Update on genetics of amyotrophic lateral sclerosis

Curr Opin Neurol. 2022 Oct 1;35(5):672-677. doi: 10.1097/WCO.0000000000001093. Epub 2022 Aug 8.


Purpose of review: ALS genetics are highly dynamic and of great interest for the ALS research community. Each year, by using ever-growing datasets and cutting-edge methodology, an array of novel ALS-associated genes and downstream pathomechanisms are discovered. The increasing plenty and complexity of insights warrants regular summary by-reviews.

Recent findings: Most recent disease gene discoveries constitute the candidate and risk genes SPTLC1 , KANK1 , CAV1 , HTT , and WDR7 , as well as seven novel risk loci. Cell type and functional enrichment analyses enlighten the genetic basis of selective motor neuron vulnerability in ALS demonstrating high expression of ALS-associated genes in cortical motor neurons and highlight the pathogenic significance of cell-autonomous processes. Major pathomechanistic insights have been gained regarding known ALS genes/proteins, specifically C9orf72 , TDP43, ANXA11 , and KIF5A . The first ASO-based gene-specific therapy trials in familial forms of ALS have yielded equivocal results stressing the re-evaluation of pathomechanisms linked to SOD1 and C9orf72 mutations.

Summary: The genetic and molecular basis of ALS is increasingly examined on single-cell resolution. In the past 2 years, the understanding of the downstream mechanisms of several ALS genes and TDP-43 proteinopathy has been considerably extended. These insights will result in novel gene specific therapy approaches for sporadic ALS and genetic subtypes.

Publication types

  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / metabolism
  • Amyotrophic Lateral Sclerosis* / therapy
  • C9orf72 Protein / genetics
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Humans
  • Kinesins
  • Motor Neurons / pathology
  • Mutation / genetics


  • Adaptor Proteins, Signal Transducing
  • C9orf72 Protein
  • Cytoskeletal Proteins
  • KANK1 protein, human
  • KIF5A protein, human
  • WDR7 protein, human
  • Kinesins