Author(s): Sunil K Jain, MD, Martin Barylak, BS
Originally published: December 29, 2022 Last updated: December 29, 2022
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Disease/ Disorder

Definition

Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy due to degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem.1

Etiology

SMA disorders are inherited in an autosomal recessive pattern. Deletions or mutations in the SMN1 gene on chromosome 5q13.2 result in deficiency of survival motor neuron (SMN) protein.2 However, phenotypic expression varies due to individuals carrying varying copies of the centromeric version of SMN, SMN2. Patients with SMA lack SMN1, the telomeric version, and thus depend on residual SMN2 production for motor neuron function and survival.4,5

Epidemiology including risk factors

Few studies have recently assessed the epidemiology of SMA. Generally, the incidence is around 10 per 100,000 live births and the prevalence is around 1-2 per 100,000 persons.6,7,8 The carrier frequency of disease-causing SMN1 mutations is estimated to be between 1/100 to 1/40.9

Because SMA is a genetic disease, there are no lifestyle related risk factors. Rather, risk factors that relate to increased inheritance of the gene mutation include family history and Caucasian race.9

Patho-anatomy/physiology

The role of SMN protein is not fully understood but has been shown to play a key role in the maintenance of motor neurons and homeostatic cellular pathways.3 Research suggests that the SMN protein in the cytoplasm transports mRNA through axons and aids with vesicle release in the synapse. Furthermore, SMN protein in the nucleus aids in the formation of the spliceosome.10,11 Lastly, SMN protein has been reported to modulate apoptosis by blocking caspases and other regulators of cell survival.12 The lack of these functions then results in characteristic degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

All SMA patients have symmetric proximal muscle weakness that is greater in the lower limbs and decreased or absent deep tendon reflexes.13 However, the severity, onset, and clinical course are stratified into 5 subtypes of SMA, 0-IV. SMA is the most common monogenic cause of infant mortality.14

SMA type 0 (aka congenital SMA) has a prenatal onset and is associated with hypotonia, arthrogryposis, early respiratory failure, severe weakness, decrease fetal movements, and death at birth or within a few months.14 Infants with SMA type 0 generally have one copy of SMN2.15

SMA type I (aka Werdnig-Hoffman) presents in the first 6 months of age with symptoms including severe symmetric flaccid paralysis, inability to sit unsupported, limited head control, weak cry, poor suck and swallow reflexes, pooling of secretion, tongue fasciculations, and increase risk of failure to thrive.14 SMA type 1 infants will often assume a characteristic “frog-like” posture when supine due to severe hypotonic leg weakness. Without ventilatory support, most infants with SMA type I live to about two years of age.14 Infants with SMA type I generally have two or three copies of the SMN2 gene.15

SMA type II (aka Dubowitz) presents at 6-18 months of age with the ability to sit but hypotonia, areflexia, and progressive proximal weakness that disproportionately affects legs over arms. Muscular weakness often leads to scoliosis and restrictive lung disease. Other symptoms include joint contractures, ankylosis of the mandible, and polyminimyoclonus of the hands. Life expectancy is more variable but around 70% of SMA type II patients will survive until 25.14 Patients with SMA type II generally have three copies of the SMN2 gene.15

SMA type III (aka Kugelberg-Welander) presents after 18 months and patients are typically ambulatory but can require a wheelchair as the disease progresses. Symptoms generally include progressive proximal weakness disproportionately affected legs; however, patients do not typically suffer from restrictive lung disease or scoliosis and life expectancy is not affected.14 Patients with SMA type III generally have three or four copies of the SMN2 gene.15

SMA type IV (aka adult SMA) presents in adulthood and is the mildest phenotype. Patients are ambulatory and typically present with mild leg weakness and proximal weakness and an unaffected lifespan.14 Patients with SMA type IV generally have four to eight copies of the SMN215 gene.

Specific secondary or associated conditions and complications

The associated complications depend on the severity and type of SMA as outlined above. Typical complications include but are not limited to restrictive lung disease, failure to thrive, swallowing difficulties, aspiration, constipation, reflux, delayed gastric emptying, scoliosis, hip subluxation, contractures, and susceptibility to fractures.9 

Essentials of Assessment

History

SMA should be suspected for any infant with unexplained proximal muscle weakness, motor difficulties or regression, and/or hypotonia. History will differ depending on SMA type as outlined above. Age of onset and symptom profile are key identifiers for SMA type.9

Physical Examination

Physical examination should focus on neurological and musculoskeletal findings for diagnosis. Neurological findings may include proximal muscle weakness, lower extremity weakness, absent or diminished lower extremity reflexes, tongue fasciculations, and signs of lower motor neuron disease. Musculoskeletal findings may include scoliosis, contractures, or hip subluxation. A complete multisystem physical exam should be performed to assess secondary complications.9

Functional Assessment

Functional assessments may be appropriate for milder subtypes of SMA. The degree of weakness, functional impairment, and clinical course vary widely among subtypes of SMA and should be considered in evaluation.

Laboratory Studies

Molecular genetic testing is the gold standard for SMA diagnosis by detecting homozygous deletions of exon 7 of SMN1. If the clinical picture suggests SMA but only a single deletion is identified, sequencing of SMN1 to look for point mutations should be pursued.16 SMN2 detection is often performed at the same time to aid in prognostic evaluation as higher SMN2 copies are associated with less severe phenotypes.17 SMA was added to the Recommended Uniform Screening Panel (RUSP) for newborns in the United States in 2018, and several states have begun newborn screening for SMA.18

Imaging

Imaging for musculoskeletal, respiratory, or gastrointestinal complications may be appropriate depending on patient presentation and can be considered for further workup.

Supplementary assessment tools

Electromyography (EMG) and muscle biopsy are not often pursued due to genetic testing but were once a standard part of diagnosis. EMG typically shows denervation changes without reinnervation for SMA I or neurogenic patterns with increased amplitude, prolonged duration, and diminished recruitment for SMA II and III. Muscle biopsy would show a neurogenic pattern. Furthermore, nerve conduction studies may show diminished motor action potentials. Lastly, creatinine kinase is typically normal although may be very mildly elevated.17

Early predications of outcomes

Early predictions of outcomes depend on the SMA type and number of copies of the SMN2 gene. Earlier the onset and fewer copies of SMN2 are correlated with mores severe outcomes.

Environmental

Environmental factors that can lead to neurological, musculoskeletal, gastrointestinal, and respiratory deficits should be assessed and avoided. 

Social role and social support system

Families of children affected by SMA may benefit from a greater social support system to cope with this difficult diagnosis. Patients affected by SMA commonly reported emotional difficulties, fatigue, and a perceived lack of societal support.19

Professional Issues

Depending on severity of weakness, accommodations in school or the workplace may be appropriate for patients and caregivers of those with SMA.

Rehabilitation Management and Treatment

Available or current treatment guidelines

Current treatment includes novel therapies as well as symptom management. Disease-modifying therapies are now available which have been shown to improve life span and decrease morbidity.20 These include nusinersen, onasemnogene abeparvovec, and risdiplam. Nusinersen is an intrathecally delivered antisense oligonucleotide that promotes functional SMN2 production.21 Onasemnogene abeparvovec is a onetime intravenous injection gene therapy that ultimately results in delivering the SMN1 gene into cells and allowing the body to produce functioning SMN protein.22 Risdiplam is an oral medication that modifies SMN2 splicing and increasing functional SMN protein levels.23  For children over the age of 2, treatment with nusinersen or risdiplam is suggested as the efficacy in this group of onasemnogene abeparvovec is unknown. The choice among treatments options should be individualized and consider cost (which can be extraordinary), risk profiles, avenues of administration, unknown effects, and availability. Furthermore, some children may be too debilitated to benefit from these treatment modalities.

Symptom management with supportive therapies and early palliative care specialists is the standard for those without disease-modifying therapy. This may include but is not limited to non-invasive ventilation (most commonly BiPAP), tracheostomy, permanent invasive ventilation, gastrostomy, fundoplication, modified diets, physiotherapy, physical therapy, bracing, orthotics, or wheelchairs to improve quality of life.9

Coordination of care

An interdisciplinary approach including physiatrists, pediatricians, geneticists, gastroenterologists, pulmonologists, neurologists, orthopedic surgeons, social workers, psychologists, and other specialists as necessary is recommended.27

Patient and family education

As this is a genetic disease, genetic counseling to patients and family members is important to make properly informed decision in the future. SMA’s autosomal recessive inheritance patterns should be explained to affected families. Preconception counseling should be offered to affected individuals and screening for planned reproductive partner.26 The American College of Medical Genetics recommends offering carrier testing to all couples regardless of race or ethnicity and the American College of Obstetricians and Gynecologists recommends that screening for SMA should be offered to all women who are considering pregnancy or are pregnant.28,29,30

External resources include the following:

Emerging/unique interventions

Novel disease-modifying therapies are at the forefront of SMA treatment and should continue to be explored and tested.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

SMA phenotypes vary significantly from SMA type 0 to type IV. At its most severe form, patients typically do not live long after birth while at its least severe patients may be largely unaffected. Screening and carrier testing should be offered to all individuals. Supportive management with a large interdisciplinary team is recommended for optimizing treatment. Disease-modifying treatment may cost in the millions USD and varies in approach and frequency of treatment.

Cutting Edge/ Emerging and Unique Concepts and Practice

Novel disease-modifying therapies and uses continue to be heavily researched. Preliminary studies suggest that combining disease modifying therapies such as nusinersen and onasemnogene may be beneficial but further research needs to be done to determine the efficacy and feasibility of this approach.24,25

Gaps in the Evidence-Based Knowledge

  • Updated epidemiology including incidence, prevalence, and carrier frequency are largely unknown and based off older studies.
  • SMN protein function and precise role in neuronal longevity should be further researched.
  • Efficacy of onasemnogene abeparvovec for children under the age of 2 is unknown.
  • Long term effects of disease-modifying therapy are unknown.
  • Efficacy and feasibility of combination therapy with disease-modifying agents is largely unknown.
  • The pathophysiology of gastrointestinal and metabolic complications of SMA are largely unknown.

References

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Author Disclosure

Sunil K Jain, MD
Nothing to Disclose

Martin Barylak, BS
Nothing to Disclose