Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD)

• Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share common genetic, pathological, and clinical features giving rise to an ALS/FTD spectrum.
• Genetic variants in the ALS/FTD spectrum including C9orf72 repeat expansions, SOD1, TDP-43, and FUS mutations are found in familial as well as sporadic patients diagnosed with either of these neurological disorders.
• Recent clinical and animal research indicate an oligogenic notion of disease development with coincidence of mutated alleles and modifier/risk factors (ATX2 intermediate repeats, EPHA4 polymorphisms, etc.).
• Elucidating the functional significance of genetic interactions could further our understanding of these major neurodegenerative diseases.

Several genetic causes have been recently described for neurological diseases, increasing our knowledge of the common pathological mechanisms involved in these disorders. Mutation analysis has shown common causative factors for two major neurodegenerative disorders, ALS and FTD. Shared pathological and genetic markers as well as common neurological signs between these diseases have given rise to the notion of an ALS/FTD spectrum. This overlap among genetic factors causing ALS/FTD and the coincidence of mutated alleles (including causative, risk and modifier variants) have given rise to the notion of an oligogenic model of disease. In this review we summarize major advances in the elucidation of novel genetic factors in these diseases which have led to a better understanding of the common pathogenic factors leading to neurodegeneration.