Canada has one of the highest rates of multiple sclerosis in the world, for reasons that scientists do not yet understand — but not for lack of trying. Over the past 20 years, a project funded by the MS Society of Canada has gathered genetic samples from 4,400 Canadians with the neurological disease, plus 8,600 of their blood relatives. Today, this biobank, which is one of the largest in the world, has produced an elusive clue to the genetics underlying this disease.

University of British Columbia scientists discovered a rare mutation that makes it very likely a person will develop a devastating form of MS.

“With the genetic mutation we have identified, we can now create animal models which are very likely to mirror the biological processes that cause disease in people,” explained Dr. Carles Vilarino-Guell, senior author of the study. He added the animal models will serve as an outstanding tool for developing new treatments which will likely target the cause of disease rather than manage symptoms.

The Start

MS occurs when the body’s immune system attacks myelin, the material that insulates neurons and enables communication within the brain and nervous system as a whole. As myelin erodes, communication between the brain and the body is disrupted, resulting in vision problems, muscle weakness, difficulty with balance, and cognitive impairments.

More than two decades ago, Dr. A. Dessa Sadovnick, a UBC professor of medical genetics and neurology, suggested some type of genetic explanation might be found for this often devastating neurological disease.

“At that time, nobody thought there was any genetic component to MS, but people did know if you looked at families, you could have more than one person affected,” Sadovnick said in a video. Despite the naysayers, she gained funding from the MS Society of Canada and the Multiple Sclerosis Scientific Research Foundation in 1993 and began to collect DNA samples along with demographic and clinical information from all the established MS clinics across Canada.

Making use of the database over the years, scientists studying MS were able to identify many individual genes that play some role in the disease, yet each made only a small contribution to the disease.

“What we tried to identify is one mutation of major effect that causes disease within families,” Vilarino-Guell said. Accessing samples in Sadovnick’s database, he and his colleagues conducted a more extensive sequencing than in the past to identify all the mutations contained within patient genomes. Next, they compared the results to the DNA sequences of samples taken from healthy family members and the general population.

In just two families, Vilarino-Guell and his colleagues isolated a key mutation responsible for significant damage.

“In these two families, 70 percent of the people who presented the mutation developed MS,” he explained.

Only one in 1,000 MS patients has this mutation, the scientists believe, and it appears to lead to the rapidly progressive form of the disease. Eventually, this discovery might reveal the biological pathway of MS and provide insight into the more common form of MS, known as “relapsing-remitting MS.”

“We’ve never been able to find a gene change that is specific to the cause of MS,” said Sadovnick.

While the research team hopes their work will pave the way to new therapies — some that might prevent development of disease — they know at the very least their work will help doctors screen for the mutation in high-risk people, which would enable earlier diagnosis and treatment before symptoms appear.

Source: Wang Z, Sadovnick AD, Traboulsee AL, et al. Nuclear Receptor NR1H3 in Familial Multiple Sclerosis. Neuron. 2016.