• Clinical science

Spinal muscular atrophy


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-Hoffman 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. Supportive therapy is aimed at preventing respiratory and orthopedic complications.


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


Epidemiological data refers to the US, unless otherwise specified.




  • Motor neuron disease that only involves the lower motor neurons (spinal ± bulbar motor neurons) → muscle weakness, hypotonia, bulbar symptoms; preserved sensations
  • Motor neurons of cranial nerves III, IV, and VI, and sacral motor neurons not affected → preserved eye movement and continence
  • Both sympathetic and parasympathetic autonomic motor neurons are also affected, but their involvement occurs late.


Clinical features

Type of SMA Type I (Werdnig-Hoffman disease) Type II Type III (Kugelberg-Welander disease) Type IV (adult SMA)
Relative frequency 25% 50% 25%
Severity Severe Intermediate Mild
Age of onset 0–6 months 7–18 months > 18 months 10–30 years
Typical features
  • Severe muscle weakness and hypotonia
    • Symmetrical involvement of proximal muscles, mostly of the lower extremities
    • Intercostal muscle weakness with initial sparing of the diaphragm → paradoxical breathing
  • Diminished or absent deep tendon reflexes
  • Severe bulbar palsy
  • Delayed motor milestones
  • Poor weight gain
  • Weak cough
  • Fine hand tremors
  • Joint contractures, kyphosis, and/or scoliosis
  • Variable degree of muscle weakness
  • Cramps, muscle aches
  • Joint pain
Motor milestones

Never sits or attains head control

Able to sit independently, but cannot stand without support

Able to stand and walk independently

Prognosis Life expectancy (< 2 years) Life expectancy (> 2 years)

Near normal life expectancy

The most common causes of death among patients with SMA are respiratory insufficiency (due to respiratory muscle weakness) and aspiration pneumonia (due to bulbar weakness)!

The older the age of onset, the better the prognosis!

Type Inon-sitters, type II → sitters, type III → walkers



  • Definitive therapy: intrathecal nusinersen
  • Supportive therapy
    • Respiratory support
      • Bulbar weakness or acute respiratory tract infections: airway clearance ± chest physiotherapy
      • Nocturnal hypoventilation: nocturnal non-invasive ventilation ± O2 therapy
      • Daytime hypoventilation: continuous non-invasive ventilation ± O2 therapy
    • Nutritional support, growth monitoring
    • Physical rehabilitation
    • Orthotics to prevent joint and spine deformities


Subtypes and variants

Non-5q spinal muscular atrophy

  • Definition: variants of SMA that are not associated with a defect in the SMN1 gene on chromosome 5q

X-linked spinal muscular atrophy

Types Etiology Prevalence Onset Clinical features
Type 1 (Kennedy's disease) Defect of NR3C4 gene on chromosome 5q 1 in 30,000 male children 30–50 years
Type 2 (type 1 X-linked arthrogryposis multiplex congenita) Defect of XPA1 gene on chromosome Xp < 1 in 100,000 male children Neonatal period
  • Slowly progressive lower motor neuron palsy of all limbs
  • Respiratory failure
  • Arthrogryposis (congenital joint contractures)
  • Bone fractures
  • Early death (< 2 years)
Type 3 (X-linked distal spinal muscular atrophy) Defect of ATP7 gene on chromosome Xq Unknown Early childhood
  • Slowly progressive lower motor neuron palsy of all limbs
  • Affects distal muscles > proximal muscles

X-linked spinal muscular atrophy is seen only among males!

Scapuloperoneal spinal muscular atrophy

Spinal muscular atrophy with respiratory distress type 1

  • Prevalence: < 1 in 1,000,000
  • Etiology
  • Clinical features
    • Onset at < 3 months
    • Hypotonia, weak cry (similar to type I SMA)
    • Early diaphragmatic palsy → elevation of the right or both hemidiaphragms → Early onset of respiratory distress
    • Progressive distal weakness → early distal contractures (e.g., finger deformities, pes equinus)

Spinal muscular atrophy with pontocerebellar hypoplasia


  1. Genetic testing: best initial and confirmatory test
  2. Further tests
    • Laboratory tests: normal or mildly elevated creatine kinase
    • EMG: spontaneous, large-amplitude, low-frequency electrical activity (rarified interference pattern)
    • Muscle biopsy: atrophy of groups of motor units interspersed with normal or hypertrophied motor units All the muscle fibers of a single denervated motor unit atrophy together. A muscle biopsy may not be able to identify type III SMA, and also cannot differentiate type I from type II.
    • Genetic testing for non-5q spinal muscular atrophy


Differential diagnoses


The differential diagnoses listed here are not exhaustive.