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Registered: 08/06/03
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X-factor may explain the riddle of autism
(The Times/ by MARK HENDERSON)
A CLUSTER of genes that could hold the key to autism has been discovered by British scientists, in a study that promises to transform understanding of the condition.
Research has identified a small fraction of the human genetic code that affects a part of the brain heavily implicated in autism. When these crucial genes go wrong, the brain struggles to cope with normal social interactions.
The findings, from the Institute of Child Health in London, offer the best explanation for why men are ten times more vulnerable to autism than women. The critical genes are found on the X chromosome, of which women have two copies but men only one, and scientists think this could be vital to the disorder’s gender profile.
David Skuse, who led the study, told the conference in Salford: “It opens a new line of research in autism. We now have evidence of a possible neural mechanism that makes autism possible.”
Once the identity of the genes has been traced more accurately, the discovery could have important implications for diagnosing and treating the condition, which is thought to affect up to 500,000 people in Britain.
It could improve early diagnosis of autism spectrum disorders, so that treatment and special education can begin sooner than at present, and might allow the development of drugs that prompt the brain to develop more normally.
Experts gave warning, however, that even if the link is confirmed, these genes are probably only some of many that make people vulnerable to autism, and that environmental factors could also be involved. The prospect of an accurate genetic test, which might be available prenatally, remains a long way off.
While scientists have long known that the causes of autism are usually genetic, the individual genes or clusters of genes that are responsible have remained elusive. The institute’s research has identified a key area of the X chromosome that, when damaged, has strong links to the condition.
In a study conducted with Eric Lander, of the Massachusetts Institute of Technology, Professor Skuse focused on genes that are essential to the development of the amygdala, the part of the brain that processes fear. This is known to be abnormal in autistic patients.
The scientists found similar abnormalities in women who were missing a section of one X chromosome. In particular, they have great trouble recognising fear or threat in another person’s face. They see threat in any eye contact, and avoid social contact as a result. That process appears to afflict autistic patients, only more acutely.
Professor Skuse said that the cluster of genes on the missing patch of X seem to be crucial to the healthy development of the amygdala. “We have shown that normal development of this brain structure is dependent on one or more genes in a small region of the X chromosome,” he said.
Differences in the way that these genes are switched on in men and women could explain why men are more vulnerable to autism. In women, the presence of two X chromosomes seems to provide a greater “dose” of the active proteins that tell the amygdala to develop normally.
Men, however, with only one X chromosome, are thus much more susceptible to any abnormality. “I think it’s pretty convincing evidence to us that an X-linked gene has a role to play in the development of those circuits that are anomalous in autism,” Professor Skuse said. “Why are males ten times more vulnerable to autism than girls?”
Further evidence for the involvement of these X-linked genes comes from women with Turner’s syndrome, a rare disorder in which they inherit one rather than two X chromosomes. Autism is 200 times more common among these women: about 5 per cent have autism, and up to 30 per cent have some autistic traits.
Many other inherited disorders that are more common in men than in women, such as Duchenne muscular dystrophy, have been linked conclusively to genetic defects on the X chromosome. When the vital X-linked gene is damaged in a woman, she has a back-up X chromosome that keeps her healthy. Men, who lack this fail-safe mechanism, develop the disease.
Professor Skuse said that men’s greater susceptibility to autism was the best clue to its genetic origins. “Autism is overwhelmingly a condition of boys,” he said. “When intelligence is in the normal range, the ratio can be as high as ten boys to one girl. This male predominance has been found in every study of autism, yet remarkably little research has been done on why males are so vulnerable. The answer must lie in the sex chromosomes.”
More research will be needed to identify exactly which genes carry a predisposition to autism and how they work.
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