staying in pediatric care. And as there are more kids that are surviving and living them like where these kids cannot just all be like the pediatric SMA clinics cannot just exponentially grow without having somewhere for them to go. And so I think something that's really interesting too, to think about is like as pediatric rehab docs is like, we can transition to the adult provider, right. But then we get rid of a medical home and now we're not seeing those kids when they're seeing their pediatric neurologist. So this is something that I think the community has to come together and kind of figure out and identify an adult. Like, do we need to start training adult neurologists to take care of us at night? Probably the answer is yes. Or do adult rehab doctors need to be able to do all of the treatment, including Spinraza and Arizdi and right. Like, is that something that rehab medicine should be taking over and the patients that have become adults? And I don't have an answer for that, but I think it's something interesting to think about as these kids are surviving and doing well into adult. Yeah. Good point. And wanting to get pregnant and have families. And that's something that we're not very comfortable talking to families about in general. Yeah. I think this was such a, such an amazing topic to talk about as a, as a rehab specialist, because just so many interesting things to think about that didn't used to be things that we had to consider and talk about like pregnancy. And so it's, it's such a fun field. Agreed. Thank you for having me. Thank you for allowing me to, to learn and share with you what I came up with. And I learned with you guys too, from what you had to include.

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