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Do twin studies still have anything to teach us about the genetics of amyotrophic lateral sclerosis?
  1. Kevin Talbot
  1. Correspondence to Professor K Talbot, University of Oxford, Department of Clinical Neurology, John Radcliffe Hospital, Oxford OX3 9DU, UK; kevin.talbot{at}clneuro.ox.ac.uk

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Population registries, uncontaminated by the referral bias seen in clinic based case series, show that approximately 5% of amyotrophic lateral sclerosis (ALS) cases are familial.1 At most, only 30% of these cases are explained by mutations in the small number of currently identified ALS related genes, including SOD1, TDP-43 and FUS.2–4 The era of Mendelian genetics for the common neurodegenerative diseases is fast drawing to a close. There are very few large families left to collect and the sun is setting on linkage studies. It is unlikely that there is another gene which explains as many familial cases as SOD1 (approximately 20%). The potentially numerous and diverse gene defects responsible for the remaining 70% of familial ALS cases will likely be identified in the future by large scale ‘deep sequencing’ projects, either through targeting genes in specific pathways or by whole genome sequencing.

There is a widespread and entirely reasonable assumption that the remaining 95% of ALS cases, which are classified as ‘sporadic’, are caused by a mixture of genetic and environmental effects, and that ALS is therefore a ‘complex’ disease like diabetes and stroke. However, in the case of ALS this is still a hypothesis and the most interesting area of uncertainty is not whether the totality of ALS has a genetic component, which it clearly does because we can identify genetic mutations in patients with familial disease and in a few cases with sporadic disease, but whether there is a subpopulation of sporadic ALS cases in which the genetic contribution is minimal or even …

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