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Gene sweep yields half a dozen autism culprits

Variety of mutations keep brain from forming proper connections

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_Study uncovers new genetic link to autism_

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July 10: Harvard researchers have uncovered at least six new genes that can

increase the risk for autism, providing hope that doctors can identify

at-risk children earlier. NBC’s Bazell reports.

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updated 7:23 p.m. ET, Thurs., July. 10, 2008

WASHINGTON - Harvard researchers have discovered half a dozen new genes

involved in autism that suggest the disorder strikes in a brain that can't

properly form new connections.

The findings also may help explain why intense education programs do help

some autistic children — because certain genes that respond to experience

weren't missing, they were just stuck in the " off " position.

" The circuits are there but you have to give it an extra push, " said Dr.

Goldstein of the Kennedy Krieger Institute in Baltimore, which wasn't

involved in the gene hunt but is well-known for its autism behavioral therapy.

The genetics suggest that " what we're doing makes sense when we work with

these little kids — and work and work and work — and suddenly get through, "

he

said.

But the study's bigger message is that autism is too strikingly individual

to envision an easy gene test for it. Instead, patients are turning out to

have a wide variety, almost a custom set, of gene defects.

" Almost every kid with autism has their own particular cause of it, " said

Dr. Walsh, chief of genetics at Children's Hospital Boston, who led

the research published in Friday's edition of the journal Science.

Autism spectrum disorders include a range of poorly understood brain

conditions, from the mild Asperger's syndrome to more severe autism

characterized by

poor social interaction, impaired communication and repetitious behaviors.

It's clear that genes play a big role in autism, from studies of twins and

families with multiple affected children. But so far, the genetic cause is

known for only about 15 percent of autism cases, Walsh said.

Large chunks of missing DNA

So Walsh's team took a new tack. They turned to the Middle East, a part of

the world with large families and a tendency for cousins to marry,

characteristics that increase the odds of finding rare genes. They recruited 88

families

with cousin marriages and a high incidence of autism, from Jordan, Saudi

Arabia, Kuwait, Oman, Pakistan, Qatar, Turkey and the United Arab Emirates.

They

compared the DNA of family members to search for what are called recessive

mutations — where mom and dad can be healthy carriers of a gene defect but a

child who inherits that defect from both parents gets sick.

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In some of the families, they found large chunks of missing DNA regions that

followed that recessive rule. The missing regions varied among families, but

they affected at least six genes that play a role in autism.

Here's why this matters: All the genes seem to be part of a network involved

in a basic foundation of learning — how neurons respond to new experiences

by forming connections between each other, called synapses.

In the first year or two of life — when autism symptoms appear — synapses

rapidly form and mature, and unnecessary ones are " pruned " back. In other

words, a baby's brain is literally being shaped by its first experiences so

that

it is structurally able to perform learning and other functions of later

life.

Troubles sculpting the brain

" This paper points to problems specifically in the way that experience

sculpts the developing brain, " explained Dr. Insel, director of the

National Institute of Mental Health, which helped fund the work.

Some earlier research had pointed to the same underlying problem, so these

newly found genes " join a growing list to suggest that autism is a synaptic

disorder, " he said.

If that sounds discouraging, here's the good news: The missing DNA didn't

always translate into missing genes. Instead what usually was missing were the

on/off switches for these autism-related genes. Essentially, some genes were

asleep instead of doing their synapse work.

" I find that hopeful " because " there are ways that are being discovered to

activate genes, " Walsh said. " This might be an unanticipated way of developing

therapies in the long term for autism: Identifying these kids where all the

right genes are present, just not turned on in the right way. "

At Kennedy Krieger, Goldstein thinks the work may provide a gene-level

explanation for why some children already are helped by intense therapy.

" We have trouble getting through to these children, but with repeated

stimulation we can do it, " he said. " These are circuits that have an ability

not so

much to recover but to work around the problem.

" Ms. Michele "

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