Genes From Middle East Families Yield Autism Clues

July 10, 2008— -- WASHINGTON (AP) - Harvard researchers have discovered half adozen new genes involved in autism that suggest the disorderstrikes in a brain that can't properly form new connections.

The findings also may help explain why intense educationprograms do help some autistic children - because certain genesthat respond to experience weren't missing, they were just stuck inthe "off" position.

"The circuits are there but you have to give it an extrapush," said Dr. Gary Goldstein of the Kennedy Krieger Institute inBaltimore, which wasn't involved in the gene hunt but is well-knownfor its autism behavioral therapy.

The genetics suggest that "what we're doing makes sense when wework with these little kids -- and work and work and work -- andsuddenly get through," he said.

But the study's bigger message is that autism is too strikinglyindividual to envision an easy gene test for it. Instead, patientsare turning out to have a wide variety, almost a custom set, ofgene defects.

"Almost every kid with autism has their own particular cause ofit," said Dr. Christopher Walsh, chief of genetics at Children'sHospital Boston, who led the research published in Friday's editionof the journal Science.

Autism spectrum disorders include a range of poorly understoodbrain conditions, from the mild Asperger's syndrome to more severeautism characterized by poor social interaction, impairedcommunication and repetitious behaviors.

It's clear that genes play a big role in autism, from studies oftwins and families with multiple affected children. But so far, thegenetic cause is known for only about 15 percent of autism cases,Walsh said.

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 cousinsto marry, characteristics that increase the odds of finding raregenes. They recruited 88 families with cousin marriages and a highincidence of autism, from Jordan, Saudi Arabia, Kuwait, Oman,Pakistan, Qatar, Turkey and the United Arab Emirates. They comparedthe DNA of family members to search for what are called recessivemutations -- where mom and dad can be healthy carriers of a genedefect but a child who inherits that defect from both parents getssick.

In some of the families, they found large chunks of missing DNAregions that followed that recessive rule. The missing regionsvaried among families, but they affected at least six genes thatplay a role in autism.

Here's why this matters: All the genes seem to be part of anetwork involved in a basic foundation of learning -- how neuronsrespond to new experiences by forming connections between eachother, 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 beingshaped by its first experiences so that it is structurally able toperform learning and other functions of later life.

"This paper points to problems specifically in the way thatexperience sculpts the developing brain," explained Dr. ThomasInsel, director of the National Institute of Mental Health, whichhelped fund the work.

Some earlier research had pointed to the same underlyingproblem, so these newly found genes "join a growing list tosuggest that autism is a synaptic disorder," he said.

If that sounds discouraging, here's the good news: The missingDNA didn't always translate into missing genes. Instead whatusually was missing were the on/off switches for theseautism-related genes. Essentially, some genes were asleep insteadof doing their synapse work.

"I find that hopeful" because "there are ways that are beingdiscovered to activate genes," Walsh said. "This might be anunanticipated way of developing therapies in the long term forautism: Identifying these kids where all the right genes arepresent, just not turned on in the right way."

At Kennedy Krieger, Goldstein thinks the work may provide agene-level explanation for why some children already are helped byintense therapy.

"We have trouble getting through to these children, but withrepeated stimulation we can do it," he said. "These are circuitsthat have an ability not so much to recover but to work around theproblem."

(Copyright 2008 by The Associated Press. All Rights Reserved.)