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Witzel, S.* ; Wagner, M. ; Zhao, C. ; Kandler, K.* ; Graf, E. ; Berutti, R.* ; Oexle, K. ; Brenner, D.* ; Winkelmann, J. ; Ludolph, A.C.*

Fast versus slow disease progression in amyotrophic lateral sclerosis–clinical and genetic factors at the edges of the survival spectrum.

Neurobiol. Aging 119, 117-126 (2022)

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Open Access Green as soon as Postprint is submitted to ZB.

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Patients with amyotrophic lateral sclerosis (ALS) show substantial differences in disease progression and survival. However, the genetic contribution to the extremes of this spectrum remains poorly characterized. We unbiasedly selected and genotyped 102 ALS patients with very short (<15 months) and 90 with very long survival (>100 months) from the ALS registry of Ulm University using whole-exome sequencing and C9orf72 repeat expansion testing followed by a clinicogenetic correlation analysis. Clinically, groups significantly differed regarding site of disease onset, age at onset, BMI at diagnosis, disease progression rates, and diagnostic latency. We found a monogenic disease cause in 31 patients (16%) without significant differences in patients with short and long survival (19% vs. 13%; p = 0.41), but differences in the genotypic architecture. C9orf72 expansions and FUS mutations were only found in fast progressors, whereas SOD1 variants were frequent in both groups contributing 52% of all monogenic cases–33% among fast and 75% among slow variants. Our genotype-phenotype correlation may be relevant for genetic counseling, estimation of prognosis, and therapeutic decisions.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Amyotrophic Lateral Sclerosis ; Disease Progression ; Exome Sequencing ; Prognostic Factors ; Sod1 ; Survival

ISSN (print) / ISBN 0197-4580

e-ISSN 1558-1497

Journal Neurobiology of Aging

Quellenangaben Volume: 119, Pages: 117-126

Publisher Elsevier

Publishing Place New York, NY [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)

Grants Universität Ulm
Deutsche Gesellschaft für Neurologie
Fondation Charcot
Deutsche Forschungsgemeinschaft
Boehringer Ingelheim
Teva Pharmaceutical Industries
Biogen