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The average prevalence at birth of proximal spinal muscular atrophy (SMA) is estimated at 1/12,000, of which more than 10% account for type 3. Prevalence worldwide ranges between 1/70,00-285,000, although studies are limited.

The disease manifests between 18 months of age and adulthood, typically presenting with frequent falls, difficulty climbing steps and proximal weakness. Patients are subdivided based on age of onset: early onset is between 18 months and 3 years of age (type 3a) and is associated with a plateau in motor development, reduced or absent reflexes, finger polymyoclonus tremor and, frequently, loss of ambulation before or around puberty. Later onset (type 3b), between 3 and 21 years of age, is associated with comparatively milder decline in gross motor function. The muscle weakness predominantly affects the legs and hip muscles and then progresses to the shoulders and arms. Abnormal gait characteristics are common in order to compensate for weakness. Typically, patients are spared scoliosis and respiratory muscle weakness but these may be a feature after loss of ambulation. Cognition is normal.

The disease is a result of degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei. Causal homozygous mutations/deletions in the SMN1 gene (5q12.2-q13.3) are responsible. SMN1 encodes the survival motor neuron protein (SMN) which is known to participate in critical pathways related to RNA processing and transport. Modifier genes include SMN2 (5q13.2), a homologous centromeric copy of SMN1, and NAIP (5q13.1), encoding neuronal apoptosis inhibitory protein. Type 3 is associated with 3-4 copy numbers of SMN2.

The disease is suspected based on clinical history and examination. The gold standard in diagnosis is genetic testing of SMN1 deletion/mutation. Muscle biopsy and electromyography should not be performed in a typical presentation.

Differential diagnoses include other disorders of the peripheral nervous system including myopathies or muscular dystrophies (dystrophinopathies, limb girdle muscular dystrophy, metabolic myopathies, or inflammatory myopathies), inflammatory neuropathies (Guillain-Barré syndrome), neuromuscular junction disorders (myasthenia gravis or congenital myasthenic syndromes), and other motor neuron disorders (non-5q form of SMA or late onset hexosaminidase A deficiency).

Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villus samples.

Transmission is autosomal recessive but around 2% of cases are caused by de novo mutations. Genetic counseling should be offered to patients and their families.

Symptomatic management is multidisciplinary and aims to improve quality of life. Physiotherapy and occupational therapies are recommended and include exercise programs. Clinical evaluations should include timed function tests including the six-minute walk test. Nusinersen, an antisense oligonucleotide, is approved for treatment of SMA in Europe and the USA. Real world data following commercial availability of the drug suggest efficacy in type 3 children and adult patients.

A wheelchair may be required during childhood for some patients (more commonly those with type 3a), whilst others retain the ability to walk into adulthood. Progression is slow and life expectancy is typically normal. Data on long-term outcomes with nusinersen treatment are not currently available.