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Keywords:

  • amyotrophic lateral sclerosis twin monozygosity concordance;
  • familial amyotrophic lateral sclerosis;
  • FUS/TLS;
  • genetic counselling;
  • truncating mutation

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 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.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.