10% of ALS cases are genetic, compared to 90% of sporadic cases, i.e. without an identified cause. Identification of mutations is necessary to better understand the mechanisms of the disease and to include patients in potential therapeutic trials targeting some of the ALS genes.
Causes of Charcot's disease
To date, four major genes have been identified as responsible for more than 50% of the genetic cases of the disease. Over 30 genes have been globally implicated in familial forms of ALS.
The superoxide dismutase 1 (SOD1) gene was identified in 1993 and to date more than 150 different mutations have been found in patients. Since then, mutations have been identified in the genes TARDBP, FUS, and C9ORF72, genes involved in RNA metabolism (for TARDBP and FUS) and in the immune response (for C9orf72). However, these mutations do not necessarily result in the loss of the function of these genes, which makes the research all the more complex. Today, more than 70% of family cases are associated with a known mutation, and research continues to find the mutations responsible for the remaining 30% of family cases.
In sporadic forms of amyotrophic lateral sclerosis (ALS), which account for 90% of cases, there are probably genetic variants of susceptibility, that is, genetic factors that increase the risk of developing the disease. The disease is considered to be multifactorial and certain environmental or lifestyle factors may also contribute to the onset of the disease in susceptible individuals. To date, neither genetic nor environmental factors have been definitively identified.
Does the environment play a role in sporadic cases of the disease?
Studies have been conducted on the influence of environmental factors. In the 1950s, a large number of cases of a particular form of ALS were observed on the island of Guam. They were attributed to a toxin present in a micro-alga that colonized seeds consumed by bats, which were themselves eaten by the islanders! Several cases of ALS have also been observed in U.S. military personnel returning from the Gulf War. Some toxic products are suspected but have not yet been identified. Finally, the risk of declaring ALS is said to be increased among certain sportsmen and sportswomen, in particular footballers and rugbymen. Pesticides, shocks received during the practice of these sports, predisposition of motor neurons of these top sportsmen? There are many hypotheses. These studies have the merit of posing the question of the role of the environment, and the sporadic cases of ALS may well be the result of a combination of several factors.
At Paris Brain Institute
Identifying New Genetic Mutations Causing ALS
Stéphanie MILLECAMPS in the team of Séverine BOILLEE seeks to identify the genetic mutations that cause the disease. Thanks to the participation of the various SLA reference centres in France, researchers were able to search for genetic mutations in 400 families affected by SLA and identify the genetic cause of the disease in 70 per cent of cases. These studies make it possible to offer a molecular diagnosis to families that wish to do so, but also to include patients with a particular mutation in the adapted clinical trials. There are still 30% of family cases to be linked to causal mutations and approaches to large-scale genetic analysis are under way to achieve this.
European collaborative work has led to the identification of a new gene involved in ALS. Named TBK1, it is involved in waste disposal within cells and in the regulation of inflammation, demonstrating the importance of immune cells in triggering and probably progressing the disease. Christian LOBSIGER in the team of Séverine BOILLEE (in collaboration with a German team), is modelling ALS linked to mutations in the TBK1 gene, to study these mechanisms and better understand the disease.
Isabelle LE BER, in the team of Alexandra DURR and Giovanni STEVANIN, took part in an international study that identified, in 2018, a new causal gene in ALS, the protein KIF5A, which was already involved in another pathology of the central motor neuron: spastic paraplegia.
