Recent Updates on the Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Mol Neurobiol. 2022 Sep;59(9):5673-5694. doi: 10.1007/s12035-022-02934-z. Epub 2022 Jun 30.


Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) primarily affect the motor and frontotemporal areas of the brain, respectively. These disorders share clinical, genetic, and pathological similarities, and approximately 10-15% of ALS-FTD cases are considered to be multisystemic. ALS-FTD overlaps have been linked to families carrying an expansion in the intron of C9orf72 along with inclusions of TDP-43 in the brain. Other overlapping genes (VCP, FUS, SQSTM1, TBK1, CHCHD10) are also involved in similar functions that include RNA processing, autophagy, proteasome response, protein aggregation, and intracellular trafficking. Recent advances in genome sequencing have identified new genes that are involved in these disorders (TBK1, CCNF, GLT8D1, KIF5A, NEK1, C21orf2, TBP, CTSF, MFSD8, DNAJC7). Additional risk factors and modifiers have been also identified in genome-wide association studies and array-based studies. However, the newly identified genes show higher disease frequencies in combination with known genes that are implicated in pathogenesis, thus indicating probable digenetic/polygenic inheritance models, along with epistatic interactions. Studies suggest that these genes play a pleiotropic effect on ALS-FTD and other diseases such as Alzheimer's disease, Ataxia, and Parkinsonism. Besides, there have been numerous improvements in the genotype-phenotype correlations as well as clinical trials on stem cell and gene-based therapies. This review discusses the possible genetic models of ALS and FTD, the latest therapeutics, and signaling pathways involved in ALS-FTD.

Keywords: Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; Mechanistic Pathways; Novel Therapeutics; Oligogenic Inheritance.

Publication types

  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / pathology
  • Frontotemporal Dementia* / genetics
  • Frontotemporal Dementia* / pathology
  • Genetic Association Studies
  • Genome-Wide Association Study
  • Heat-Shock Proteins / genetics
  • Humans
  • Kinesins
  • Membrane Transport Proteins / genetics
  • Mitochondrial Proteins / genetics
  • Molecular Chaperones
  • Multifactorial Inheritance
  • Mutation


  • CHCHD10 protein, human
  • DNAJC7 protein, human
  • Heat-Shock Proteins
  • KIF5A protein, human
  • MFSD8 protein, human
  • Membrane Transport Proteins
  • Mitochondrial Proteins
  • Molecular Chaperones
  • Kinesins