Spinal Muscular Atrophy is Now a Treatable Genetic Condition

Proximal spinal muscular atrophy (SMA), also known as 5q SMA, is the most common genetic disease affecting the lower motor neurons. This autosomal recessive condition, which manifests with progressive muscle weakness and atrophy, is caused by sequence variations in the SMN1 (survival of motor neuron 1) gene, located on chromosome 5q.¹ SMA affects approximately 1 in 11,000 live births and people of all ethnic and racial groups.

Clinical Presentation and Classification

People with SMA can present with a wide spectrum of severity, ranging from severe hypotonia in infancy to mildly progressive proximal weakness in adulthood. SMA historically has been subdivided into different types based on the maximum motor milestone achieved.² In rare cases, an infant may manifest severe hypotonia at birth, which is called SMA type 0. Infants with severe SMA, with obvious manifestations during the first 6 months of life, including inability to achieve independent sitting, have SMA type 1. SMA type 2 includes children who achieve independent sitting but cannot walk without assistance (ie, “sitters”). SMA type 3 includes children who achieve independent walking (ie, “walkers”). Some people with SMA do not develop obvious symptoms until adulthood; this represents SMA type 4. Because SMA is a progressive disease, people can lose their maximum milestone (eg, a person with SMA type 3 can become nonambulatory, or a person with SMA type 2 can lose the ability to sit independently). These classifications were developed before disease-modifying therapies (medications designed to restore SMN [survival of motor neuron] protein expression) became available, and are less meaningful in individuals who started disease-modifying therapy early in the disease course, because these individuals likely exhibit milder symptoms than would occur in the natural course of disease without treatment. Therefore, many clinicians now classify SMA cases on the basis of genetic testing results (ie, SMN2 [survival of motor neuron 2] copy number), followed by the maximum motor milestone achieved (eg, sitting, walking), further qualified by treatment history.

The progressive weakness in untreated SMA results in progressive loss of motor function, with weakness of axial, upper extremity, and lower extremity muscles. As a result, individuals not only are impaired in mobility but also develop other issues, including respiratory insufficiency, bulbar and swallowing dysfunction, gastrointestinal dysmotility, and orthopedic problems.^3,4 Therefore, people with SMA require multidisciplinary care to address complex medical issues to minimize morbidity and improve survival and quality of life.

Genetics

SMA is caused by biallelic variations in the SMN1 gene. More than 95% of people with SMA have homozygous deletions of the SMN1 gene^3,5; the remainder have a deletion of 1 allele and a loss-of-function variation on the other SMN1 allele. In either case, the result is a deficiency of SMN protein, which results in progressive degeneration of motor neurons that reside in the anterior horn of the spinal cord. These sequence variations only cause a relative deficiency of SMN protein expression, because of low levels of SMN protein expression from a second paralogous gene: SMN2. SMN2 only differs from SMN1 at 5 different nucleotides, the most important difference being at coding position 840 (the sixth nucleotide sequence of exon 7), where there is a thymine in SMN2 instead of a cytosine, which is present in SMN1.⁶ This difference does not change the protein sequence but does alter the alternative splicing behavior of the SMN2 pre-messenger RNA (mRNA). This alteration in splicing results in only approximately 10% full-length mRNA (with the complete coding sequence); the remaining transcripts will exclude exon 7, which yields a truncated, nonfunctional, and unstable SMN protein (Figure 1A). Therefore, in people with SMA in whom SMN1 is deleted or mutated, low levels of functional SMN protein are synthesized from SMN2 (Figure 1B).

Because all people with SMA have biallelic variations in SMN1, this alone cannot account for the broad spectrum of clinical severity. An inverse correlation between SMN2 copy number and the predicted severity of disease, in which more copies of SMN2 would likely result in a milder form of SMA, has been established.⁶ This correlation is modest, however, and other genetic modifiers contribute to disease severity.

Diagnostic Testing

In most cases of symptomatic SMA, there is reasonable clinical suspicion for SMA, and genetic testing often is ordered early. In milder cases of SMA, however, the clinical presentation of mild proximal weakness in an ambulatory older child or adolescent often leads the clinician to suspect a muscular dystrophy or myopathy. EMG can help redirect the clinician to consider SMA.

Genetic testing for SMA involves evaluation of SMN1 copy number, typically performed in parallel with SMN2 copy number testing. If this evaluation reveals no copies of SMN1, then the diagnosis of 5q SMA is confirmed. One copy of SMN1 would be consistent with the individual being a carrier of SMA. If the diagnosis of SMA remains clinically suspected in a person with 1 copy of SMN1, sequencing of the SMN1 gene can be performed to look for a smaller loss-of-function sequence variation (eg, nonsense, point , frameshift) that would suggest that the SMN1 gene that is detected is altered. Some commercial laboratories have optimized their next-generation sequencing platform to capture SMN1 copy number, smaller sequence variations in SMN1, and SMN2 copy number simultaneously, thereby eliminating a tiered algorithm of testing that historically was needed in more diagnostically challenging cases.

Disease-Modifying Treatments

There are 3 Food and Drug Administration (FDA)–approved disease-modifying medications for people with SMA (Table 1): nusinersen (Spinraza; Biogen, Cambridge, MA), onasemnogene abeparvovec-xioi ([OA] Zolgensma; Novartis, East Hanover, NJ), and risdiplam (Evrysdi; Genentech, South San Francisco, CA). All 3 work by restoring SMN protein expression in spinal cord motor neurons.

In people with SMA, low levels of SMN protein are expressed from the SMN2 gene. Thus, one of the strategies to treat SMA is to modulate splicing of the SMN2 pre-mRNA to increase expression of full-length SMN protein (Figure 2). Nusinersen is a synthetic antisense oligonucleotide that binds to a splice suppressor site within intron 7, thereby enhancing the inclusion of exon 7 in the SMN2 mRNA, resulting in more full-length SMN2 mRNA and thus more expression of functional SMN protein. The medication is a liquid solution that is injected intrathecally, such that SMN protein expression can be increased in the spinal cord motor neurons, the target tissue of this therapy. Double-blind, sham-controlled clinical trials in symptomatic infants with SMA type 1 (A Study to Assess the Efficacy and Safety of Nusinersen [ISIS 396443] in Infants With Spinal Muscular Atrophy [ENDEAR], NCT02193074)⁷ or SMA type 2 (A Study to Assess the Efficacy and Safety of Nusinersen [ISIS 396443] in Participants With Later-Onset Spinal Muscular Atrophy [CHERISH], NCT02292537)⁸ established the clinical efficacy of nusinersen. The current dose of nusinersen is 12 mg for people with SMA of all ages,⁹ although a higher dose is being studied for older individuals.

OA is a gene transfer therapy in which the SMN1 complementary DNA sequence has been packaged into an adeno-associated virus serotype 9 (AAV9) capsid (Figure 3). The treatment is given as a 1-time intravenous treatment to people with SMA who do not have antibodies against the AAV9 capsid. The dose is 1.1x10¹⁴ vector genomes per kilogram (vg/kg). OA was approved by the FDA in 2019 for children younger than 2 years with SMA.¹⁰ The efficacy of this treatment was established in 2 open-label studies of symptomatic infants with SMA type 1: START (Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1, NCT02122952) and STR1VE (Gene Replacement Therapy Clinical Trial for Participants With Spinal Muscular Atrophy Type 1, NCT03306277).^11,12 Other countries and regions have approved OA with different parameters. The European Medicine Agency, for example, has approved OA for people with biallelic variations in the SMN1 gene and a clinical picture of SMA type 1 or up to 3 copies of SMN2.¹³

Risdiplam is a small molecule that modulates splicing of the SMN2 pre-mRNA, resulting in increased SMN2 mRNA that includes exon 7. As with nusinersen, more full-length SMN2 mRNA results in increased expression of functional SMN protein (Figure 2). The efficacy of risdiplam was established in an open-label clinical trial of infants with SMA type 1 (Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam [RO7034067] in Infants With Type 1 Spinal Muscular Atrophy [FIREFISH], NCT02913482)¹⁴ as well as a double-blind, placebo-controlled study of individuals ages 2 to 25 with later-onset SMA (type 2 or type 3) (A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam [RO7034067] in Type 2 and 3 Spinal Muscular Atrophy Participants [SUNFISH], NCT02908685).¹⁵ Risdiplam was approved by the FDA in 2020 and is indicated for people of all ages with SMA. The dosing is 0.15 mg/kg for infants under 2 months, 0.2 mg/kg for children 2 months to 2 years, and 0.25 mg/kg for individuals over 2 years, up to a maximum of 5 mg total per day.¹⁶

Evidence for Disease-Modifying Treatments in Presymptomatic SMA

Some clinical trials have been designed to recruit presymptomatic participants. NURTURE (A Study of Multiple Doses of Nusinersen [ISIS 396443] Delivered to Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy, NCT02386553) is an open-label clinical trial of presymptomatic infants with SMA who received their first dose of nusinersen within 42 days of life.¹⁷ SPR1NT (Pre-Symptomatic Study of Intravenous Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy for Patients With Multiple Copies of SMN2, NCT03505099) is an open-label clinical trial of presymptomatic infants who were treated with OA within 42 days of life.^18,19 RAINBOWFISH (A Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy, NCT03779334)^20,21 is an ongoing open-label clinical trial of presymptomatic infants with SMA who started risdiplam within 42 days of life.

The rationale for treating presymptomatic individuals is to prevent motor neuron loss before the disease has advanced. If an individual has not lost a substantial number of motor neurons, the potential for normal or mildly abnormal motor development may be preserved. “Presymptomatic” only means that there are no obvious symptoms of SMA; it does not mean that the individual has not yet lost any motor neurons. This is particularly true among people with 2 copies of SMN2, who likely have the most severe cases of SMA, and in whom abnormal motor development likely would be noted despite early treatment. Nonetheless, participants from the presymptomatic studies (NURTURE, SPR1NT, and RAINBOWFISH) who would likely have SMA type 1 (ie, people with 2 copies of SMN2) demonstrated better outcomes with improved survival and motor milestones^17,18,21 compared with similar but symptomatic participants who were treated in the pivotal studies of their respective medications (ENDEAR, STR1VE, and FIREFISH).^7,12,14 These studies clearly demonstrate that early treatment results in better outcomes and that people with SMA should be treated when presymptomatic.

These results provide a strong rationale for newborn screening for SMA. SMA was added to the US Recommended Uniform Screening Panel for newborn screening in July 2018, and as of 2023, 48 states include SMA as part of their newborn screening panel. Because newborn screening typically only tests for homozygous deletions of SMN1, approximately 95% of neonates with SMA would be diagnosed on newborn screening; thus approximately 5% of people with SMA will be diagnosed after developing symptoms of SMA, which would delay treatment in these individuals, likely resulting in poorer outcomes than if they had received early treatment.

Treatment of Adults With SMA

One of the early concerns with nusinersen was the absence of evidence for safety and efficacy of nusinersen among adults. The use of nusinersen in clinical practice has facilitated a number of real-world evidence studies supporting the efficacy of nusinersen in adults.²² One of the largest real-world evidence studies was published out of Germany.²³ The investigators documented Hammersmith Functional Motor Scale Expanded (HFMSE) results (the primary outcome measure) and other motor outcome measures among adults with SMA receiving nusinersen as part of standard of care. The study was not randomized or placebo-controlled; nonetheless, 96% of people treated with nusinersen for 14 months did not worsen, and 68% had improved scores on the HFMSE.

Data on efficacy of risdiplam in adults were provided in part 2 of SUNFISH,¹⁵ the double-blind, placebo-controlled portion of the study. Adults with SMA who were younger than 25 years comprised part of a larger group that included children and adolescents. Participants in this larger group (2 to 25 years old) were randomized to risdiplam or placebo. The participants taking risdiplam were found to have better motor function scores on the 32-item Motor Function Measure than participants taking placebo. Real-world evidence studies for risdiplam in adults are planned.

Transitions of Care

People with SMA traditionally have been cared for by a multidisciplinary team of pediatric providers, and many people with SMA continue to be cared for by the same pediatric providers after they become adults. Disease-modifying therapies, however, result in improved survival of people with SMA, and a substantial increase in the number of adults with SMA is expected in the coming years. In addition, adults with SMA have re-engaged with neurologic care owing to the growing number of available therapies. The number of adults with SMA will likely grow beyond the capacity of current pediatric providers. Thus, a system of transitioning people with SMA to adult providers is necessary. This will need to involve neurology providers as well as other specialties, including rehabilitation, pulmonology, orthopedics, and speech therapy. Use of disease-modifying treatments in symptomatic people with SMA will also reveal emerging phenotypes that are in part a function of the specific medication used and the stage of the disease when treatment was started. This will add to the diversity of people with SMA, further justifying the need for individualized, multidisciplinary supportive treatment of people with SMA.

Summary

SMA is an autosomal recessive genetic neuromuscular disease resulting in motor neuron degeneration. The disease is caused by biallelic sequence variations in the SMN1 gene, most commonly deletions of SMN1. People with SMA present with hypotonia, progressive muscle weakness, and atrophy, resulting in loss of mobility, respiratory insufficiency, orthopedic issues, and other symptoms. Multidisciplinary care is designed to address the needs of individuals with SMA.

Three FDA-approved disease-modifying medications are available for SMA treatment, all of which aim to restore SMN protein expression. The outcome of treatment depends more on when treatment is initiated than on the specific agent used. Because presymptomatic treatment results in better outcomes, it is critical to identify the disease as early as possible. Newborn screening can identify approximately 95% of newborns with SMA, which facilitates treatment of people with SMA when they are presymptomatic or minimally symptomatic.

With disease-modifying treatment, people with SMA will have improved survival, and there will be a growing population of adults with SMA. SMA care centers must develop a system to transition care to a multidisciplinary team of adult providers with experience in SMA.