Gene mutation identified

Gene mutation identified

Maeve Haldane | Not many people may know about peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN) aka Andermann's syndrome, nor its effects, but those in the Charlevoix/Saguenay-Lac St. Jean region are all too familiar with the debilitating disease. Recent research by the team of Dr. Guy Rouleau, neurologist and McGill professor of neurology and neurosurgery, pinpoints the gene responsible for this disorder, which could lead to its eventual elimination.

ACCPN is a neurodegenerative disease that impairs mobility early in life, and leads to a shortened lifespan. It can be detected by the time children are one or two years old and their physical and mental abilities deteriorate over time. By adolescence, most patients are confined to a wheelchair, and they generally don't live past their thirties or forties.

Hundreds of these children live in Quebec's Saguenay-Lac St. Jean region, where one in 22 adults is a carrier of the defective gene. If both parents are carriers, there is a one in four chance that their child will be afflicted with ACCPN.

At an October 8 press conference at the Montreal General Hospital, PhD candidate Heidi Howard talked of how she discovered the gene through five years of research with more than 80 families. The problem lies in the development of the corpus callosum, the bridge between the two hemispheres of the brain. Those with ACCPN either don't have a corpus callosum, or it's very thin or abnormal.

Howard explained that the corpus callosum "coordinates both sides of the body. [Without it] the left hand doesn't know what the right hand is doing."

The culprit is gene KCC3, the potassium chloride cotransporter. Corpus callosum abnormalities occur if the gene's protein, which transports potassium and chloride in and out of the cell, malfunctions. No one is yet sure how that works exactly, but the gene's mutation, and hence the protein's inability to function properly, is what causes the debilitating ACCPN.

The team's suspicion was confirmed by collaboration with investigators at Vanderbilt University who produced mice with a disrupted KCC3 gene. The mice exhibited the same illness as the children with ACCPN.

"It's very difficult to replace one gene's function with another," said Rouleau. "Sadly, treatment is not immediate."

Pinpointing the disease to just one gene does not make researchers' work any easier than if many genes were responsible. "The devil is in the details," said Rouleau. "To replace the function of a gene is not easy." But possibly, researchers will figure out how to activate other genes in the nervous system to perform the same function as KCC3.

Definitely, the work will allow for the creation of a rapid, cheap diagnostic test that can be used to tell if someone carries the gene mutation. The testing will be possible on the amniocentesis of pregnant women as well. Further characterization of the gene will help in designing specifically targeted drugs.

By announcing the research findings, Rouleau is confident other doctors will "come out of the woodwork who've been looking at KCCs."

Although the Saguenay-Lac St. Jean region is the most concentrated area where this malfunctioning gene is found, two other families have been found with the gene, one Turkish, diagnosed in Germany, and one in Italy. Rouleau suspects more cases are likely to turn up in countries such as Tunisia, Somalia and Holland.

Also present at the press conference were Alain Coudé and Louise Gagné. After they discovered their twin daughters, Alexandra and Valerie, had the disease, they decided to act, rather than ask "Why me?" They started up "La Fondation des jumelles Coudé" which has been instrumental in supporting the research. At the press conference, Gagné said, "Maybe one day, the disease will be eradicated."