Homozygous deletion of the survival motor neuron 2 gene is a prognostic factor in sporadic ALS

Background: Spinal muscular atrophy (SMA) results from mutations of the sur vival motor neuron (SMN) gene on chromosome 5. The SMN gene exists in two h ighly homologous copies, telomeric (SMN1) and centromeric (SMN2). SMA is ca used by mutations in SMN1 but not SMN2. The clinical phenotype of SMA appea rs to be related to the expression of SMN2. Patients suffering from the mil der forms of SMA carry more copies of the SMN2 gene compared with patients with more severe SMA. It is suggested that the SMN2 gene is translated into an at least partially functional protein that; protects against loss of mo tor neurons. Objective: To investigate whether genetic mechanisms implicate d in motor neuron death in SMA have a role in ALS. Method: The presence of deletions of exons 7 and 8 of SMN1 and SMN2 was determined in 110 patients with sporadic ALS and compared with 100 unaffected controls. Results: The p resence of a homozygous SMN2 deletion was overrepresented in patients with ALS compared with controls (16% versus 4%; OR, 4.4; 95% CI, 1.4 to 13.5). P atients with a homozygous SMN2 deletion had a shorter median time of surviv al (p < 0.009). Furthermore, multivariate regression analysis showed that t he presence of an SMN2 deletion was independently associated with survival time (p < 0.02). No homozygous deletions in SMN1 were found. Carrier status of SMA appeared to be equally present in patients and controls (1 in 20). Conclusions: These results indicate that, similar to SMA, the SMN2 gene can act as a prognostic factor and may therefore be a phenotypic modifier in s poradic ALS. Increasing the expression of the SMN2 gene may provide a strat egy for treatment of motor neuron disease.