- Clinical science
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.
|Type of SMA||Type I (Werdnig-Hoffman disease)||Type II||Type III (Kugelberg-Welander disease)||Type IV (adult SMA)|
|Age of onset||0–6 months||7–18 months||> 18 months||10–30 years|
|Typical features|| || |
|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 older the age of onset, the better the prognosis!
Type I → non-sitters, type II → sitters, type III → walkers
- Definitive therapy: intrathecal nusinersen
- Respiratory support
- Nutritional support, growth monitoring
- Physical rehabilitation
- Orthotics to prevent joint and spine deformities
|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|
|Type 3 (X-linked distal spinal muscular atrophy)||Defect of ATP7 gene on chromosome Xq||Unknown||Early childhood|| |
X-linked spinal muscular atrophy is seen only among males!
- Prevalence: < 1 in 1,000,000
- Congenital absence of muscles
- Progressive atrophy of scapular muscles and peroneal muscles (fibularis longus, brevis, and tertius)
- Progressive laryngeal muscle palsy
- Prevalence: < 1 in 1,000,000
- Clinical features
- Prevalence: unknown (less than 40 cases have been reported so far)
- Etiology: defect in VRK1 gene on chromosome 14q → atrophy of the cerebral cortex, cerebellar and brain stem hypoplasia, absent dendate nucleus, loss of neurons in the basal ganglia
- Onset at 0–6 months
- Limb weakness, hypotonia
- Bulbar palsy
- Oculomotor defects: strabismus, nystagmus, oculomotor apraxia
- Cognitive defects
- Life expectancy < 1 year
- Genetic testing: best initial and confirmatory test
- Laboratory tests: normal or mildly elevated creatine kinase
- : 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
- 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 (Fazio-Londe syndrome)→ predominantly bulbar weakness with minimal involvement of anterior horn cells
- Motor neuron degeneration associated with severe arthrogryposis (e.g., Pena-Shokeir syndrome, Marden-Walker syndrome)
The differential diagnoses listed here are not exhaustive.