Spinal muscular atrophy is a motor neuron disease that manifests with muscle atrophy and weakness. Although there are several genetic etiologies, more than 95% of spinal muscular atrophy (SMA) patients carry a homozygous deletion in the survival motor neurons (SMN) gene on chromosome 5q11-q13. Based on age at onset and severity of symptoms, three SMA types have historically been described; all are autosomal recessive. The three SMA types are allelic and clinically on a continuous spectrum with SMA1 being the most severe, and SMA3 the milder phenotype. The SMN gene has two almost identical forms on chromosome 5, one telomeric (SMN1) and one centromeric (SMN2). The phenotypic severity of SMA is associated with the SMN2 copy number. SMN1 gene mutation is embryonic lethal in the absence of SMN2 gene. A quantitative study of SMN2 copy number in 375 patients with SMA types 1, 2, and 3 showed that 80% of SMA1 patients had one or two SMN2 copies, 82% of SMA2 patients had three SMN2 copies, and 96% of SMA3 patients had three or four SMN2 copies. In theory, SMA carriers have approximately 50% SMN protein. A mouse model for SMA was made by knocking out the SMN1 gene and introducing the human SMN2 transgene. The murine SMA phenotype is mitigated by increasing the SMN2 copy number, confirming the observation in humans. These findings have become the basis for attempted treatment to increase SMN2 expression in children with SMA.

Direct deletion analysis has high sensitivity and specificity and can be used for diagnosis without muscle biopsy in suspected cases; it is also effective in antenatal diagnosis in an at-risk fetus. Point mutations are found in the few who lack a deletion. The SMN protein is depleted in the spinal cords of patients. How absence of SMN leads to the disease, however, still has to be elucidated.