Researchers at Montreal hospitals were in the forefront of an international team that recently announced a breakthrough discovery in understanding some forms of leukodystrophy, a debilitating and ultimately fatal neurodegenerative disease that appears in childhood. Their research found that a mutated gene was responsible for causing three forms of the disease. Pediatricians are hailing the findings as a significant step that could lead to developing new diagnostic tests and improved genetic counselling.
The discovery of the specific gene is especially important because traditional diagnoses fail to reveal the disease in a large number of affected children—between 30 and 40 per cent, according to estimates. In part, this is because the symptoms of each form of leukodystrophy evolve at their own rate. Typically, affected children appear normal at birth, but within two years they develop tremors. They then have trouble walking, breathing and swallowing. By their teens, they are either bedridden or must rely on wheelchairs. Life expectancy is less than 30 years. No cure or treatments exist.
The various forms of leukodystrophy are genetically inherited. Problems surface when the disease begins to affect the brain’s white matter. White matter is the covering that protects axons, the strands that connect nerve cells and allow impulses to be transmitted throughout the body’s nervous system. Neurodegenerative symptoms arise if the impulses are disrupted or misguided.
Pinpointing a specific leukodystrophy gene mutation was made possible by an international team of scientists and spearheaded by two Montreal researchers: Dr. Bernard Brais, formerly of the Centre hospitalier de l’Université de Montréal research centre, who is now a clinician-scientist at the Montreal Neurological Institute and Hospital at McGill University and the McGill University Health Centre (MUHC); and Dr. Genevieve-Bernard who is a clinician-researcher at the Montreal Children’s Hospital at the MUHC. Both scientists are also affiliated with the MUHC Research Institute.
The genetic mutation was discovered in the POLR3A gene. Researchers found that mutations in that gene localized on chromosome 10 led to three forms of leukodystrophy. The first form to be discovered, Tremor-Ataxia with Central Hypomyelination (TACH), was found to be more prevalent among families inQuebec. The other two forms are Leukodystrophy with Oligodontia (LO); and Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism syndrome (4H syndrome). The mutated gene was also found in patients in several European countries as well as in theUSA,Syria, andGuatemala.
POLR3A is closely affiliated with a protein complex called RNA Polymerase III (Pol III), which plays an important role in gene expression. The complex had been studied for a few decades but not until now has its role in leukodystrophy been suspected.
“If we can identify which targets of Pol III, when decreased, lead to the disease, we could develop therapeutic strategies to replace them,” explains Dr. Brais, a neurologist who specializes in research on rare genetic diseases among French Canadians.
Several funding agencies contributed to the team’s research, including the Association Europeene contre les leucodystrophies, the Reseau de medicine genetique appliquée du Quebec, the Fonds de recherché en santé du Quebec, and the Fondation sur les leucodystrophies.
The Fondation sur les leucodystrophies was set up by aQuebeccouple, Marjolaine Verville and Eric Tailleur. Their son, Alexis, has an unknown form of the disease. Now twelve years old, he shows advanced symptoms and is in a wheelchair.
Dismayed that there were no treatments available for leukodystrophy and that little research was being carried out into the source of the disease, the couple created their own foundation in 2006 in the hope that research could help not only their son but others as well. Their foundation notes that siblings of a child with leukodystrophy have a one-in-four chance of having the disease as well.
Three years ago, the couple met Dr. Brais, who at the time was close to discovering the specific gene mutation but had not yet identified it. Spurred on by the couple’s foundation, he found the gene mutation in 20 patients nearQuebec City. Dr. Brais and Dr. Bernard then organized the international team that began looking at similar cases around the world.
The Fondation sur les leucodystrophies is hoping to raise enough money to continue funding Dr. Brais’ research for the next three years.The international team’s research was published in the September issue of the American Journal of Human Genetics.