Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor neurons, leading to paralysis and early death. The disease with fatal outcome occurs in adulthood and affects 1-3 people per 100,000 persons/year with a prevalence of 4-6 cases/100,000. It is characterized by motor neurons progressive degeneration in spinal cord, brain and motor cortex. ALS is clinically characterized by weakness and wasting of the muscles of the limbs, bulbar and respiratory muscles. The disease usually begins in the fifth or sixth decade of life and, in the majority of affected individuals, progresses to death, in most cases for respiratory failure after 3-5 years of onset.
ALS causes are largely unknown, although recently several causative genes have been identified by the diffusion of new technologies for screening. In November 2011, the experimental evidence of the presence of intronic expansion in C9orf72 gene has in fact changed the scenario. Approximately 90% of the forms of ALS are sporadic (sALS) and the etiology is not known. The familial forms (fALS) accounts for around 5%-10% of cases and are very heterogeneous from a genetic perspective.
The genetic mechanisms involved in ALS are likely to be more complex than initially assumed. It is necessary the understanding of the pathogenesis of ALS to investigate the processes that lead to the development of the disease and at the same time provide new molecular therapeutic targets. With the discovery of C9orf72 as a major causative gene in ALS, the genetic causes of this disease are now identify in 60% of familial forms.
In recent years, genetic and histopathological findings led to the hypothesis that similar pathological processes are at the basis of ALS and frontotemporal lobe dementia (FTD). Although there is a great diversity/variability in the genetic causes, a high degree of overlap between these pathologies has been highlighted by the histopathological point of view. Genes linked to ALS and/or FTD, like C9ORF72 (especially), TARDBP, FUS, OPTN, VCP, and PFN1 UBQLN2 may still converge on a same pathogenic pathway and, therefore, provide new therapeutic common targets for different forms of ALS and ALS-FTD.