SMA1

SMA1, short for spinal muscular atrophy type 1, is the most severe form of spinal muscular atrophy, a genetic disorder characterized by degeneration of lower motor neurons in the spinal cord and brainstem, leading to progressive muscle weakness. Symptoms typically appear in infancy, often before 6 months, and the condition was historically known as Werdnig–Hoffmann disease.

Genetics and mechanism: SMA1 is inherited in an autosomal recessive pattern and results from homozygous deletions or mutations in the SMN1 gene on chromosome 5q13, causing a deficiency of the survival motor neuron (SMN) protein. The SMN2 gene copy number modulates disease severity because SMN2 can produce limited functional SMN protein; more SMN2 copies generally correlate with a milder phenotype.

Clinical features: Infants with SMA1 exhibit marked hypotonia, poor or absent head control, weak suck and cry, and reduced spontaneous movement. Tongue fasciculations, facial weakness, and diminished reflexes are common. Respiratory insufficiency with recurrent infections is typical, and there is rapid progression of proximal limb and trunk weakness, hindering motor milestone achievement. Without treatment, life expectancy is often limited to early childhood.

Diagnosis: Diagnosis is confirmed by genetic testing showing SMN1 deletion or mutation. SMN2 copy number is analyzed to support prognosis. Electromyography and nerve conduction studies may aid assessment but are not definitive for SMA1.

Management: Care is multidisciplinary, focusing on respiratory support, nutritional management, physical and occupational therapy, and orthopedic considerations as needed. Disease-modifying therapies are available, including nusinersen, onasemnogene abeparvovec, and risdiplam, which aim to increase SMN protein production or replace SMN1 function. Early treatment improves outcomes, and newborn screening programs aid early identification.