Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: A clinico-genetic study in Germany

Background and purpose: Mutations in the FUS/TLS have been associated with amyotrophic lateral sclerosis (ALS) in a few percent of patients. Methods: We screened 184 familial (FALS) and 200 sporadic German patients with ALS for FUS/TLS mutations by sequence analysis of exons 5 6 and 13 15. We compared the phenotypes of patients with different FUS/TLS mutations. Results: We identified three missense mutations p.K510R p.R514G p.R521H and the two truncating mutations p.R495X and p.G478LfsX23 in samples from eight pedigrees. Both truncating mutations were associated with young onset and very aggressive disease courses whereas the p.R521H p.R514G and in particular the p.K510R mutation showed a milder phenotype with disease durations ranging from 3years to more than 26years the longest reported for a patient with a FUS/TLS mutation. Also in a pair of monozygous twins with the p.K510R mutation a remarkable similar disease course was observed. Conclusions: Mutations in FUS/TLS account for 8.7 (16 of 184) of FALS in Germany. This is a higher prevalence than reported from other countries. Truncating FUS/TLS mutations result in a more severe phenotype than most missense mutations. The wide phenotypic differences have implications for genetic counselling. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.