Amyotrophic lateral sclerosis and spinocerebellar ataxia 2

Amyotrophic lateral sclerosis (ALS) is usually sporadic, but 5%–10% of patients have a hereditary form of the disease. About 20% of familial patients have mutations in the SOD1 gene,¹ and recently other gene mutations have been found in familial ALS: TDP-43, FUS, and VCP.^2,–,5 Interestingly, the protein products of 2 of these genes, TDP-43 and FUS, are likely involved in RNA metabolism. TDP-43 forms cytoplasmic inclusions in neurons of patients with both sporadic and familial ALS and frontotemporal dementia.

Genetic risk factors may play a role in sporadic as well as familial ALS, but the results of association studies have been mixed. For example, the gene for the neurotrophic factor VEGF is a possible risk factor in various European populations,⁶ but studies in other populations did not confirm the finding.⁷ It is now clear that there is no genetic risk factor for ALS as strong as APOE is for Alzheimer disease, and finding and confirming weaker risk factors requires large studies in multiple populations with well-matched controls.

Several months ago, Elden and colleagues⁸ reported a novel risk factor for ALS in ATXN2, the gene for the polyglutamine expansion neurodegenerative disease spinocerebellar ataxia 2 (SCA2). This gene showed up in a screen for modifiers of TDP-43 toxicity in yeast and has a similar effect in Drosophila.⁸ TDP-43 and …