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Mental Activity May Affect Autism-Linked Genes
Study Suggests That Altering Ill Children's Experiences Could Change
the Disease

By David Brown
Washington Post Staff Writer
Friday, July 11, 2008; A02

New research suggests that some cases of autism arise from defects in
genes that can be turned on or off by mental activity, a finding that
sheds light on the devastating condition and might eventually lead to
strategies to treat it.

The findings are drawn from gene scans of about 100 Middle Eastern
families in which autism is unusually common. The disorder is marked
by social isolation, speech problems and strange, repetitive
activities.

The study, done by a large international team and reported today in
the journal Science, adds to the growing evidence that autism may
result from problems in the immensely complicated process by which
some networks of brain cells expand and many others die in the first
few years after birth.

The fact that three of the half-dozen genes identified in the new
report are regulated by "neuronal activity" -- feeling, thinking,
doing -- suggests in theory that changing the experiences of autistic
children could change the course of the disease.

"The genes implicated in our study are ones that interact with the
environment and are involved in how the brain converts what it sees
from the environment," said Christopher A. Walsh, a neurologist and
chief of genetics at Children's Hospital in Boston who headed the
team. "If we can activate those genes by other mechanisms, we might be
able to help the kids."

Other researchers agreed that the discovery that some "autism genes"
are also "experience genes" is provocative and, at some level,
hopeful.

"If that is a general mechanism, then the other genes that have been
identified as associated with autism should be expected to be driven
by activity, as well. But we don't know that yet," said Daniel H.
Geschwind, who is co-director of the Center for Autism Research and
Treatment at the University of California at Los Angeles.

The study demonstrates that "environmental experiences and influences
that shape postnatal brain development are not irrelevant," said
Isabelle Rapin, a pediatric neurologist at the Albert Einstein College
of Medicine in New York. She added, however, that "we have but the
most primitive ideas about what the proteins coded by identified
missing or mutated genes do."

Autism is one of the more urgent health problems of the 21st century
-- and one of the more mystifying. A study by the Centers for Disease
Control and Prevention last year reported that 1 in every 150 American
children has an "autism spectrum disorder," which includes conditions
from the severe and disabling to the mild and often-overlooked.

Some states have experienced huge increases. In California, the number
of children getting services for autism tripled from 1987 to 1998 and
then doubled between 1998 and 2002. In Minnesota, diagnosed autism
increased from two cases per 1,000 schoolchildren in 1998 to 6.6 cases
per 1,000 in 2002.

In most cases, the problems are apparent by age 3. In many, a normally
developing child suddenly regresses, stops talking and becomes
interested in only a few highly stereotyped activities.

Studies have suggested that genes probably contribute about 70 percent
to a child's risk of developing autism. Whether environmental
exposures or life events can trigger the disease is unknown. Numerous
studies have found that childhood vaccinations, and a mercury-
containing preservative that vaccines once contained, almost certainly
do not play a role.

The new study, led by Walsh and Eric M. Morrow, a psychiatrist at
Harvard Medical School, studied 104 families from the Arab Middle
East, Turkey and Pakistan. In 88, the parents were cousins. The
average family had two autistic children. One Kuwaiti and one
Pakistani family, however, each had four.

Marriage between first cousins doubles the risk of neurological birth
defects. The researchers said they think that shared ancestry would
increase the risk of autism caused by recessive mutations that cause
problems only when a child inherits the defective gene from both
parents. By studying cases caused by such rare events, researchers can
often learn about the biochemical and genetic underpinnings of the far
more common cases in which there is no inbreeding.

The researchers found six genes with mutations or missing pieces.
Three had been identified by Michael E. Greenberg, a Harvard
neurobiologist, as members of a group of genes that are regulated --
turned up or down -- by the activity of the cells containing them and
of the nerve networks those cells inhabit. Furthermore, two of the six
genes are known to be involved in the growth of axons, the tendrils
that nerve cells send out to contact other cells.

Many brain cell connections are prenatal, hard-wired and do not depend
on experience. The new findings suggest that autism may involve
problems that occur later, when nerve networks branch out and make
solid connections, or loosen and are pruned back, a process essential
to learning.

"Autism is a disorder of social learning for sure," Morrow said.

If there is a connection between the genes' activity and that of brain
cells responding to experience, then it may be possible to stimulate
the cells in a way that wakes up or gets around the defective genes.

The researchers looked for one of the gene defects in autistic
children whose parents were not related and found it, but it remains
unclear how applicable this study is to garden-variety autism.

Many of the Middle Eastern children had other neurological problems,
such as epilepsy. Whether the activity-driven gene defects are also
present when autism occurs by itself is unknown.

© 2008 The Washington Post Company
http://www.washingtonpost.com/wp-dyn/content/article/2008/07/10/AR2008071002750.html?hpid=sec-health