CANADIAN BREAKTHROUGH OFFERS HOPE ON AUTISM
Project makes possible DNA test to identify children most likely at risk to condition
CAROLYN ABRAHAM
From Monday's Globe and Mail 19th Feb 2007
A massive international effort led by Canadian scientists has homed in on the genes behind autism - a breakthrough that could revolutionize how the mysterious and surprisingly common condition is both detected and treated. Touting it as the most significant advance in the field in 30 years, researchers say the landmark project has put within reach a DNA test to identify children with autism early enough to counter the condition's worst effects.
"I don't think it's inconceivable that we're going to be able to prevent autism down the road," said study leader Peter Szatmari, director of the Offord Centre for Child Studies at McMaster Children's Hospital in Hamilton. "The clinical implications of this discovery are unprecedented." Doctors currently rely on psychological tests to diagnose autism spectrum disorders in children at age 2 or 3. But a DNA test could identify those affected as babies, or perhaps even before they are born.
Dr. Stephen Scherer and Dr. Peter Szatmari led an international project to discover the genetic architecture underlying autism susceptibility.
The findings, based on the largest autism DNA collection ever assembled, could also allow parents who have children with autism to learn through genetic screening their chances of having another affected child. "If you know ahead [of time] of your predisposition to autism, you can make an informed decision," said Marie Jolicoeur, a Burlington, Ont., mother who has two sons with autism disorders and whose family contributed DNA to the project.
Using new genome scanning tools, researchers have found that several different autism-related genes can play a role in different families. This helps to explain why no two children - not even identical twins - have identical symptoms.
The researchers have pinpointed at least five areas of the genome that harbour genes linked to autism susceptibility, including those crucial for brain function. They have also found a genetic mutation tied to the disorder in girls - who are four times less likely than boys to develop autism disorders.
The work has also highlighted how autism can spring from genetic quirks not seen in either parent - suggesting that a genetic glitch has randomly emerged in the sperm or egg cells of the father or mother prior to conception.
Co-author Steve Scherer, senior scientist of genetics and genomic biology at Toronto's Hospital for Sick Children, said, "It may be that 5 to 10 per cent of autism cases are arising from these de novo [new] mutations." The research, released yesterday in an advance online publication of the journal Nature Genetics, is the first part of a two-phase study run by the Autism Genome Project. It involves more than 137 researchers from 50 academic institutions in eight countries and the study of nearly 8,000 people from 1,600 families who have at least two members diagnosed with an ASD.
Dr. Szatmari, who set the ground rules for the unprecedented collaboration that began in 2002, said "the effort has meant the putting aside of individual ambitions to work together as a team."
Autism disorders have only recently been recognized as the most common serious developmental condition of childhood, affecting roughly one in 165 children. Experts refer to it as a spectrum because the complex neurological condition can range so widely in severity.
Some suffer severe cognitive impairment, others are savants. Many battle gastrointestinal problems and show a strong preference for strict routines and repetitive behaviours. But social deficits are its hallmark, impaired language, communication and the ability to interact with others. Once considered rare, autism disorders seem to have risen dramatically over the last two decades. But Dr. Szatmari said many experts believe the increase can largely be explained by greater awareness, different diagnostic criteria and the specialized resources often made available to those with an ASD compared with another form of developmental condition.
Despite the growing awareness, autism's causes have stumped experts. Many suspect environmental triggers - prenatal hormones, toxins, food allergies and infections. But experts have long known genes play a major role. Autism disorders tend to run in families; if one identical twin has an ASD, there is a 65- to 92-per-cent chance the other will also develop the disorder. Doctors also see subtle forms of autism in parents that may not have been diagnosed.
"Still, for 99 per cent of autism cases, we don't know the underlying genes," Dr. Scherer said. But with onetime scientific competitors sharing their families, researchers say they had enough statistical power to make connections. They also had the technology to run genome-wide scans and detect a type of genetic mutation only recently discovered.
These mutations, known as copy number variations, or CNVs, involve vast stretches of genetic code that are misplaced, repeated or deleted. Late last year, Dr. Scherer and other colleagues reported that these quirks were far more common in the general population than expected - that people can carry extra copies of genes or be missing them completely and still be healthy.
But in this study, the scientists found certain CNVs were linked to autism - particularly if it was not seen in either parent or 500 DNA control samples and if it encompassed a genome region believed to be involved in brain function.
"These CNVs arise randomly all the time," Dr. Scherer said, "but sometimes, [depending on where they arise] they result in ASD." Among the key findings is the involvement of a gene called Neurexin1, which researchers believe has an impact on how neurons communicate with each other. They have also found a suspicious region of Chromosome 11 that houses genes involved in the brain chemical glutamate, an important neurotransmitter.
"Nobody knew glutamate was involved in autism," Dr. Szatmari said. But it is known to be involved in epilepsy, he said, "and 20 per cent of children with autism also have epilepsy. "All these straggly little threads are beginning to tie together into a string."
The second phase of the project, is to map the specific genes that contribute to autism.
But in uncovering "the genetic architecture" in the first phase, Dr. Scherer said autism seems much like cancer, a condition with many faces, arising from many different types of genetic mutations.
"We have to be careful," he said, "not to overinterpret the results."
Genetic counsellors at Sick Kids Hospital are already preparing for questions from parents, many of whom heard the study results at a meeting last November.
Generally, parents with one affected child are told they have a 5- to 10-per-cent chance of having another child with an ASD.
But Ms. Shuman said that's a general estimate based on population averages, and for some parents the chances could be much higher or lower.
For Ms. Jolicoeur, it is too late to consider how she and her husband, Craig Marshall, would use the information, having already had their three children, two of whom have autism. Her eldest son, Eric, 18, who read the National Geographic with his father at the age of 3, was diagnosed at age 7 with Asperger syndrome, a high-functioning form of autism, usually characterized by normal intelligence, obsessive interests in particular subjects and striking talents. But Eric's diagnosis came only after his brother Luc, 14, was diagnosed at 3 with pervasive developmental disorder, a more severe form of autism.
Still, Ms. Jolicoeur believes the discoveries, and those ahead, will be important for her youngest son, Marc, 12, who does not have a spectrum disorder and was born before Luc and Eric were diagnosed. "Marc has already said he doesn't think he would have children," she said. "But then he says, 'No, I think I would maybe have one.'"
People often ask her how she and her husband cope. "I tell them life is chaotic, busy, but it's all we have ever known," Ms. Jolicoeur said. "It is also loud and fun."
Her family has been part of Dr. Szatmari's research for more than 10 years. Ms. Jolicoeur understands that talk of screening for autism traits is controversial, since those at the mild end of the spectrum, and their advocates, see their unusual personality traits as characteristics society should accept.
But she said "it is valid" for people to have all the information they can to make their own decisions. "I didn't sign up to raise children with special needs," she said, "but they are your kids, and you love them unconditionally."