Truncating mutations in FUS/TLS give rise to a more aggressive ALS‐phenotype than missense mutations: a clinico‐genetic study in Germany. Issue 3 (6th December 2012)

• Record Type: Journal Article
• Authors: Waibel, S.; Neumann, M.; Rosenbohm, A.; Birve, A.; Volk, A. E.; Weishaupt, J. H.; Meyer, T.; Müller, U.; Andersen, P. M.; Ludolph, A. C.
• Is Part Of: European journal of neurology. Volume 20:Issue 3(2013:Mar.)
• Page Start: 540
• Page End: 546
• Publication Date: 2012-12-06
• Subjects: Neurology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/ene.12031
• Languages: English
• ISSNs: 1351-5101

Abstract

<abstract abstract-type="main" id="ene12031-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ene12031-sec-0001" sec-type="section"> <title>Background and purpose</title> <p>Mutations in the <italic>FUS/TLS</italic> have been associated with amyotrophic lateral sclerosis (ALS) in a few percent of patients.</p> </sec> <sec id="ene12031-sec-0002" sec-type="section"> <title>Methods</title> <p>We screened 184 familial (FALS) and 200 sporadic German patients with ALS for <italic>FUS/TLS</italic> mutations by sequence analysis of exons 5, 6 and 13–15. We compared the phenotypes of patients with different <italic>FUS/TLS</italic> mutations.</p> </sec> <sec id="ene12031-sec-0003" sec-type="section"> <title>Results</title> <p>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 <italic>FUS/TLS</italic> mutation. Also, in a pair of monozygous twins with the p.K510R mutation, a remarkable similar disease course was observed.</p> </sec> <sec id="ene12031-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Mutations in <italic>FUS/TLS</italic> account for 8.7% (16 of 184) of FALS in Germany. This is a higher prevalence than reported from other countries. Truncating <italic>FUS/TLS</italic> mutations result in a more severe phenotype than most missense mutations. The wide phenotypic differences have implications for genetic counselling.</p> </sec> </abstract>