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

Simon Witzel, Matias Wagner, Chen Zhao, Katharina Kandler, Elisabeth Graf, Riccardo Berutti, Konrad Oexle, David Brenner, Juliane Winkelmann, Albert C. Ludolph

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)117-126
Number of pages10
JournalNeurobiology of Aging
Volume119
DOIs
StatePublished - Nov 2022

Keywords

  • Amyotrophic lateral sclerosis
  • Disease progression
  • Exome sequencing
  • Prognostic factors
  • SOD1
  • Survival

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