Observational Study of Spinal Muscular Atrophy Type 2 and 3

Abstract

Spinal muscular atrophy (SMA) is the leading genetic cause of death in infancy, with an estimated incidence of 1 in 6000 to 1 in 10 000 live births.^1-4 Most patients have a homozygous SMN1 deletion of exon 7, making diagnostic confirmation readily available.^5,6SMN2 is an inverted duplication that differs from SMN1 by 5 nucleotides, the only critical difference being an 840C>T transition in exon 7 that alters splicing.⁷ The resulting messenger RNA lacks exon 7 (Δ7 SMN2 messenger RNA) and produces a protein with reduced stability. However, the expressed SMN2 is partially able to rescue the phenotype.⁸ The clinical severity is inversely related to SMN2 copy number.^9,10 This observation has been replicated in transgenic mice by knocking out the SMN gene and introducing a human SMN2 transgene.¹¹ The homozygous SMN1 mutation affects motor neurons in the spinal cord and ultimately leads to muscle atrophy and weakness. In all but the most severe infantile forms of SMA, there is histological and electrophysiological evidence of reinnervation that partially compensates for functional loss.^12,13