The aims of this study were i) to identify whether mutations in CHMP2B contribute significantly to the pathogenesis of familial and apparently sporadic ALS, by screening for genetic alterations in a cohort of 433 ALS cases in whom the clinical phenotype had been documented serially throughout the disease course; ii) to investigate in CNS tissue changes in the gene expression profile of motor neurons from cases with CHMP2B mutations compared to neurologically normal controls, and iii) to investigate the functional effects of CHMP2B mutations in an in vitro system. The gene discussed is CHMP2B; the disease is amyotrophic lateral sclerosis.