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Both amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) fall within the spectrum of motor neuron diseases. Chromosome 5 SMA, a leading cause of infant death, is characterized by lower motor neuron degeneration without signs of upper motor neuron involvement. In this issue of Neurology®, Blauw et al.¹ provide firm evidence that duplications of the SMN1 (“survival of motor neuron”) gene, which is the gene that is deleted or mutated in SMA, are an important risk factor for sporadic ALS. A brief review of the genetics of ALS and SMA enables us to better appreciate the authors' findings.

ALS occurs sporadically, but is familial in 10%. Approximately 20% of familial cases are caused by autosomal dominant and rarely recessive mutations in SOD1 (superoxide dismutase 1). SOD1 mutations have also been described in about 2% of sporadic cases. Mutations in genes such as the TARDBP (TAR DNA-binding protein; TDP-43), FUS/TLS (fused-in-sarcoma/translocated in liposarcoma), ANG (angiogenin), VAPB (vesicle-associated membrane protein B), OPTN (optineurin), and others have been observed mostly in familial patients. Further, mutations in 3 genes, ALS2 (alsin), SETX (senataxin), and sigma R1 (sigma-1 receptor), have been reported in juvenile ALS families. Although environmental/toxic exposures, autoimmune, infectious, and systemic processes may play a role in ALS, direct causation has not …