Key Facts

SMA is the commonest genetic cause of infant death. Caused by deficiency of survival motor neurone (SMN) protein. The advent of disease-modifying therapies (nusinersen, gene therapy, risdiplam) has transformed the prognosis, particularly when given pre-symptomatically.

Epidemiology

Incidence ~1 in 10,000 live births. Carrier frequency ~1 in 40-50. SMA type 1 accounts for ~60% of cases. No sex predilection. Newborn screening increasingly being implemented (included in UK newborn screening pilot).

Aetiology

Homozygous deletion or mutation of SMN1 (survival motor neurone 1) gene on chromosome 5q13. SMN2 (paralogous gene) partially compensates but produces predominantly truncated, unstable protein (~10% full-length SMN). SMN2 copy number is the main disease modifier.

Pathophysiology

Deficiency of SMN protein → selective degeneration of alpha motor neurones in the anterior horn of the spinal cord → progressive denervation and atrophy of skeletal muscles. Proximal muscles affected more than distal. SMN protein is essential for RNA processing and motor neurone survival. Higher SMN2 copy number partially rescues the phenotype.

SMA Type 1 (Werdnig-Hoffmann Disease)

• Onset <6 months; severe hypotonia ("floppy baby"); never achieve sitting
• Tongue fasciculations (hallmark); absent deep tendon reflexes
• Paradoxical (diaphragmatic) breathing; bell-shaped chest
• Feeding difficulties; bulbar weakness
• Normal cognition; alert, bright eyes
• Death from respiratory failure by age 2 without treatment

SMA Type 2

• Onset 6-18 months; can sit independently but never walk
• Proximal weakness, tremor of fingers (polyminimyoclonus)
• Scoliosis, joint contractures
• Respiratory complications later; survival to adulthood

SMA Type 3 (Kugelberg-Welander Disease)

• Onset >18 months; can walk independently (may lose ability in teens/adulthood)
• Proximal weakness, waddling gait, Gower sign
• Near-normal lifespan

SMA Type 4

• Adult onset (>21 years); mildest; slowly progressive proximal weakness

Red Flags

• Floppy infant with tongue fasciculations and absent reflexes → SMA type 1
• Progressive proximal weakness in child with normal cognition

Genetic Testing

• SMN1 gene analysis: homozygous deletion of exon 7 (and usually exon 8) confirms diagnosis in ~95%; MLPA or qPCR
• SMN2 copy number: determines prognosis and guides treatment decisions
• Carrier testing: for family members; prenatal diagnosis available

Bloods

• CK: normal or mildly elevated (unlike muscular dystrophies where markedly raised)

Neurophysiology

• EMG: denervation pattern (fibrillations, positive sharp waves, large-amplitude polyphasic MUPs); normal sensory nerves
• NCS: reduced CMAP amplitudes; normal sensory conduction

Other

• Muscle biopsy: rarely needed now (genetic testing is diagnostic); shows grouped atrophy (neurogenic)
• Respiratory function: serial FVC, sleep study; essential for monitoring

Disease-Modifying Therapies

• Nusinersen (Spinraza): antisense oligonucleotide; increases SMN2 exon 7 inclusion → more functional SMN protein; intrathecal injection; loading doses then 4-monthly; ENDEAR trial (type 1), CHERISH trial (type 2); NICE TA588
• Onasemnogene abeparvovec (Zolgensma): AAV9-mediated gene therapy delivering functional SMN1; single IV infusion; most effective when given pre-symptomatically or early in type 1; NICE HST15
• Risdiplam (Evrysdi): oral SMN2 splicing modifier; daily oral liquid; FIREFISH (type 1) and SUNFISH (type 2/3) trials; NICE TA755

Supportive Care (MDT)

• Respiratory: NIV, cough assist devices, chest physiotherapy, proactive management of respiratory infections
• Nutrition: nasogastric or gastrostomy feeding in type 1/severe type 2
• Orthopaedic: scoliosis management (bracing, surgery), contracture prevention
• Physiotherapy: maintain function, prevent contractures
• Palliative care: especially type 1 if treatment not available or not chosen

Referral Criteria

• All suspected SMA: urgent paediatric neurology referral
• Specialist neuromuscular centre for treatment decisions

Type 1 without treatment: death by age 2. With nusinersen/gene therapy: significant improvement in motor milestones and survival. Type 2: survival to adulthood; progressive scoliosis and respiratory compromise. Type 3: near-normal lifespan; variable motor disability. Pre-symptomatic treatment (identified by newborn screening) gives the best outcomes — many treated infants achieve near-normal motor development. SMN2 copy number is the strongest predictor of natural history.

SMA Classification

Key SMA Trials