TY - JOUR
T1 - Phenotypes and malignancy risk of different FUS mutations in genetic amyotrophic lateral sclerosis
AU - Naumann, Marcel
AU - Peikert, Kevin
AU - Günther, Rene
AU - van der Kooi, Anneke J.
AU - Aronica, Eleonora
AU - Hübers, Annemarie
AU - Danel, Veronique
AU - Corcia, Philippe
AU - Pan-Montojo, Francisco
AU - Cirak, Sebahattin
AU - Haliloglu, G. knur
AU - Ludolph, Albert C.
AU - Goswami, Anand
AU - Andersen, Peter M.
AU - Prudlo, Johannes
AU - Wegner, Florian
AU - van Damme, Philip
AU - Weishaupt, Jochen H.
AU - Hermann, Andreas
N1 - © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
PY - 2019/12
Y1 - 2019/12
N2 - Objective: Mutations in Fused in Sarcoma (FUS or TLS) are the fourth most prevalent in Western European familial amyotrophic lateral sclerosis (ALS) populations and have been associated with causing both early and very late disease onset. FUS aggregation, DNA repair deficiency, and genomic instability are contributors to the pathophysiology of FUS-ALS, but their clinical significance per se and their influence on the clinical variability have yet to be sufficiently investigated. The aim of this study was to analyze genotype–phenotype correlations and malignancy rates in a newly compiled FUS-ALS cohort. Methods: We cross-sectionally reviewed FUS-ALS patient histories in a multicenter cohort with 36 novel cases and did a meta-analysis of published FUS-ALS cases reporting the largest genotype–phenotype correlation of FUS-ALS. Results: The age of onset (median 39 years, range 11–80) was positively correlated with the disease duration. C-terminal domain mutations were found in 90%. Among all, P525L and truncating/ frameshift mutations most frequently caused juvenile onset, rapid disease progression, and atypical ALS often associated with negative family history while the R521 mutation site was associated with late disease onset and pure spinal phenotype. Malignancies were found in one of 40 patients. Interpretation: We report the largest genotype–phenotype correlation of FUS-ALS, which enables a careful prediction of the clinical course in newly diagnosed patients. In this cohort, FUS-ALS patients did not have an increased risk for malignant diseases.
AB - Objective: Mutations in Fused in Sarcoma (FUS or TLS) are the fourth most prevalent in Western European familial amyotrophic lateral sclerosis (ALS) populations and have been associated with causing both early and very late disease onset. FUS aggregation, DNA repair deficiency, and genomic instability are contributors to the pathophysiology of FUS-ALS, but their clinical significance per se and their influence on the clinical variability have yet to be sufficiently investigated. The aim of this study was to analyze genotype–phenotype correlations and malignancy rates in a newly compiled FUS-ALS cohort. Methods: We cross-sectionally reviewed FUS-ALS patient histories in a multicenter cohort with 36 novel cases and did a meta-analysis of published FUS-ALS cases reporting the largest genotype–phenotype correlation of FUS-ALS. Results: The age of onset (median 39 years, range 11–80) was positively correlated with the disease duration. C-terminal domain mutations were found in 90%. Among all, P525L and truncating/ frameshift mutations most frequently caused juvenile onset, rapid disease progression, and atypical ALS often associated with negative family history while the R521 mutation site was associated with late disease onset and pure spinal phenotype. Malignancies were found in one of 40 patients. Interpretation: We report the largest genotype–phenotype correlation of FUS-ALS, which enables a careful prediction of the clinical course in newly diagnosed patients. In this cohort, FUS-ALS patients did not have an increased risk for malignant diseases.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85074799436&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31682085
U2 - https://doi.org/10.1002/acn3.50930
DO - https://doi.org/10.1002/acn3.50930
M3 - Article
C2 - 31682085
SN - 2328-9503
VL - 6
SP - 2384
EP - 2394
JO - Annals of clinical and translational neurology
JF - Annals of clinical and translational neurology
IS - 12
ER -