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Duke Study Finds Link Between Patients with Autistic Disorder and Patients with Rett Syndrome Mutations

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Duke Health News 919-660-1306

DURHAM, N.C. – A new genetic study, conducted by Duke
University Medical Center researchers, has shown that two
similar neurodevelopmental disorders – Rett disorder (RD) and
autism – once considered to be clinically distinct, may not be
as different as previously believed.

The researchers' findings suggest that female patients who
have been diagnosed with autism should be considered for
genetic screening to detect the presence of a mutation in the
MeCP2 gene, which is known to cause RD.

Both disorders are considered pervasive developmental
disorders and, while both share many clinical similarities, RD
is characterized by an smaller-than-normal head size
(microcephaly) and loss of ability to control ones' hands.
Generally, RD, which overwhelmingly strikes girls, is a
progressive disease that ultimately leads to severe mental
retardation by early adulthood; autism's symptoms tend to be
more diffuse and not as progressive.

"Screening patients with autistic disorder for the MeCP2
gene, especially the girls, could help us better classify the
patients and may give clues to long-term prognosis in the
disease," said Margaret Pericak-Vance, director of Duke's
Center for Human Genetics (CHG) who together with John Gilbert
and Dr. Jeffery M. Vance are the lead researchers on the
project. With its collaborators, the CHG runs one of the
largest programs aimed at unlocking the genetic basis of
autism.

This finding will help genetic researchers better understand
the underlying causes of autism or RD, which, over time, could
lead to new insights into both disorders.

While it is known that there are many complex genetic roots
to autism, the genetics of RD are comparatively simpler – more
than 80 percent of patients diagnosed with RD have a specific
mutation in the MeCP2 gene on the X chromosome. This mutation
is not inherited, but occurs after conception.

In their study, the Duke researchers analyzed 69 girls who
had been diagnosed with autism, but who showed none of the
classical clinical signs of RD. They found that two had
mutations in the MeCP2 gene.

The results of the team's study were presented Friday at the
International Congress of Human Genetics in Vienna.

In 1999, a team of researchers from Baylor College of
Medicine demonstrated that a mutation in the MeCP2
(methyl-CpG-binding protein 2) gene on the X chromosome caused
RD. This explains why RD almost always affects only females.
Females have two copies of the X chromosome, but only one
normally remains functional in each cell. Which copy remains
working is random, the researchers say, so in RD females enough
normal X chromosomes remain working to support life, but the
presence of the abnormal RD containing X chromosome in the rest
of the cells causes the disease.

Males, on the other hand, have only one copy of the X
chromosome. Therefore, boys with the RD-containing X chromosome
have no normal chromosome present and die before or shortly
after birth, they said.

While the role of the MeCP2 gene is still seen as crucial to
the development of RD, and maybe autism, new findings have
muddied the scientific waters.

"In the past year or so, milder cases of RD have been found
as well as males with a mutation in the MeCP2gene,"
Pericak-Vance said. "This leads us to the question of what
exactly is Rett disorder?

"Based on clinical descriptions, we find patients who look
like they have RD, but don't have MeCP2 mutations; and we can
find patients without the classical clinical signs of RD who do
have MeCP2 mutations," she continued. "However, we're finding
this occurs more and more as we get in to the genetic roots of
different diseases – what we see clinically isn't always as
straightforward once we understand the underlying genetics of a
disorder."

RD is the most common cause of mental retardation in
females, with an incidence of about 1 in every 10,000 to
15,000. Children usually appear normal through the ages of 6
to18 months, then start exhibiting such behaviors as repetitive
hand movements, body rocking, prolonged toe walking and sleep
disorders.

Autism is a complex disease that affects two to 10 per
10,000 people, making it the third most common developmental
disability – almost as common as Down syndrome. But because of
the broad differences in severity of the disease, doctors have
difficulty diagnosing it with certainty. Some children simply
talk later than normal, while others have severe withdrawal and
self-destructive patterns of repetitive head banging and
difficulty sleeping or other manifestations.

Joining CHG investigators in the study were researchers from
the CHG; University of New Mexico; University of Helsinki,
Finland; University of South Carolina; and Baylor College of
Medicine.

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