About this condition
Spinal Muscular Atrophy (SMA)
Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by loss of function of SMN1 (survival motor neuron 1) gene, resulting in degeneration of anterior horn motor neurons. Incidence is approximately 1 in 6,000–10,000 live births; carrier frequency is approximately 1 in 50 across populations. SMA is characterized by progressive weakness, starting proximally and advancing distally, with respiratory and bulbar involvement in severe forms. The disease is classified into types based on age of onset and maximum motor function achieved: Type I (severe, onset <6 months, never able to sit independently, often fatal by age 2 without treatment), Type II (intermediate, onset 6–18 months, able to sit but never walk), Type III (mild, onset >18 months, able to walk), and Type IV (adult-onset). Approximately 95–98% of SMA cases are caused by homozygous deletion of SMN1 exons 7–8; the remaining cases result from homozygous or compound heterozygous point mutations. Disease severity is dramatically modulated by SMN2 copy number: SMN2 encodes an almost identical protein but with a critical splicing difference that produces mostly non-functional truncated protein; however, approximately 15% of SMN2 transcripts include exon 7, producing functional SMN protein.
SMN1 and SMN2 are nearly identical genes (99.9% sequence homology) located in tandem in chromosome 5q13—a region of high sequence homology and frequent copy number variation. SMN encodes survival motor neuron protein, crucial for snRNP biogenesis and mRNA splicing in neurons; loss of SMN protein causes motor neuron degeneration. SMN2 is present in multiple copies in most individuals (1–4 copies, median 2) due to duplication. While SMN2 cannot fully compensate for SMN1 loss due to exon 7 splicing deficiency, the number of SMN2 copies critically determines disease severity: 1–2 copies typically produce Type I (severe); 3 copies produce Type II (intermediate); 3–4 copies correlate with Type III (mild). Presymptomatic SMA patients discovered through newborn screening with 2–3 SMN2 copies are at risk for Type I or II; those with ≥4 copies have lower immediate risk, though early treatment can prevent phenotype expression regardless.
SMN1/SMN2 genotyping is critical for SMA diagnosis and therapy selection. Three approved therapies are available: nusinersen (Spinraza), an antisense oligonucleotide administered intrathecally that modulates SMN2 splicing to increase exon 7 inclusion and full-length SMN2 protein production; onasemnogene abeparvovec (Zolgensma), a gene therapy using AAV9 to deliver functional SMN1 cDNA intravenously as a single infusion—a one-time curative approach now preferred in presymptomatic patients; and risdiplam (Evrysdi), an oral splicing modifier enabling home-based treatment. Presymptomatic treatment (newborn-diagnosed infants) produces dramatically improved outcomes—most treated presymptomatic infants never develop observable SMA symptoms and achieve normal or near-normal motor milestones. SMN2 copy number helps predict natural disease severity and guides prognostication, though early treatment can prevent phenotype expression even in patients destined to be Type I.
- Gene locus
- SMN1/SMN2 (5q13.2)
