Evidence for rare Mendelian forms of multiple sclerosis (MS) has come from a new study published in PLOS Genetics. The mutations that were identified provide new insight into the underlying causes of MS and suggest a need for new therapeutic approaches.

Although MS aggregates in some families, the idea that single mutations can cause heritable MS has been controversial. In 2016, Carles Vilariño-Güell and colleagues identified a pathogenic mutation in one family with MS, suggesting that Mendelian forms of MS can exist. Now, Vilariño-Güell and his team have applied the same approach to a much larger group of families.

“Our aim was to determine the existence of Mendelian forms of MS and to identify genes and mutations causing disease that could provide a better understanding of the biological mechanisms that underlie MS onset,” says Vilariño-Güell.

The researchers used whole-exome sequencing to analyse the genomes of 132 individuals with MS from a total of 34 different families. Following the identification of mutations, a further 2,502 people with MS were screened for the same mutations, and a database of MS-associated variants was screened for other mutations in the same genes.

In total, the analysis identified 12 genes linked with familial MS. “These findings show that Mendelian forms of MS indeed exist,” states Vilariño-Güell. “The mutations are extremely rare and have a reduced penetrance, but most of the people who had one of the mutations developed MS in their lifetime.”

The 12 genes that were identified provide intriguing insights into the pathogenesis of MS. The genes relate to the fibrinolysis and complement pathways, inflammasome assembly, Wnt signalling, nuclear receptor complexes, and cation channels and exchangers, all of which contribute to interconnected immunological pathways.

“These mutations indicate that the root of the disease is not the adaptive immune response but the innate immune system,” says Vilariño-Güell. “Thus, we may be targeting the ‘wrong’ system with current treatments, as those address the symptoms but not the causes.”

we may be targeting the ‘wrong’ system with current treatments

Identification of potentially causal mutations in MS provides the opportunity to create new animal models, and Vilariño-Güell says that this is the key next step. “Models based on human mutations have a greater potential to mimic the biological processes of disease in humans, and provide a better translational efficacy for new treatments,” he concludes.