Rare Genetic Mutation May Explain Some Forms Of Multiple Sclerosis

Rare Genetic Mutation May Explain Some Forms Of Multiple Sclerosis

Canadian scientists have uncovered a single genetic mutation that significantly heightens a person’s chance of developing a progressive and severe form of multiple sclerosis. While no single factor is responsible for causing the neurological disease, the discovery points to possible treatment options.

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A new paper published in the science journal Neuron shows that a mutation in a single gene — designated HR1H3 — is an important causal factor for the progressive form of multiple sclerosis (MS). Alterations to this gene, which regulates inflammation and immunity, were detected in seven individuals from two unrelated Canadian families, all of whom displayed symptoms of rapidly progressive MS. Because this gene is now associated with elevated risk for the disease, scientists are hopeful the discovery could lead to new treatment options.

Scientists aren’t entirely sure what causes MS, but it likely arises from a combination of genetic and environmental factors. This autoimmune disorder, which affects about 2.5 million people globally, causes damage to the brain and spinal cord, disrupting the ability of the nervous system to communicate. Signs and symptoms vary and depend on the amount of nerve damage and the nerves affected. Some people with severe MS have lost the ability to walk independently or at all. There is no cure for MS, though treatments exists to manage symptoms and help speed recovery from attacks (called remissions).

Most people with the condition have what’s called relapse-remitting MS, where patients experience long periods of remission without any new symptoms. Eventually, most people with this form of the disease will move on to a secondary progressive phase of MS in which symptoms begin a steady march and become increasingly severe. In primary progressive MS, there is no relapse-remitting phase, and the disease gradually gets worse over time; there are no well-defined attacks, and there’s little or no recovery. This form of the disease — which is the focus of the new research — affects about 10 per cent of all patients with MS.

Rare Genetic Mutation May Explain Some Forms Of Multiple Sclerosis

The family trees of the two families with the MS-causing mutation. “M” signifies individuals with the mutation; black circles represent individuals with MS and age of disease onset; grey circles or squares denote individuals with the mutation whose health is unknown. (image credit: Carles Vilarino-Guell/University of British Columbia)

The suggestion that genetics may have something to do with MS has only recently been taken seriously. The new study, led by Carles Vilarino-Guell and Anthony Traboulsee from the University of British Columbia and Vancouver Coastal Health is bolstering the suggestion that some forms of MS are partly inherited. In the two families studied, two-thirds of the patients with the mutation developed the progressive form of the disease. It’s the first time that scientists have isolated a genetic mutation that has a strong and direct influence on the origin of MS.

“This mutation puts these people at the edge of a cliff, but something still has to give them the push to set the disease process in motion,” noted Vilarino-Guell in a statement. That something is still not known, but the discovery of this mutation shows that a genetic pathway exists — one that leads to the rapidly progressive form of the disease.

The mutation in NR1H3 and its association with primary progressive MS may have something to do with this gene’s role in controlling inflammation, innate immunity (the part of our immune system that prevents infection from foreign organisms) and lipid regulation (the ability of the body to metabolise naturally occurring molecules, such as fats and vitamins). These are all considered important factors for the disease.

“The authors have identified one contributing factor, but I wouldn’t say they found a cause,” cautioned Michael Demetriou from the University of California, Irvine, who wasn’t involved in the study. Other contributors to MS include environmental factors such as age, gender, infectious diseases and geography. Some evidence even suggests that Vitamin D and smoking plays an important role. Demetriou also pointed out that this mutation isn’t 100 per cent predictive, nor does it apply to the vast majority of MS cases (this mutation is found in only one out of every 1000 MS patients). Regardless, Demetriou says it’s an important and interesting finding that’s relevant to the MS community at large.

“The study does suggest that targeting this signalling pathway may be an excellent strategy for treating progressive multiple sclerosis,” he said. “As we currently don’t have any drug therapies for progressive MS, this would be a very big deal. There are some treatments in the pipeline but this represents a potentially new therapy for progressive MS. Drug treatments may be many years away but this study suggests that targeting this pathway may have some benefit.”

It’s also important to point out that this study — which only involved two families — tapped into an excruciatingly small sample pool. In future, larger studies involving more families and more people will be required to validate these results and to identify other genetic mutations and causal factors.

Lastly, this research could offer clues about the more common relapsing-remitting form of the disease, while also pointing to the possibility of using personalised medicine to treat MS. As Michelle Apperson from the University of California, Davis, pointed out, “In the future, we may be able to look at a patient’s genetic profile or other biomarkers and choose a medication that best fits that individual.”


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