http://www.montrealgazette.com/technology/Parental+persistence+finally+pays/
5417551/story.html




Parental persistence finally pays off
 
 
 

Grim diagnosis stirred couple to action and now a Montreal-led team of
doctors has found the gene behind their son's condition
 
 
 
By CHARLIE FIDELMAN, The Gazette September 17, 2011 
After he was diagnosed with a rare, baffling and grim genetic disorder, his
parents refused to accept that nothing could be done to save their boy - and
others like him.
 
There was no cure, no remedy, and no one was looking for one. So Marjolaine
Verville and Eric Tailleur of Quebec established a foundation to hasten a
cure.
 
This week, their efforts paid off with a breakthrough discovery.
 
Dr. Bernard Brais, lead investigator of a Montrealled international team of
researchers, identified the gene responsible for the mutation behind three
forms of childhood degenerative diseases.
 
Published in the September issue of the American Journal of Human Genetics,
the findings are crucial to the development of diagnostic tests, genetic
counselling for families, and new avenues of therapy.
 
"It's the first step," Verville told The Gazette, happy that families in
Quebec "and all over the world can finally have a diagnosis."
 
Five years ago, Alexis, now 12, became the poster boy for a group of
neurodegenerative inherited diseases called leukodystrophies. Scientists had
dubbed this disorder the "white matter disease" - leuko means white in Greek
- because of the abnormal amount of white substance visible in brain images
of affected individuals.
 
Leukodystrophies are caused by a dysfunction of the myelin sheath, the fatty
covering that acts as an insulator around nerve fibres in the brain that
transmit nerve impulses. Different types of mutations in this gene have now
been identified in individuals in various countries but one mutation occurs
more frequently in Quebec.
 
It has a bleak outcome. Babies who look normal at birth develop tremors and
walking difficulties as toddlers, followed by a steady decline in mobility
functions, swallowing and breathing.
 
The disease evolution varies but many need wheelchairs or are bedridden by
the time they reach their teens. Few survive into their 30s.
 
"You feel very far and isolated when your doctor doesn't know what you
have," Verville said, adding that the rate of this orphan disease, as rare
disorders are called, is estimated at about one child in 5,000.
 
Three years ago, after seeking help from one specialist after another,
Alexis's parents met Brais, a neurologist and genetic specialist, then with
the Université de Montréal, whose expertise is in genetic mutations in rare,
orphan diseases in descendants of French Canadians.
 
Brais was not aware of the couple's foundation, Verville said. "We met by
chance," Verville recalled. "He told me that he was convinced that he had
localized (but not identified) the defective gene."
 
The couple went home to think about their next step and decided to invest
"in a train that was already en route somewhere," she said.
 
"We knew he was on the right road."
 
Alexis's parents asked Brais to find the defective gene responsible for his
illness. "Look, there's no research being done on our child and we know of
others in Quebec who have this, and this is unacceptable," Brais recalled.
 
An estimated 30 to 40 per cent of individuals remain without a precise
diagnosis despite extensive investigations, explained Brais, now affiliated
with the Montreal Neurological Institute and Hospital.
 

After finding a small cluster of 20 patients in the Bellechasse area near
Quebec City with mutations in the POLR3A gene, Brais contacted researchers
working on similar cases around the world and screened for mutations in the
same gene in patients in the U.S., Syria, Guatemala, France and other
European countries.
 
The international team led by Brais and Geneviève Bernard at the Montreal
Children's Hospital found that the gene mutation on chromosome 10 is
responsible for these forms of leukodystrophies: Tremor-Ataxia with Central
Hypomyelination (TACH) first described in Quebec cases, Leukodystrophy with
Oligodontia (LO), and 4H syndrome or Hypomyelination, Hypodontia and
Hypogonadotropic Hypogonadism syndrome.
 
The discovery came as a surprise, Brais said.
 
"The POLR3A gene is well known because it codes for a protein that's part of
an important complex (in human development) that's been studied for 40
years," Brais said. "No one saw it."
 
Now the pressure is on to move from diagnosis to treatment, Brais said:
"That's the time race we are in because every day these children are getting
worse."
 
"It's a significant discovery," said Dr. Michael Shevell, head of pediatric
neurology at the Montreal Children's Hospital, who did not participate in
the study.
 
What's remarkable is that the team moved so quickly on a gene that was
described only last year, Shevell said.
 
The study brings fresh insight into underlying causes of three types of
leukodystrophies, and may expand scientific knowledge to other forms, he
added.
 
Alexis's parents say they cannot bring themselves to hope because they fear
disappointment. Alexis is now in a wheelchair.
 
"We know his disease is very advanced," Verville said. "But whatever
happens, it's worth it.
 
"We know that one day children will be cured of this disease."
 
The research was funded with a $300,000 grant from Leukodystrophies
Foundation (leucofondation.com/ index-next.html) with support from
l'Association Européenne contre les Leucodystrophies, the Réseau de médicine
génétique appliquée du Québec (RMGA) and the Fonds de recherche en santé du
Québec (FRSQ).
 
cfidelman@ montrealgazette.com
 
© Copyright (c) The Montreal Gazette
 
 
 
 


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