Spinal muscular atrophy

Last updated: May 15, 2023

Summary

Spinal muscular atrophy (SMA) refers to a group of autosomal recessive motor neuron diseases that are caused by apoptosis of lower motor neurons. Patients typically present during infancy or early childhood with progressive weakness, hypotonia, muscle atrophy, hyporeflexia/areflexia, and varying degrees of bulbar weakness. The severity of disease is related to the age of onset; type 1 SMA (Werdnig-Hoffmann disease) is associated with death within the first two years of life as a result of respiratory muscle paralysis or aspiration pneumonia. With other types of SMA, children usually survive to adulthood, but motor milestones may be delayed and joint contractures and/or deformities of the spine can occur. The diagnosis is confirmed by genetic testing. In 2016, the FDA approved the use of nusinersen, which is highly effective in halting the progression of SMA; in 2019, onasemnogene abeparvovec, a potentially curative genetic therapy, was approved. Supportive therapy is aimed at preventing respiratory and orthopedic complications.

Epidemiology

Incidence: 4–10 per 100,000 live births
Sex: ♂ > ♀

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Autosomal recessive: defect in the SMN1 gene on chromosome 5q: → defect in the assembly of small nuclear ribonucleoprotein (snRNP) to form the SMN complex → apoptosis of lower motor neurons (especially the anterior horn cells in the spinal cord) in the later stages of fetal development and postnatal period

Pathophysiology

Congenital motor neuron disease that only involves the lower motor neurons (spinal ± bulbar motor neurons) → muscle weakness, hypotonia, bulbar symptom
Sensations are not affected
Motor neurons of cranial nerves III, IV, and VI, and sacral motor neurons are not affected → preserved eye movement and continence

Clinical features

Overview of spinal muscular atrophy types ^[1]
Type of SMA	Type 0 SMA	Type I SMA (Werdnig-Hoffmann disease)	Type II SMA	Type III SMA (Kugelberg-Welander disease)	Type IV SMA (adult SMA)
Proportion of all SMA cases ^[2]	< 1%	∼ 55%	∼ 30%	∼ 15%	< 1%
Severity	Very severe	Severe	Intermediate	Mild	Mild
Age of onset	Prenatal	0–6 months	7–18 months	> 18 months	10–30 years
Typical features	Prenatal: absent or decreased fetal movements At birth ^[3] Severe muscle weakness and hypotonia Respiratory failure	Severe muscle weakness (flaccid paralysis) and infantile hypotonia (frog-leg posture) Symmetrical involvement of proximal muscles, mostly of the lower extremities Intercostal muscle weakness → paradoxical breathing Upper cranial nerves are not affected. Diminished or absent deep tendon reflexes Severe bulbar palsy Respiratory failure Atrophy and fasciculations of the tongue Fasciculations of the fingers Weak cry and cough Inability to swallow → difficulty feeding, drooling, ↑ risk of aspiration Recurrent hip dislocation	Fine hand tremors Delayed motor milestones Poor weight gain Weak cough Musculoskeletal abnormalities Joint contractures Hip dislocation Kyphosis Scoliosis	Variable degree of muscle weakness Cramps, muscle aches Joint pain
Motor milestones	Typically, none are achieved	Never sits	Able to sit independently, but cannot stand without support	Able to stand and walk independently
Life expectancy	< 6 months	< 2 years	Approx. 30 years	Near normal life expectancy

The most common causes of death in individuals with SMA are respiratory insufficiency (due to respiratory muscle weakness) and aspiration pneumonia (due to bulbar weakness).

The later the age of onset, the better the prognosis.

Type I → non-sitters, type II → sitters, type III → walkers

Diagnosis

Genetic testing: best initial and confirmatory test
Further tests
- Muscle biopsy: atrophy of groups of motor units interspersed with normal or hypertrophied motor units
- EMG: spontaneous, large-amplitude, low-frequency electrical activity (rarified interference pattern)
- Laboratory tests: normal or mildly elevated creatine kinase

Differential diagnoses

Congenital myasthenic syndromes: muscle weakness induced by fatigue, ptosis, extraocular muscle palsy
Congenital myopathies: more prominent hypotonia and weakness in proximal muscles
Certain viral infections (polio, coxsackievirus, echovirus, West Nile virus): much more acute onset of flaccid paralysis, ascending paralysis (i.e., starts distally)
Hypotonic cerebral palsy : non-progressive weakness
Muscular dystrophies : ↑↑ creatine kinase, characteristic findings on muscle biopsy
Rare juvenile form of amyotrophic lateral sclerosis: predominantly bulbar weakness with minimal involvement of anterior horn cells
Motor neuron degeneration: associated with severe arthrogryposis
Progressive muscular atrophy: a nonhereditary, adult-onset, progressive lower motor neuron disorder

The differential diagnoses listed here are not exhaustive.

Treatment

Definitive therapy ^[1]
- Nusinersen
  - An antisense nucleotide that alters differential splicing of the transcript of the SMN2 gene, so it produces a functional SMN1 protein
  - Requires annual intrathecal injections
- Onasemnogene abeparvovec
  - An agent based on an adeno-associated virus 9-based vector that carries a normal copy of SMN1 to the lower motor neurons of the spinal cord
  - Should be administered intravenously once in a lifetime
- Risdiplam
  - mRNA splicing modulator that improves the efficiency of SMN2 gene transcription → ↑ systemic SMN protein concentration
  - Can be given orally, in contrast to nusinersen
Supportive therapy
- Respiratory support
- Nutritional support
- Physical rehabilitation
- Orthotics to prevent joint and spine deformities

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