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Spinal Muscular Atrophy Physician Lecture

​This presentation offers​ an overview of the symptoms and types of spinal muscular atrophy and introduce the concept of gene therapy. It also discusses the treatment landscape for spinal muscular atrophy.

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  • ​Woman: Good afternoon, everyone. We are excited to have you join us today as part of our Boys Town Physician Education Series for April. We encourage you all to stay connected with us and take advantage of these free monthly CME opportunities for all physicians' virtual style. Before we get started, I'd like to announce that this series is jointly provided by Boys Town National Research Hospital and Creighton University.

    Today, we will be hearing from Dr. Isabella Herman. Dr. Herman received her combined M.D. And Ph.D. degrees studying developmental neuroscience from Baylor College of Medicine. She subsequently completed pediatric neurology residency at Baylor College of Medicine and Texas Children's Hospital. Combining her clinical and research interest, she additionally completed a post-doctoral fellowship in neurogenetics at Baylor College of Medicine in Houston, Texas.

    Dr. Herman joined the Boys Town Pediatric Neurology team in 2021 and is seeing patients who need her specializations in neurogenetic and rare diseases, neuroimmunology, and first-time seizures. Dr. Herman is also a member of the American Academy of Neurology, the Child Neurology Society, and the American Society for Human Genetics. Pl​ease welcome Dr. Isabella Herman.

    Dr. Herman: Hi, everybody. Thank you for this great introduction. So today, I will talk about one of my favorite topics, "Spinal Muscular Atrophy: A Success Story for Gene Therapy." So the objectives of this talk will be to provide an overview of the symptoms and types of SMA, or spinal muscular atrophy, to discuss the treatment landscape for SMA and introduce the concept of gene therapy, to discuss the importance of universal newborn screening for SMA.

    So, the outline of my talk is as follows, discuss the clinical presentation and symptoms of SMA. Discuss the genetic mechanisms and pathophysiology leading to SMA. Introduce the different types of SMA in relation to the underlying genetic pathophysiology. Provide an overview of the concept of gene therapy in relation to the treatment landscape for SMA. Discuss newborn screening for SMA and how it leads to a new neurological urgency. And then last but not least, briefly talk about future directions for SMA and other rare neurogenetic diseases with available treatment.

    So first, we'll start off with discussing the clinical presentation and symptoms of SMA. So, what is SMA? SMA is a group of hereditary diseases that progressively destroys motor neurons. Motor neurons are nerve cells in the brain stem and spinal cord that control essential muscle functions, such as speaking, walking, breathing, and swallowing. And this eventually leads to muscle weakness and atrophy or muscle wasting.

    Motor neurons specifically control movements in the arms, legs, chest, face, throat, and tongue. When there are disruptions in the signals between motor neurons and the muscles such as an SMA, the muscles gradually weaken and begin wasting away causing problems. So, SMA is a neuromuscular disease affecting motor neurons. The motor neurons that are predominantly affected in SMA are found within the anterior horn of the spinal cord, as you can see in the cross-section on the right side.

    Spinal cord motor neurons are essential in controlling muscle function. So, on the left, you can see a cross-section of the spinal cord kind of highlighting in this schematic figure where the motor neuron is located. This is the motor neuron that degenerates in spinal muscular atrophy. This motor neuron is important in signaling to the muscle fibers.

    Within SMA, what happens is that the motor neuron atrophies starts wasting away dying off then causing problems with muscle function, which you can see on the right side. This is an example of a motor neuron and how it, you know, affects the muscle fiber. And if the muscle fiber is not innovated by the motor neuron because of problems, the muscle fiber does not work the way that it's supposed to.

    So, this is another schematic here where the degeneration of motor neurons leads to the gradual decrease in mass and strength of muscles. So, on the left side, you see a motor neuron innovating a muscle fiber in a healthy individual. You can see that the motor neuron signals to the muscle fiber and forms multiple types of synapses at the neuromuscular junction. And the signal from the motor neuron to the muscle is what causes muscle function to happen or muscle contraction.

    When the motor neuron starts wasting away as is the case in spinal muscular atrophy, these interactions between the motor neuron and the muscle no longer happen. The muscle does not get the innovation that it needs and begins wasting away. So, over the course of the last several decades, we have learned that SMA is a multi-organ disease. Not only does it affect the skeletal muscles, but we also know that patients that are affected with SMA have problems with cardiac function such as structural heart defects. They also have problems with the gastrointestinal tract. And because of the muscles wasting away and weakening, you also have irregular bone remodeling often leading to scoliosis.

    So, this is more a molecular depiction here of what happens on the cellular level where if you don't have, you know, the proper innovation that happens with normal motor neurons, you have problems in the astrocytes, which are the support cells of the brain and spinal cord. You have problems with the muscles, with the blood vessels, with the Schwann cells, which lead to, you know, perpetuating the signal between the nerve fibers and the muscle problems in the neuromuscular junction. And then last but not least, the motor neurons that we've already talked about.

    So, symptoms of SMA are highly variable depending on the type of SMA. Typically, patients when they're first diagnosed, look completely normal in the newborn period. But when you start doing an examination, you see that there's profound loss of, you know, muscle strength and low muscle tone. And eventually, as these children grow older, they're wheelchair-dependent, and without treatment depending on the type, most don't learn how to walk.

    So, symptoms of SMA range from mild to profound. When you first have a newborn baby, you will notice that affected infants have poor suction when nursing or drinking formula. There's a weak cry. There's delayed head control. So when you lift them up by the arms, the head will just flop backwards instead of with normal strong infants, the head will come with the arms. When these babies get older, they will have a rounded spine when sitting.

    And then depending on the type of SMA, if you have patients that are affected at later ages, they will have difficulty walking, problems with falls, arm and leg weakness, and then difficulty standing up from support. So, on the left side, you can see, you know, an infant with spinal muscular atrophy, a severe form of spinal muscular atrophy, which is type one where you can see that the chest is not formed the way that it's supposed to. And this is because of progressive weakness in the respiratory muscles.

    When you take an X-ray as these patients gets older, as you can see in panel B, there's profound scoliosis, which is just, you know, progressive curvature of the spine. And then panel C shows how the calf muscles progressively waste away with spinal muscular atrophy. On the right side, you can see a family with an affected child that is suffering from spinal muscular atrophy. The child cannot move, is either bedridden or wheelchair-dependent, and requires a tracheostomy because a child cannot breathe on his own due to spinal muscular atrophy.

    So, what exactly is SMA? I like this slide because it is a nice summary. So, SMA is caused by a mutation in a gene called SMN1. And we'll go into detail a little bit later. But this mutation in SMN1 causes deficiency of a protein that's called SMN or survival motor neuron protein, and that leads to defects in motor neurons. These defects in motor neuron protein function eventually causes loss of motor neurons in the anterior horns of the spinal cord and prevents the signaling between the brain and the skeletal muscles. And that, as we've already talked about, causes progressive muscle weakness and atrophy.

    So, SMA is one of the most common neurogenetic diseases. And that's why it's important to talk about it and raise awareness for the disease. After cystic fibrosis, SMA is the most common fatal autosomal recessive disease in the U.S. We'll talk a little bit more about what autosomal recessive means. SMA is the most common genetic cause of infant death. Approximately 1 in 11,000 newborns have SMA. And within the United States, there's about 10,000 to 12,000 individuals that live with SMA. And because it is a genetic disease, we've identified that about 1 in 50 individuals carry the genetic mutation that could predispose their children to having SMA.

    So with this, I'll talk about the genetic mechanisms and pathophysiology leading to SMA. So, SMA is caused by mutations or deletions of the survival motor neuron 1 or SMN1 gene. Humans, in addition to SMN1, have a second gene called SMN2 that is nearly identical to SMN, but has one mutation in it that makes it largely nonfunctional. SMN protein is highly important during development of the neuromuscular system and remains important for proper function and survival of the motor neuron. And that's why the name of SMN is called survival motor neuron protein.

    In a healthy person, SMN1 produces a protein that is critical to the function of the nerves that control all muscles. If there is a mutation in SMN1, people with SMA do not produce normal levels of this protein. Without SMN protein, the nerve cells cannot properly function and eventually die, leading to the debilitating and fatal muscle weakness that we see in the disease.

    So, SMA, as I briefly mentioned, is an autosomal recessive inherited disease. So, 1 in 50 individuals in the United States carry the genetic change. If these individuals, for example, a father and a mother with each one carrying the genetic change have children, there is a 25% chance or 1 in 4 that the children will have SMA. Fifty percent of the children will be carriers just like the parents and they will be asymptomatic. And then 25% will have a healthy child.

    So, if two carriers that carry a genetic change for SMA have children, one-fourth of their children have a chance of having the disease. And this family from the Cure SMA website depicts, you know, this inheritance pattern very nicely where mom and dad both carry the genetic change. They have one affected child and then two children that are asymptomatic with the disease.

    So, SMN protein, SMN1 and SMN2, are located on chromosome 5 of our genes. And this is a depiction of chromosome 5. As I mentioned, SMN1 has a cousin or another gene that is very similar called SMN2. And SMN2 is very important to talk about because it affects the clinical presentation of SMA. So, how does SMA work? So, SMN1 is found in the DNA or genetic material of all of us. This is translated into RNA, messenger RNA, and then protein.

    In healthy individuals, SMN1 produces 100% functional protein. If you have SMA and you have a deficiency in this gene, you don't make this protein causing the symptoms. Now, this is where SMN2, the cousin of SMN1, comes into play. As you can see here, there is going to be one specific genetic change that SMN2 has that is not found in SMN1. Because of this specific genetic change, the messenger RNA and the protein become nonfunctional. So, typically, in SMN1, you have exons 1, 2, 3, 4, 5, 6, 7, and 8, which make the full-length protein.

    In SMN2, you have 1, 2, 3, 4, 5, 6. There's no exon 7 because of this mutation. And then there's only 10% of functional protein, and 90% of the protein made by this gene is nonfunctional. So, when we look at the genetic mutational landscape in SMA, we find that 95% of genetic changes have full-out deletions of SMN1. So, the genetic carriers of the disease do not carry, you know, sufficient amount of SMN1 but will have SMN2. However, 5% of mutations are not full-blown deletions of the gene, but they're point mutations, as you can see here.

    And this is important because when we talk about newborn screening in a little bit, we'll see that newborn screening will capture 95% of mutations. But if you have suspicion that a child who's passed newborn screening has SMA, you still want to test for the 5% of mutations that can cause the disease.

    So, there are different types of genetic testing related to SMA. There's diagnostic genetic testing, which confirms that you have the disease. There's familial genetic testing, which if you have a family member with a disease, you can test if you or any other members of your family are carriers or also carry the genetic mutation. And this is very similar to the carrier testing. So, if know, a husband and a wife or partners would like to have children, they can test themselves to see if they're carriers for SMA given that there's a high carrier frequency of 1 to 50 in the United States.

    We can also determine prenatal testing for SMA where you can test if your unborn baby has inherited SMA. And this is typically done when the couple already has affected children, or if there's a high chance that the baby who's growing in mom's tummy is affected. And this happens via something called chorionic villus sampling, amniocentesis, which this is a picture of where you can actually take out fluid from the amniotic sack and test if the cells that the baby sheds carry, you know, SMA. And then you can do preimplantation genetic diagnosis where via in vitro fertilization, the embryos can be tested for the disease.

    So, with this, we'll introduce the different types of SMA in relation to the underlying genetic pathophysiology. So, SMA severity and type correlates with SMN2. And it specifically correlates with SMN2 copy numbers. Each SMN2 copy, as we discussed previously, makes approximately 10% of functional protein, 90% of the protein is nonfunctional. The more copies of SMN2 a person has, the less severe the SMA phenotype will be.

    So, this image right here shows that, you know, on the bottom, the SMN2 copy number from 1, 2, 3, 4, 6 through 8. And if you only have one SMN2 copy number, you have the most severe type of SMA, which is called type 0. The more copy numbers you have, the less severe your disease phenotype or the more normal your muscle strength will be. SMA is a spectrum and the severity and type correlates with SMN2 copy numbers. So, the disease severity is most severe when you have only one or a few SMN2 copies, but the higher the SMN2 copy number, the greater the amount of SMN protein and the less severe your disease.

    So, there's a total of five types of SMA from type 0, which is in utero and it's fatal within days to weeks, all the way down to type 4, which has normal lifespan. The most commonly newly identified type of SMA is in the infant period, and it's generally type 1 where there's an incidence of 60% of newly identified cases. And as you can see in this column right here, we have nice determinations of the maximum motor function achieved by these patients.

    So, SMN0, the most severe one, there's decreased movement right at birth. These patients never learn to sit, never learn to, you know, walk. SMN1, never sits independently. SMN2 will sit independently. SMN3 will walk. And then there will be a slow decline with patients in adulthood who have SMN4. So, this is a nice kind of summary of the previous, you know, chart where type 0 is identified before birth. Type 1 occurs between 0 to 6 months. They're not able to sit without support. There's poor head control.

    Type 2 will occur by 18 months. They can sit without support, but cannot walk. Type 3 will be a little bit later on set. They can learn how to walk but not able to climb stairs, for example, or jump. And then type 4 is the least severe, and it occurs typically after the age of 20. So, with this, we'll provide an overview of the concept of gene therapy in relation to the treatment landscape for SMA.

    How is SMA managed? Treating the cause of SMA with medications is important, but it's also important to provide care for the complications that come up with SMA. And this can be breathing-related care, care related to eating and swallowing, and then care related to movement and posture. There's a new paradigm shift in how SMA is treated. And, you know, the goal is to provide multidisciplinary care in SMA where you have this kind of core of SMA patients, the SMA families, and then a team of multidisciplinary experts that includes, you know, genetic counseling, a geneticist, physiotherapy, rehabilitation, an orthopedic doctor, very important. And I want to emphasize this as psychological and social support services given the devastating nature of the disease.

    Palliative care is very important, pulmonary and acute care, nutrition, swallowing, and GI, and then a team that is familiar with novel disease-modifying agents.

    So, the management strategies of SMA include respiratory, GI and nutritional, orthopedic, and rehabilitation, and psychological care. And there's different types of assessments that are made within each category. And each specialist involved in the care of the patient will follow these specific assessments and provide the necessary intervention. And again, emphasizing the psychological aspect where you want to assess the patient and the family for depression and anxiety and provide counseling and pharmacotherapy if necessary to help them cope with the disease and be able to have the best mental capacity to care for the child and for themselves.

    So, the management strategies of SMA include SMN-dependent therapeutic strategies and SMN or gene-independent therapeutic strategies. So, when we talk about the treatment for SMA, we'll talk briefly about gene therapy, which, you know, is kind of the frontier of rare disease research where it replaces the missing SMN1 gene via a viral vector. We can also activate SMN2 protein to provide additional levels of SMM2 protein beyond, you know, the 10% that SMN2 typically does.

    And then more general, you know, SMN independent therapeutic strategies include ways to provide neuroprotection, which the goal is to protect against neuronal injury or degradation, to provide muscle enhancement where you prevent and restore loss of motor functions. And this is where physical therapy, occupational therapy, exercises are extremely important. And then ways to promote neuronal function where you enhance neuronal transmission. And muscle enhancement and neuronal function go hand in hand and it happens frequently when you enroll the patient into physical occupational therapy and provide them with exercises that can help strengthen their nerves and their muscles.

    So, possible points of therapeutic strategies for spinal muscular atrophy include the motor neuron itself, where we talked about protection against injury or death. You can work on the motor axon of the motor neuron where there will be improvement of signal transduction to the muscles, improved axonal transport. You can work directly on the synapse where you can try to enhance, you know, and promote the formation of the synapses rather than the loss of the synapses.

    You can enhance synaptic function. And then working directly on the neuromuscular junction, where you have improved development and formation of the neuromuscular junction, you prevent the degeneration and you have improved synaptic function. And then for the muscle, you prevent or restore loss of muscle function.

    So, for SMA, there are three FDA-approved medications. And these are fairly new. The earliest approval for medication or treatment for SMA was in 2016. In 2016, this is the first medication for SMA. It's called Spinraza or Nusinersen. It is intrathecally administered. So, patients who get this medication require lumbar punctures. After an initial loading dose, they will have a lumbar puncture with medication administration every four months for the rest of their lives.

    The cost of this medication is $750,000 for the first year. And then any subsequent year for the rest of this patient's life, it is $375,000. The most recently approved medication in 2020 is Evrysdi or Risdiplam. It is an oral medication that the patient is expected to take for the rest of their lives. It is approved for patients aged 2 months and older. And the yearly cost of the medication is $100,00 to $340,000 depending on the weight of the patient because it is dosed weight-based.

    One of the most exciting treatments for SMA was approved in 2019, and this is Zolgensma or onasemnogene abeparvovec. And this is gene therapy. And, you know, gene therapy for this disease with this medication gets as close to a cure as we have for the disease, but it is not a cure. This is the most expensive medication on the market. It is a single IV dose, a single IV infusion over the course of an hour. And the cost of this medication is $2.1 million for the single infusion.

    So, talking a little bit about the mechanism of the first two medications, Spinraza and Risdiplam, they work on SMN2. They don't work on the SMN1 gene. So, the goal of these medications is to increase the amount of functional SMN protein. And the way that it does is as we discussed earlier in SMN2, you have a mutation that prevents you from forming the full-length protein. So, if you see here, it goes from six directly through eight. It is missing this important exon 7, which missing the important exon 7 leads to nonfunctional protein.

    So, what Risdiplam and Spinraza or Nusinersen do are they allow for the formation or the inclusion of this important exon 7 and thus help increase the amount of functional SMN protein. And this is a molecular mechanism called splicing or alternative splicing.

    So, the last medication that I was talking about gene therapy was Zolgensma. We know that over the course of the last decade or so, there's been a lot of work in gene therapy and how to provide cures for rare neurogenetic diseases. There's two ways by which gene therapy can work. Early on for other diseases, for example, for certain sickle cell diseases and other non-neurological diseases, what would happen is that, you know, ex vivo gene therapy would occur.

    So, what would happen is that the patient would get stem cells or progenitor cells extracted typically from the blood or the bone marrow. These cells in a dish are genetically modified to include, you know, the gene or the protein that these cells are normally missing in the patient. And then once this inclusion happened in the dish, these cells are typically administered back into the patient. And this is called ex vivo. What happens with Zolgensma or other types of viral-based gene therapy is that with AAV specifically, the AAV will carry the gene that will provide the full-length protein and then directly administered into the patient, therefore providing in vivo gene therapy.

    So, Zolgensma is an FDA-approved gene therapy for SMA. And gene therapy is as close to a cure as we can come to for rare genetic diseases. So, this image right here, you know, is a very nice depiction of kind of the goal of what happens with gene therapy where you're trying to, you know, repair the damaged gene that is causing the disease. So, you know, to summarize here, you have a healthy gene. This healthy gene is packaged into a viral vector. The viral vector with a healthy gene is then administered into the patient.

    The company that, you know, made Zolgensma has a nice video, and I'll show the video briefly about what the disease processes in SMA and how gene therapy with Zolgensma works in SMA.

    Man: SMA is a neurodegenerative disease resulting from the loss of function of the survival motor neuron 1, or SMN1 gene. SMN1 produces SMN protein, which is critical for neuronal survival. SMN1 has a backup gene, SMN2, whose splicing variability results in only 10% functional SMN protein. Without functional SMN1, patients with SMA rely solely on the insufficient levels of protein produced by SMN2.

    SMN2 copy number is an important modifier for disease severity in SMA. In patients with SMA, there is significant variability in SMN2 copy number. Those with the most severe forms of SMA often have two copies of SMN2. Without sufficient SMN protein production, patients experience irreversible neuronal loss resulting in progressive physical visibility, life-threatening medical emergencies, and premature death. Zolgensma targets the genetic root cause of SMA caused by mutations in the SMN1 gene by inserting a fully functional copy of the human SMN gene.

    To combat the neurodegenerative nature of the disease, Zolgensma enables continuous SMN protein production, which can halt the progression of disease and preserve motor neurons. Zolgensma is composed of a fully functioning copy of the human SMN gene, which codes for the SMN protein patients need. Zolgensma is self-complementary and has a promoter that activates the human SMN gene and initiates continuous protein expression.

    The genetic elements of Zolgensma are packaged in the adeno-associated virus, serotype 9 or AAV9 vector, which enables delivery of the gene into motor neuron cells. The AAV9 vector is non-pathogenic and the viral genes have been removed to decrease immunogenic potential and eliminate potential viral replication. Zolgensma is administered as an intravenous infusion. Once in the body, the AAV9 vector is able to cross the blood-brain barrier. Having crossed the blood-brain barrier, the AAV9 vector can efficiently enter motor neuron cells, but is not known to cause disease in humans.

    Once inside the cell, the AAV9 vector travels into the cell nucleus. Once inside the cell nucleus, the AAV9 vector releases the human SMN gene. The Zolgensma SMN gene is designed to replace the function of the defective SMN1 gene without being integrated into the patient's genome. The SMN gene is introduced to target cells as recombinant self-complementary DNA. Zolgensma is also built with a hybrid cytomegalovirus enhancer, chicken beta-actin promoter. It activates expression of the SMN gene.

    Together, these critical elements of Zolgensma enable the continuous and sustained production of SMN protein over time. By targeting motor neurons throughout the CNS, Zolgensma stops the widespread neuronal cell death and subsequent muscle degeneration, characteristic of SMA, preserving motor neurons and sustaining neuromuscular function.

    Dr. Herman: So, I like this video because it helps highlight, you know, what SMA is. It also helps, you know, simplify the discussion of what gene therapy is. And if, you know, we see patients in the clinic with SMA where we have to have a discussion about the different treatment options, showing a video like this allows the family to kind of visualize what goes into, you know, gene therapy and the potential treatment that the child would be receiving.

    Okay. So, summarizing the different types of treatments for SMA. You have Nusinersen, which is Spinraza. It's the intrathecally administered medication. It is important that we talk briefly about adverse events, for example, low platelets, problems with lumbar punctures because this is repeated lumbar punctures every four months. And then there is monitoring that has to happen when administering this medication, including monitoring the platelet count, coagulation studies in the urine.

    Risdiplam is the oral medication. It's a small molecule. It has to be given daily. It is approved only for ages two months and older. There may be some drug interactions with other medications a patient could be taking. The adverse events of fever, diarrhea, and rash. One of the advantages of Risdiplam or Evrysdi is that there's no monitoring that's required.

    And then gene therapy with Zolgensma. It's a single dose IV administered medication. It is only approved for patients less than two years of age. Limitations to the treatment, this is really important. Every patient that is considered for the therapy has to be monitored, checked for certain titers of the adeno-associated virus. And if they have high levels of adeno-associated virus antibodies in their system, that's a contraindication to giving the medication. So, you either have to bridge with one of the other medicines and wait for the titer to go down or directly choose one of the other medications.

    There's baseline evaluations that go into gene therapy. So, it looks very simple, but it's actually a very complicated process. You have to test liver functions. You have to test for the antibodies. Some individuals that get gene therapy will have liver injury, transaminitis, low platelets, elevated troponins, heart enzymes, and then there's, you know, monitoring that goes into administering the medication, including testing for liver functions, platelets, and then troponins.

    So, even though it sounds very good, any of these treatments obviously have pros and cons and there's a discussion to be had with the families which way to go with regards to treatment. So, the reason that treating SMA is very important is because of obviously the symptoms, the morbidity, and mortality to the patient, but also when you consider the amount of cost that is involved in giving these medications, the United States has come up with a financial analysis and there's something called ICER, which is an incremental cost-effectiveness ratio. And this is done for most, if not all, you know, expensive drugs that are used on the market.

    So, if we look at the figure or the graph on the left side, these are on the bottom different references that, you know, try to calculate what the annual cost would be of untreated patients with different types of SMA. So, if we look at, you know, the patients that survive past the neonatal period, that's typically SMN1 because SMA0 patients typically don't survive past a few days or weeks after birth. So, depending on the type of study that you look at, the annual cost of treating these patients without providing Evrysdi or Zolgensma or Spinraza is anywhere from $100,000 to over $150,000. And that's medical cost for when these patients present to the hospital, to their specialists, or any other treatment facilities.

    So, depending on the severity of the disease, the less severe form of SMA you look at, it's obviously less, but anywhere like reaching still $50,000. And this is just per year. So, the longer the patient lives untreated, the higher the cost will be obviously. So, if you take into account providing treatment for these patients with different types of treatments, you know, the incremental cost-effectiveness ratio is actually very high.

    So, for Nusinersen or Spinraza, it ranged anywhere from $210,000 to $1.1 million per quality-adjusted life years gained. For Zolgensma, the gene therapy, you save anywhere from $30,000 to $250,000 for treating symptomatic patients. If you catch these patients before they're symptomatic, the quality-adjusted life year incremental cost-effectiveness ratio significantly increases. So, the earlier you identify these patients, provide the treatment, even though the treatment is very expensive, the less the overall financial burden on society and everybody else will be. So, treating and identifying these patients is extremely important despite the cost of the medications.

    So with this, it's important to briefly talk about newborn screening for SMA and how it leads to a new neurological urgency. So, newborn screening has revolutionized pediatric medicine. Newborn screening is a public health program of screening infants shortly after birth for conditions that are treatable but not clinically evident in the newborn period.

    The first disease that was actually part of newborn screening was phenylketonuria. And that was identified in the 1960s. Over the course of the, you know, following five to six decades, a lot more diseases have been added to the newborn screening panel because now there's treatment for a lot of these diseases. So, the goal of newborn screening is to identify infants at risk for these rare conditions that you would otherwise not pick up early enough and to confirm the diagnosis and provide intervention or treatment that would change the clinical course of the disease and prevent or ameliorate the clinical manifestations. So, identifying these children early, providing the necessary treatments, will significantly decrease morbidity and mortality depending on the disease.

    So, newborn screening in Nebraska currently screens for 38 treatable conditions, and SMA screening was added to the Nebraska Newborn Screening panel in 2020. So, newborn screening for anybody that has worked, you know, in the newborn care nursery or has had children of their own, newborn screening is typically done via this heel-stick, you know, the first screen is done before the patient is discharged from the hospital to go home with the family. And this is important to identify all of these diseases that are potentially treatable.

    So, because of these treatments that have been identified for SMA, there's been a worldwide initiative to add spinal muscular atrophy, or SMA, to newborn screening. Newborn screening is not only done in the United States, but it's done in a lot of countries worldwide. This is a nice figure from November 2020 in a recent paper where there was an expert consensus guideline of how to treat the disease. And we can see that the United States is kind of at the forefront with a lot of states screening for SMA. And then there's a few isolated countries throughout the world that are screening for the disease. So, most countries as of right now do not screen for SMA.

    So, this graph is the number of states that screen and are not screening for spinal muscular atrophy as of March of this year, so March 2022. So, we know that there's 44 states that currently screen for SMA, and 95% of newborn babies in the United States are screened for SMA. Now, as I mentioned earlier, a full deletion of the SMN protein is present in about 95% of patients. So, 95%, you know, of babies will be screened for the most common genetic change that causes SMA, but 5% of children would still fall within the category of potentially having SMA.

    So, if you have a child who pass newborn screening, but the clinical picture is still highly suspicious for SMA, there's other testing that should be done and the child should definitely be referred to a pediatric neurologist for further evaluation. So, just because a child passed newborn screening doesn't completely rule out the diagnosis.

    So, SMA newborn screening has led to a new neurologic urgency. With the approvals of nusinersen, onasemnogene abeparvovec or Zolgensma, and risdiplam treatment paradigms have evolved from a primarily palliative or reactive approach to a more proactive care model. So, trying to identify these patients before they actually have symptoms is the goal. Given the progressive and degenerative disease pathophysiology, early treatment allows for the best possible disease outcome.

    It is imperative that identified infants undergo comprehensive neurological and genetic evaluation with the goal of initiating treatment safely as soon as possible. Because for SMA, time equals neurons, so the longer a patient with SMA remains untreated, the worst the long-term outcome will be because these neurons atrophy in the muscles degenerate, and you can't bring back these neurons that have already died off. So, treating before symptom onset is the goal.

    So, what are some of the future directions for SMA and other rare neurogenetic diseases? So, now that we have three treatments available, there is databases out there to try to track what would be the best possible outcome. Could you potentially combine some of these treatments to get to the best possible, you know, developmental outcome for these patients? Right now, there's no clinical trials that have combined, you know, the three available treatments.

    It is also important, you know, to implement universal newborn screening. So, the remaining states that have not implemented newborn screening, I think it's important that newborn screening would be implemented eventually. With, you know, SMA being a success story for gene therapy, there's a lot of work in the rare disease community looking at gene therapy for other rare genetic diseases, for example, Duchenne muscular dystrophy. And with these available gene therapy options in the future and other treatments, some other diseases are in the pipeline to be added to newborn screening where if we can identify them early, treat them early, it can prevent a lot of damage down the road.

    And then the National Institute of Neurological Disorders and Stroke by the NIH established something called NeuroNext, which is a Network for Excellence in Neuroscience Clinical Trials. So, with the establishment of this program, the emphasis by this department has been to promote clinical trials specifically within neurological diseases and neurogenetic diseases.

    So, the conclusions of my talk are as follows, SMA is a progressive neurogenetic disorder affecting motor neurons and leads to progressive weakness. SMA is heritable. It is a genetic disease. Untreated SMA has high morbidity and mortality. Novel treatments and newborn screening have revolutionized the outcome of SMA patients. Early identification and treatment of SMA are imperative because time equals neurons. And gene therapy is a new frontier of treatment for rare genetic diseases.

    So, with this, I wanted to thank you very much for giving me the opportunity to talk about this very important topic. And if there's any questions, I'm happy to take them. Thank you.

    Woman: Thank you, Dr. Herman, for your time and expertise today. Again, we encourage you all to stay connected with us and take advantage of our free monthly CME opportunities. Watch for follow-up email communications announcing our upcoming presenters with the Boys Town Physician Education Series, or visit our website at Thank you for joining us today.​

Physician Education Pediatric Neurology