SETX mutations in ALS4, a rare juvenile-onset familial form of ALS, presumably cause a gain-of-function, as loss-of-function mutations in the SETX gene are responsible for autosomal recessive Ataxia with Oculomotor Apraxia type 2 (AOA2), and AOA2 carriers do not develop motor neuron disease [67, 68]. This evidence concerns the gene SETX and amyotrophic lateral sclerosis.