Spinal muscular atrophy

SMA is caused by mutations in the SMN1 gene, located on chromosome 5q13.2, which encodes the survival motor neuron protein essential for motor neuron maintenance. In about 95% of cases, the disease results from a homozygous deletion of SMN1; the remaining cases involve point mutations or compound heterozygosity. The severity is modulated by the number of copies of the nearly identical SMN2 gene, which produces a small amount of functional protein. Higher SMN2 copy numbers generally correlate with milder phenotypes, but this correlation is not absolute. The deficiency of SMN protein leads to motor neuron degeneration in the anterior horn of the spinal cord and brainstem nuclei, causing progressive muscle weakness and atrophy.

SMA is classified into types 0 through 4 based on age of onset and achieved motor milestones. Type 1 (Werdnig-Hoffmann disease) presents before 6 months with severe hypotonia, inability to sit, and respiratory failure; without treatment, death typically occurs by age 2. Type 2 manifests between 6 and 18 months, with children able to sit but not walk. Type 3 (Kugelberg-Welander disease) appears after 18 months, with patients achieving independent ambulation, though later losing it. Type 4 is adult-onset with mild proximal weakness. A rare type 0 is prenatal-onset with severe arthrogryposis. The disease primarily affects proximal muscles, with tongue fasciculations and areflexia being common signs.

Diagnosis is confirmed by genetic testing showing biallelic SMN1 mutations, typically via PCR or MLPA. Newborn screening is increasingly implemented, allowing early intervention. Three disease-modifying therapies have been approved: nusinersen (Spinraza), an antisense oligonucleotide administered intrathecally; onasemnogene abeparvovec (Zolgensma), a gene therapy delivering a functional SMN1 copy; and risdiplam (Evrysdi), an oral small molecule that modulates SMN2 splicing. These therapies have dramatically improved outcomes, especially when initiated presymptomatically. Supportive care includes respiratory support, nutritional management, and physical therapy to maintain function and quality of life.

Beyond the classic motor symptoms, SMA affects other systems: cardiac defects, metabolic abnormalities, and autonomic dysfunction have been reported. The SMN protein is involved in RNA splicing and is expressed in all tissues, explaining systemic effects. Historically, SMA was first described by Guido Werdnig in 1891 and Johann Hoffmann in 1893, but the genetic basis was not identified until 1995. A notable historical figure is the neurologist Kugelberg and Welander who described the juvenile form in 1956. The discovery of SMN2 as a modifier led to the development of therapies targeting its splicing. Additionally, some patients with SMA have been found to have cognitive advantages, with studies suggesting higher IQ scores in type 2 and 3 patients compared to controls.

SMN1

Survival motor neuron 1 gene; mutations cause SMA.

SMN2

A nearly identical gene that produces a small amount of functional SMN protein; copy number modifies severity.

Antisense oligonucleotide

A short synthetic nucleic acid that modifies RNA splicing; used in nusinersen.

Gene therapy

A treatment that delivers a functional gene to cells; used in onasemnogene abeparvovec.