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 G erman 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. K 510 R , p. R 514 G , p. R 521 H , and the two truncating mutations p. R 495 X and p. G 478Lfs X 23 in samples from eight pedigrees. Both truncating mutations were associated with young onset and very aggressive disease courses, whereas the p. R 521 H , p. R 514 G and in particular the p. K 510 R mutation showed a milder phenotype with disease durations ranging from 3 years to more than 26 years, the longest reported for a patient with a FUS / TLS mutation. Also, in a pair of monozygous twins with the p. K 510 R mutation, a remarkable similar disease course was observed. Conclusions Mutations in FUS / TLS account for 8.7% (16 of 184) of FALS in G ermany. 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.