Sonia Gobeil can trace her ancestors to the pioneers who first settled the isolated Saguenay region northeast of Quebec City, but she had never heard of the devastating brain disease they passed on through their genes until her son was diagnosed with it.
The disease, an inherited form of ataxia, affects the part of the brain that co-ordinates movement. It can skip generations and miss entire branches of family trees, only to pop up according to the laws of genetics and chance, leaving most patients in a wheelchair by the time they are 40. It is more common in the Saguenay and Charlevoix regions of Quebec than anywhere else in the world.
The history of the disease there begins with a small population of immigrants from France who first settled the Charlevoix region in the 17th century. Researchers suspect that several of those people carried a copy of a rare genetic mutation that on its own is benign, but can wreak havoc in the brains of those unlucky enough to inherit two copies – one from each parent.
The population grew and, 100 years later, the migrants pushed the government to open the territory around the Saguenay River for settlement. There, they carved out a society in the forested wilderness, largely cut off from the rest of the province and generating their own distinctive genetic map. For generations, families were large – 11 children a household on average in the early 1900s – and marriages outside the Catholic faith were discouraged by the church. The Saguenay also got few newcomers. The first passable road to Quebec City, 200 kilometres away, was opened in 1951.
Today, the Saguenay remains strikingly homogeneous: 98 per cent of its 273,000 residents are francophone Quebeckers, and immigrants make up less than 1 per cent of the population.
The remoteness has produced a form of proud self-reliance, a trait that’s now being put to the service of probing the region’s genetic history and dealing with its legacy. In addition to autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), which Ms. Gobeil’s two sons have, three other genetic diseases are much more common in the region than elsewhere in the world. One causes a buildup of lactic acid in blood and can be deadly; another is an enzyme deficiency that can lead to liver and kidney failure. The third causes a birth defect in which the structure that connects the two hemispheres of the brain is missing or only partially formed. Since 2010, couples have had access to free genetic screening. About 1,800 people have been screened so far for the diseases, which affect one in five in the region. A local group goes into elementary and high schools to teach children about hereditary diseases, using simple devices like beaded necklaces to explain DNA and genetics.
Ms. Gobeil’s first born, François, was three when his pre-school teachers noticed that his gait was awkward when he ran. She and husband Jean Groleau didn’t think the problem was serious. They were shocked when doctors diagnosed the boy, now nine, with ARSACS. Their second son, Laurent, who is now six, also has the disease. François can’t skate or play hockey, which he loves. Both boys have a stiff left leg.
After François was diagnosed, the couple learned there was no treatment and no research under way to find one.
“Knowing there was no research being done was like a punch in the stomach. But at the same time, we saw it as an open door.” The condition is hereditary; we can’t change that they have it. But with research, we can do something about it and try to change the path of the future,” said Ms. Gobeil, a lawyer in Montreal.
She and her husband, also a lawyer, set up a foundation, which so far has raised $3-million, and brought together a high-powered team of scientists. That team recently discovered ARSACS may be related to much more common brain disorders, particularly Parkinson’s disease, which puts it at the centre of a promising new avenue of research.
The scientists are also poised to begin screening drugs to see which ones might be effective against ARSACS, which was discovered in the late 1970s and damages the cerebellum, the part of the brain that co-ordinates the movements of muscles. This results in an unsteady gait that gets worse as patients age, as well as muscle wasting and speech impairments.
Bernard Brais, the scientist co-ordinating research for the Ataxia of Charlevoix-Saguenay Foundation, is from the Saguenay. After he and Ms. Gobeil started working together, they discovered they are distantly related.
“I could have children with this disease,” said Dr. Brais, who also works at the Montreal Neurological Institute and Hospital. “Rare diseases in Quebec, in particular, are familial things. If we don’t take care of it, who will?”
Three hundred Quebeckers have the disease. In the Saguenay, one in 22 people carry one copy of the genetic mutation.
Denis Girard, a 32-year-old who lives in the rural community of Saint-Ambroise in the Saguenay-Lac St. Jean region, showed signs of ARSACS at an early age. As a toddler, he stumbled. His legs stiffened as he got older. By his early 20s, he was using a cane. Now, he is often mistaken for a drunk.
“I’m like the Leaning Tower of Pisa,” Mr. Girard said. “I tilt forwards. It’s like I have to chase after my balance.”
When Mr. Girard reflects on his history, he sees traits replicated here and there, like leaves on a family tree that mysteriously bear the same markings. His older brother has Charlevoix-Saguenay ataxia. His father’s two cousins had it. His cousin’s 11-year-old son, Jérémie, has it too.
“When I was about eight years old, my parents told me their genes were sick, that it was nature,” he said. ”I know it’s genetics, but at the same time, the way it pops up, it’s random chance.”
Mr. Girard, who uses a walker to get around, said his disease has never stopped him from leading a full life. But he welcomes medical advancements and possible treatments.
Jérémie’s mother, Nicole Fortin, said the recent discovery offers hope. Her son struggles with his balance and with fine motor skills such as buttoning his clothes.
Ms. Fortin praised the perseverance of Mr. Groleau and Ms. Gobeil. “They were gutsy to go off the beaten path,” she said. “And it’s not just for their children. This can have repercussions for a lot of people.”
The foundation holds an annual fundraiser and the Canadian Institutes of Health Research and other organizations have also pitched in money for research. The link between ARSACS and other more common brain diseases may make it easier to attract additional funding, says Ms. Gobeil. It could also mean that her sons and other patients may benefit from research already underway on the role that the “batteries” in brain cells play in other degenerative brain diseases.
“This could help us, we hope, “ says Ms. Gobeil. The disease is also found in other parts of the world, including Western Europe, where it can be caused by different genetic mutations. Mr. Groleau, who is not from the Saguenay region, carries one of these.// The disorder is slowly progressing in the couple’s two sons. François can’t skate or play hockey, which he loves. Both boys have a stiff left leg. Their mother is helping them focus on the positive.
“We are trying to enjoy life.”
The power of mitochondria
Brain cells are more vulnerable to energy shortages than other cells, which is why many researchers now suspect that mitochondria – often described as the “power plants” of cells – play a role in a number of devastating diseases.
There is growing evidence that problems with mitochondria are related to Parkinson’s disease, a progressive, incurable neurological disorder with a wide array of symptoms including tremors, stiffness and loss of speech, says Peter McPherson, a researcher at the Montreal Neurological Institute and Hospital (MNI). Researchers are also investigating the role they play in Alzheimer’s disease, the leading cause of dementia.
Most cells in the body – like skin or bone cells – are frequently replaced, but many brain cells last a lifetime. They also are huge energy consumers, which may be why they are more vulnerable if their power plants aren’t working properly, says Bernard Brais, who co-ordinates research for the Ataxia of Charlevoix-Saguenay Foundation and also works at the MNI. In brain cells, the slender branches that connect with other cells need a lot of energy.
Mitochondria are actually like mobile power plants, breaking off from the mother ship to travel to the parts of the cell that need energy, Dr. Brais says. Some brain cells, including those in the part of the brain that co-ordinates movement, have hundreds of thousands of branches that connect with other cells and are particularly dependent on mobile mitochondria.
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