Genetic mutations have been linked to early onset multiple sclerosis in a small number of cases, lending weight to the hypothesis that genetic factors underlie multiple sclerosis more widely.
Mutations in the gene NR1H3 were found in two separate families which both had strongly inherited cases of early-onset, rapidly progressing multiple sclerosis. However, in those families 70 percent of people with the gene variant developed the disease, suggesting that while some cases of multiple sclerosis may be linked to genetic risk factors, environmental factors may be necessary to trigger the disease.
'This mutation puts these people at the edge of a cliff,' confirmed senior study author Dr Carles Vilarino-Guell, an assistant professor of medical genetics at the University of British Columbia 'but something still has to give them the push to set the disease process in motion.'
Yet the 70 percent figure is much greater than the penetrance of other mutations that have been linked to multiple sclerosis in the past, as most previously identified multiple sclerosis risk genes 'have a really small overall effect' on the likelihood of developing the disease, Dr Carles Vilarino-Guell told CBC News.
NR1H3 is involved in two pathways that could be important in multiple sclerosis: lipid production, and the switching off of inflammation. In multiple sclerosis the myelin sheaths around the nerves are attacked by the immune system when inflammation is mistakenly switched on and targets the body's own tissues.
In the paper, published in the journal Neuron, the researchers suggest that the mutation makes inflammation more intense, and that repair of the lipid membrane after damage may be impaired. Both factors would contribute to faster disease progression.
Only one in 1,000 multiple sclerosis patients are thought to carry the mutation, but its discovery helps reveal the biological pathway that leads to the rapidly progressive form of the disease, which affects around 15 percent of people with multiple sclerosis, and may even suggest a target for new treatments.
Drugs boosting the effect of the gene could decrease early inflammatory damage of the myelin sheaths, delaying the nerve damage that gives rise to the main symptoms of the disease. There are experimental drugs that target the NR1H3 gene pathway, but they are yet to be tested in humans.
Professor Dessa Sadovnick, also a senior author, told CBC News that most people with multiple sclerosis have a relapsing-remitting form of the disease 'where they have attacks and then a complete or partial recovery'.
However, she added, such people normally go on to develop the progressive form of the disease after many years, when their disease would be very similar to that of the families in this study. 'It's the progressive phase for which there's really no known therapy,' Professor Sadovnick said. 'And this will hopefully help those with relapsing-remitting [multiple sclerosis] who become progressive as well as these primary progressive families.'