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Duke Geneticists Unraveling the Tangled Web of Autism


Duke Health News 919-660-1306

DURHAM, N.C. -- Less than three years after beginning a
search for genes that confer a risk of developing autism, Duke
geneticist Margaret Pericak-Vance and her colleagues have found
evidence of two defects that may be linked to the complex
combination of behaviors called autistic spectrum disorder.

Such behaviors include failure to make eye contact, social
withdrawal, lack of language, and repetitive behaviors such as
rocking or head banging. Doctors believe that the disorder
begins during development of the brain, possibly even before
birth, and that the change prevents affected people from
properly processing sensory information from their

Pericak-Vance, director of the Duke Center for Human
Genetics and lead investigator of the autism genetic studies at
Duke, and her team located defects in tiny sections of
chromosomes 15 and 7. And, for the first time, they said they
have evidence of a genetic mechanism that hides the effect of
some genes.

"You could say we have it narrowed down to a line-up of good
suspects, but we still can't finger the culprit until we get
direct evidence," Pericak-Vance said. "In this case, that most
likely will be more than one gene. It will probably include
variations of many genes that in combination interact to result
in autistic behavior. Those details will come with continued
research of our suspect genes."

The research was supported by the Duke's Center for Human
Genetics, the National Alliance of Autism Research, and by
grants from the National Institutes of Health.

The collaborative group of scientists, which included
researchers and clinicians from Duke, the University of South
Carolina, and Johns Hopkins University, located and collected
genetic information on more than 100 families with at least two
autistic children. By comparing the genes from parents and
siblings to the genes of autistic children, the scientists were
able to narrow their search to a few small pieces of
chromosomes, the carriers of genetic information. Now, in a
series of papers, some in press, the scientists report:

Confirmation that a small region of chromosome 15 is
duplicated or deleted in some autistic children. This area of
chromosome 15 is highly unstable and prone to genetic
rearrangement. The region includes genes for Prader-Willi
Syndrome and Angelman syndrome, two disorders which can
manifest autistic-like behavior. (November 1999 issue of the
journal Neurogenetics.)

Completion of a detailed genetic map of the chromosome 15
candidate genes (Dec. 15, 1999 issue of the journal

Discovery that this same area of chromosome 15 contains
genes that recognize a powerful chemical signal in the brain
called GABA or gamma aminobutyric acid. Pericak-Vance and her
colleagues found evidence that at least one form of autism is
associated with a genetic marker in the vicinity of a GABA
receptor gene. (January 2000 issue of the American Journal of
Medical Genetics)

Completion of a detailed genetic and behavioral study of a
subset of children with the chromosome 15 defect. The Duke
researchers concluded that autistic children with a particular
genetic profile may be a specific subtype that can be
distinguished from other forms of autism. These children all
have two copies of the same small region of chromosome 15,
while people without autism only have one copy per chromosome.
(Neuropsychiatric Genetics, in press).

Confirmation that another genetic variation in chromosome 7
also predisposes children to autism. The scientists said the
findings suggest that genes inherited from one parent may be
masked during development, a phenomenon called imprinting.
(November 1999 issue of Genomics).


Autism is a complex disease that affects 2-10 per 10,000
people, making it the third most common developmental
disability - almost as common as Down's 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 with self-destructive patterns of repetitive head
banging and difficulty sleeping.

In the past, many parents endured frustration and shame when
told that their withdrawn, silent, autistic child is a product
of their own poor parenting. But the Duke researchers are now
demonstrating that autism is a complex genetic syndrome that
may actually turn out to be several related disorders, each
with its own individual treatment.

"One of the biggest difficulties has been coming up with a
firm way of diagnosing autism," said Dr. Michael Cuccaro,
associate professor of neuropsychiatry at the University of
South Carolina, Columbia, and a collaborator on the project.
"There has never been any definitive diagnosis beyond
behavioral classifications. One major outcome that I see to the
genetic studies is a way to finally identify more precisely who
has autism. This information would be extremely useful for
families who are often confused with differing medical

For example, when the scientists looked at the children's
behaviors, they noticed a pattern of similar behaviors in some
of the children. Some had speech delay, lack of social skills,
and "stereotyped" or repetitive behaviors, that seemed to
cluster in together with a specific genetic defect. In
addition, these children had seizures and hypotonia, or low
muscle tone, characteristics that are not normally associated
with autism. These children all had a duplication of part of
chromosome 15.

"We would like to be able to link subtypes of autism with
more specific intervention strategies," Cuccaro said. "For
example, some children may benefit more from medicines, some
with behavioral interventions, although many will need

In fact, scientists at Duke's Center for Human Genetics are
teaming with psychiatrists who treat patients with a variety of
psychiatric disorders to investigate the genetic component of
mental illnesses.

"At this time, diagnosis of psychiatric disorders is as
superficial as, say, fever," said Dr. Ranga Krishnan, chairman
of Duke's department of psychiatry. "All we can say is the
patient has a fever. We are diagnosing based on a symptom. With
the genetic approach, we may be able to classify psychiatric
disorders based on an underlying genetic and biochemical cause,
just as fever is now classified based on what caused it,
whether it be bacterial, viral, etc. This has fundamental
implications in that it could lead to a new and possibly
different classification of psychiatric disorders and new
treatment approaches that may be more specific."

The researchers began their quest to find genes associated
with brain abnormalities by using the same approach they used
to find genes associated with Alzheimer's disease and other
neurological disorders. They went to the source: families with
more than one child diagnosed with autism. By studying such
families, the researchers can look in detail at sections of
chromosomes that are the same in affected children. When they
looked in detail at a section of chromosome 15 in 63 families
with at least one autistic child, they found that the autistic
children had genetic abnormalities in this tiny region of
chromosome 15 that contains about 50 genes.

"Our studies, and those of others show that the genetic
errors that lead to autism are introduced when a piece of a
chromosome breaks apart and recombines during the formation of
sperm and eggs," said Pericak-Vance. "As a result some children
with autism have an extra copy of a piece of chromosome 15 and
in some, the piece is missing. We believe the gene or genes
responsible for the behavioral changes we see in some children
with autism are located in this area of chromosome 15."

The scientists aren't sure which of the genes in the region
lead to autistic behaviors, but they have identified a few
strong candidates.

In the January 2000 issue of the American Journal of Medical
Genetics, Pericak-Vance and her colleagues made a careful
genetic analysis of the possibility that one of the three GABA
receptor subunit genes on chromosome 15 is linked to autism.
They were not able to definitively link the GABA genes to
autism, but they were able to say that at least one gene in the
GABA region of chromosome 15 is associated with autism. The
complex nature of autism makes it difficult to single out any
one gene, and in fact, more than one gene may be involved, the
researchers say.

"GABA is the major inhibitory neurotransmitter in the
brain," said John Gilbert, a researcher at Duke's Center for
Human Genetics. "Any change in the brain structures that
recognize GABA could have implications during brain development
and function. It makes a nice story if GABA turns out to be
involved in autism, but we can't be sure yet."

To that end, Gilbert, Pericak-Vance, Dr. Jeffery Vance and
their colleagues reported in the Dec. 15, 1999 issue of the
journal Genomics that they have completed a detailed genetic
map of the area of chromosome 15 that contains the suspected
autism genes. The map is a milestone that will help researchers
mark off which genes are definitely not involved and narrow
down the list of candidate genes until an affected gene or
genes emerges.

In the November issue of the journal Genomics, the
researchers reported another potential genetic link to autism.
This link is on chromosome 7.

"Our results show that just as on chromosome 15, the region
of chromosome 7 suspected to be involved in autism is
exceptionally susceptible to breaking apart and recombining
with its chromosome pair. Apparently, in some cases this
recombination goes awry and parts of the chromosome are not
duplicated faithfully. The result is that a piece of chromosome
7 is inverted or turned upside-down with respect to the rest of
the chromosome in some cases of autism."

The researchers also found evidence of a genetic mechanism
that hides the effect of genes. One such mechanism is called
imprinting, in which genes inherited from one parent are
"masked" during development. Such a mechanism may be at work
here, Pericak-Vance said, since the area of chromosome 7 is
known to have imprinted genes. The same is true for the
autism-associated region on chromosome 15. Although the data is
suggestive, the researchers have no direct evidence yet that
this is the case.

Currently, the Duke research team is making progress
narrowing down the potential candidate genes on chromosomes 7
and 15 by studying additional families and by using their
existing genetic maps and genetic markers to test each
potential gene candidate.

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