Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) comprises a diverse group of inherited neuromuscular disorders characterized by spinal cord alpha motor neuron degeneration with resultant progressive weakness and atrophy.¹ First described in the 1890s,² the causative gene was identified in 1995.³ Thereafter, a spectacular 25-year journey led to approval of the first available therapy—the disease-modifying therapy (DMT) nusinersen, an antisense oligonucleotide (ASO).^4-6

The most common form of SMA, accounting for 95% of cases, results from autosomal recessive loss-of-function mutation in survival motor neuron 1 (SMN1) gene at chromosome 5q13.7 The most common genetic cause of infant mortality, SMA occurs in approximately 1 in 11,000 live births.⁶

Most individuals with SMA have deletions or mutations in both SMN1 copies and expression of SMN2, which produces mostly a truncated SMN that is unstable, nonfunctional, and rapidly degraded. Some full-length messenger RNA (mRNA), however, is produced by SMN2, resulting in about 10% full-length and functional SMN levels compared with that seen in people with 2 SMN1 alleles.⁸ Despite the fact that SMN is ubiquitously expressed, the motor neurons are selectively vulnerable to the absence or low levels of SMN1.⁹

Other rare (<5%) predominantly proximal SMAs not related to SMN1 deletion or mutation are inherited in X-linked or autosomal patterns. Phenotypic presentations vary and may include pontocerebellar hypoplasia; microcephaly; lower-extremity, scapulohumeral, or bulbar dominance; and arthrogryposis. Identification of causative genes for these rare forms has improved significantly with next generation DNA sequencing (NGS).

Clinical Features

There are 5 types of SMA ranging from most to least severe (SMA0 to SMA4) (Table).^8,9 The main phenotypic determinant is SMN2 copy number, which is inversely correlated with disease severity in most cases.¹⁰ The majority of individuals with SMA1 have 2 copies of SMN2; those with SMA2 have 3 copies, and those with SMA3 have 3 to 4 copies. Not all SMN2 are the same, however. Adults with 2 SMN2 copies and a milder phenotype have a G859C SMN variant that increases the amount of full-length SMN mRNA. Several other disease modifiers have been proposed; overexpression of the actin-binding protein plastin 3 (PLS3), neurocalcin delta (NCALD) downregulation and calcineurin-like EF-hand protein 1 (CHP1) reduction are recognized as SMN-independent protective modifiers.

The majority of people with SMA2, 3, and 4 who survive past age 2 years live to adulthood. The 20-year survival for type 2 is 77% to 93%, and those with types 3 and 4 have an essentially normal life span. It should be noted, however, that SMA is progressive with a continuous decline in strength and motor function. There is a pattern of steady decline in those with type 2a, who are able to sit, and a relatively stable phase followed by pronounced decline in the third decade for types 2b and 3a. A similar, relatively stable phase followed by a marked decline after age 40 is noted in type 3b.¹¹

Despite the wide use of the classification shown in the Table, development of new treatments has made some shortcomings of this classification apparent; for example, some children with SMA1 have onset in infancy, 2 SMN2 copies, and gained the ability to sit unaided or even walk independently. A practical classification to accommodate new understanding of the natural history of disease is to use functional status at initial evaluation to define individuals as nonsitters, sitters, and walkers. This approach was used in the standard-of-care documents to guide supportive management.^12,13

It is practical to use the term adults with SMA, for all persons age 18 years or more with genetically confirmed SMN-related SMA. This group can be further divided based on their current function as nonsitters, sitters, and walkers. The nonsitters or severely affected nonambulatory adults (Figure 1A) include those who would have been classified as having SMA1 or SMA2 who tend to have severe diffuse weakness with residual trace movements in the hands, marked facial and bulbar weakness, and areflexia with significant contractures and scoliosis. These individuals typically have severe restrictive thoracic disorder and recurrent aspiration pneumonia and need feeding tubes, tracheostomies, and ventilation. Individuals with SMA who can sit or are nonambulatory with moderately severe weakness (moderately severe ambulatory group (Figure 1B) include adults who would have been classified as having SMA2 or SMA3, characterized by severe proximal predominant weakness affecting the legs more than the arms. Typically, these people have diminished or absent deep tendon reflexes, scoliosis, and moderate-to-severe restrictive thoracic disorder; they usually need for bilevel positive airway pressure (BiPAP) support. Individuals who can walk (Figure 1C) and would previously have been classified as having SMA3 or SMA4 have proximal weakness predominately of the legs. Some maintain a remarkable ability to ambulate despite profound weakness, probably because of the segmental distribution of the weakness allowing for development of compensatory mechanisms. A waddling gait due to hip abductor weakness is common. Usually, there is minimal or no facial, bulbar, or respiratory muscle weakness, but fasciculations in limb muscles and calf hypertrophy may be seen.

Genotype classification by SMN2 copy number is emerging to help predict SMA type and stratify patients to guide therapy for those identified through newborn screening.

Diagnosis

Clinical suspicion for SMA should arise in hypotonic infants and individuals of any age with a symmetric predominantly proximal pattern of weakness. Genetic testing that includes quantitative analysis of SMN1; identification of homozygous deletions; and SMN2, for which copy number has important prognostic and therapeutic implications is the diagnostic standard. There are several methods for quantitative analysis including multiplex ligation-dependent probe amplification (MLPA), quantitative polymerase chain reaction (qPCR), or NGS.¹²

The absence of both full SMN1 copies confirms diagnosis of SMA in about 96% of people (Figure 2). The remaining 4% represents compound heterozygotes with an SMN1 deletion of 1 allele and an intragenic missense or frameshift mutation of the other. Thus, if only 1 SMN1 copy is found, sequencing of the gene is required to identify the intragenic mutations.¹²

Newborn screening for SMA has been added to national recommendations, but adopted by only some states. Such screening allows detection of 95% of cases before symptom onset, making early therapeutic intervention possible.^12,13

Genetic tests have made EMG and muscle biopsy obsolete for diagnosis of SMA, although these studies may be used in adults for whom alternative diagnoses are considered. This takes into account that several disorders causing proximal weakness in older children and adolescents mimic SMA, particularly myopathies and muscular dystrophies. Creatine kinase (CK) elevation (see HyperCKemia in this issue) and calf hypertrophy in some with SMA might add to the confusion.

Treatment

Supportive Care

Aggressive supportive treatments remain a cornerstone of therapeutics and are upheld by the International SMA Standard of Care Committee expert panel. The management of SMA in a multidisciplinary care setting has a pivotal role because multiple organ systems are involved and nonpharmacologic therapies are also required. Proactive care has become the norm and introducing interventions and involving specialty therapists earlier in the disease process can potentially maximize the benefit of treatment^.12,14

The level of care varies depending on the motor milestone (ie, whether a person can sit or walk). For each motor status, there are validated clinical markers that can be used to follow the disease course and response to therapies.^8,14

Respiratory Care. More severely affected individuals have difficulty handling secretions, recurrent pneumonia, and sleep-disordered breathing, that are the main causes of morbidity and mortality. Respiratory needs are functionally assessed with physical examination, pulse oximetry, end tidal CO₂, sleep studies, cough peak flow, and spirometry.¹⁴

Respiratory therapists should be involved in earlier interventions including cough assist (using devices or manual techniques), oral suctioning, and nebulized bronchodilators.¹⁴ Noninvasive ventilation using BiPAP is also worthwhile and leads to fewer hospitalizations, longer lives, and possibly, improvement in lung development and function.¹³ The use of tracheotomy and chronic ventilation is an option for selected individuals.¹³

Gastrointestinal and Nutritional Issues. Arising from bulbar dysfunction and gastroesophageal dysmotility, gastrointestinal issues can include dysphagia, aspiration, acid reflux, delayed emptying, and constipation.¹² Symptomatic therapy (eg,proton pump inhibitors or H₂ blockers) may reduce discomfort. Nissen’s fundoplication is often used for infants with SMA1 who are refractory to medical treatment. Nutritional status must be maintained with gastrostomy tubes reserved for select individuals.¹⁸ Children with SMA tend to require less caloric intake than their age-matched peers, leading to risk of both over- and undernourishment.

Orthopedic Complications. Kyphoscoliosis and chest deformities can lead to thoracic insufficiency and subsequent respiratory issues. Hip instability, contractures, and fractures can limit mobility and cause discomfort. Joint contractures should be addressed with physical and occupational therapy including optimal stretching, passive range-of-motion exercises, bracing, and use of assistive devices.¹² The goal of such interventions is to maximize function and independence. Scoliosis in particular should be monitored every 6 months until skeletal maturity and yearly after skeletal maturity. A Cobb angle of 50^o or more or a rate of progression of 10^o per year are signs that intervention is needed.¹³

Surgical correction of orthopedic problems after age 4 years, preferably with an orthopedic surgeon who has experience with neuromuscular disorders, can improve quality of life (eg, spinal instrumentation to preserve truncal balance and realign the thorax). Rigid bracing does not stop scoliosis progression but may help posture.¹²

Acute care preplanning with defined goals, interventions, and management strategies can help eliminate challenges in this setting.¹⁴ Such planning reduces burden of disease for affected individuals and families. Prophylactic influenza and pneumococcal vaccinations reduce complications as well.¹⁴

Approved Disease-Modifying Therapies

As the barriers to providing DMTs for SMA are overcome, it is also important to note which therapies have been shown ineffective. Early therapeutic trials of gabapentin, riluzole, albuterol, creatine and carnitine, valproic acid, hydroxyurea, phenylbutyrate, and olesoxime showed no clinical benefits. A small molecule, RG-7800, doubled SMN protein levels in clinical trial participants with SMA; however, trials of this drug were stopped after unexpected retinal toxicity occurred in long-term animal studies.^15,16

Nusinersen Approved by the Food and Drug Administration (FDA) for all types of SMA in all ages, nusinersen is an ASO that targets SMN2 by enhancing exon 7 inclusion during pre-mRNA splicing to produce full-length functional SMN. Administration is via intermittent intrathecal injections because nusinersen does not cross the blood-brain barrier. Initially, 4 loading doses are given over a 2-month period; thereafter, life-long maintenance doses are given every 4 months.

In double-blind sham-controlled clinical trials,^5,6 51% of infants treated with nusinersen at age 7 months or less had subsequent motor milestone development as assessed with the Hammersmith Infant Neurological Examination (HINE) compared with none (0%) of the children treated with sham. Death or the need for permanent ventilation occurred in 39% of infants treated with nusinersen and 68% of children treated with sham. In children treated between the ages of 2 and 12 years, 57% who were treated with nusinersen had motor milestone development on HINE compared with 26% of those treated with sham. In an open-label, single-arm study of presymptomatic infants diagnosed with SMA genetically, it was shown that early treatment has the greatest benefit.¹⁶

Although clinical trials for nusinersen did not include participants over age 15 years;, the drug is approved for all individuals and data is being collected to examine efficacy in this age group. Scoliosis or spinal fusion may make alternative intrathecal delivery methods necessary, including
fluoroscopic- and ultrasound-guided cervical puncture,
subcutaneous intrathecal catheter systems, CT-guided lumbar transforaminal approaches, and lumbar laminectomy.^17,18 Risks versus benefits of each method is unclear and choice largely depends on available resources and expertise.

Onasemnogene, an SMN1 Gene-Replacement Therapy

Onasemnogene abeparvovec is a gene-replacement therapy that delivers exogenous SMN1 complementary DNA (cDNA) via an adeno-associated viral (AAV) vector, approved by the FDA while this article was written. It is approved for use in symptomatic or presymptomatic children under age 2 years with genetically confirmed SMA.

The AAV vector that delivers SMN1 into neurons establishes itself as a persistently expressing epitope with little incorporation into the host genome. Epitopes of AAV vectors can remain for a very long time in terminally-differentiated cells such as motor neurons, allowing for 1-time dosing.

In clinical trials, 15 symptomatic children with 2 SMN2 copies, age 6 months or less, who received onasemnogene via intravenous injection survived event-free for 20 months. Importantly, the 12 of 15 children who were given a higher dose of the drug had functional motor improvement as measured by the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. After 20 months, 11 of these 12 children sat unassisted and 2 walked independently. Some children had elevation of serum aminotransferase levels that responded to treatment with prednisolone.¹⁹ Longer-term data up to 5 years show continued motor developed, no need for permanent ventilation, and no toxicity concerns.¹⁶

In trials of onasemnogene in presymptomatic infants age 2 years and less with SMN1 deletion and 1 to 4 SMN2 copies, 34 of 36 infants have survived event free and continued to achieve motor milestones over a period of up to 4 years.²⁰ There is also an ongoing study of intrathecal delivery of onasemnogene treatment for children age 6 months to 5 years²⁰ and plans to study the drug in older individuals with SMA. These remarkable results of treatment with onasemnogene are transformative, but there is still a need for continued long-term monitoring of the treated individuals to better understand the duration of the therapeutic effect and the long-term effects on the phenotype.

Phosphorylated neurofilament heavy chain is emerging as a useful serum biomarker with levels that help to differentiate between infants with SMA vs healthy individuals and also normalize with SMN-directed therapies.

Future Directions

Small Molecule mRNA Splicing Modulators

An exciting treatment strategy uses small molecules, branaplam or risdiplam, to enhance exon 7 inclusion into SMN2 mRNA, with subsequent increased levels of SMN. Although early human studies of branaplam were stopped when toxicity occurred in a parallel preclinical toxicity study, this issue has been resolved, and the study in participants with SMA1 resumed.

In an open-label trial to evaluate the safety and efficacy of risdiplam in infants, age 1 to 7 months, with SMA1, no toxicity led to withdrawal from the study and 86% of infants treated gained 4 or more points on the 64-point CHOP INTEND scale after 6 months of treatment.

In individuals, age 2 to 25 years, with SMA2 or 3 (ambulatory and nonambulatory), 58% had motor function improvements defined as Motor Function Measure score increases of 3 or more points, 12 months after treatment. A third open-label phase 2 clinical trial of risdiplam for children and adults, age 2 to 60 years, with SMA2 or 3 is investigating safety, tolerability, and efficacy of risdiplam in individuals previously treated with other SMN2-targeting small molecule therapies or nusinersen after washout period.²⁰

Both branaplam and risdiplam are orally administered, which may affect tissues outside the central nervous system (CNS). These drugs may be an attractive alternative to intrathecal administration for some patients and families, or for patients with spinal fusion and could potentially be considered in combination with other therapies as well.

Other Candidates

Enhancing muscle mass and contractility and mass of the muscles with reldesemtiv, a fast-skeletal muscle troponin complex activator, is also being studied. Reldesemtiv slows the rate of calcium release and sensitizes the sarcomere to calcium, thereby increasing contractility. A double-blind placebo-controlled phase 2 study of children, age 12 years or less, with SMA2 or 3, showed no dose-limiting or toxicity issues.²⁰ Although the target serum level was not reached, improvement in lung function maximum expiratory pressure (MEP) and concentration-dependent increase from baseline in the 6-minute walk test (6MWT) were seen.

Conclusion

The treatment landscape for SMA is evolving at an unprecedented rate with 2 existing FDA-approved DMTs available and others in development. The promise of a treatment that can modify the natural history of the disease has raised awareness regarding the importance of diagnosis. This should lead to increasing implementation of newborn screening and a higher index of clinical suspicion. As the number of people with SMA who are identified and survive grows, the need for multidisciplinary clinics and care centers is greater than ever. With our evolving understanding of the natural history of SMA, the validity of the traditional classification is questionable and new pragmatic function-based and genotype-based classifications are in development. Combination therapies will need to be explored and biomarkers to monitor disease progression and response to treatment are needed.