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Searching for the Genetic Link to Autism


Duke Health News 919-660-1306

The events of Feb. 3, 1995, are etched in Zoe Ireland's
brain. On that day she and her husband, Dan, and their four
children drove 500 miles from their home near Modesto, Calif.,
to Los Angeles, only to learn what they already feared: both
their pre-school aged boys were autistic. The family was
devastated. Autism, they learned, is a brain disorder that
makes learning spoken language and forming social relationships
difficult. It somehow prevents people from properly processing
what they sense around them.

"Both boys were diagnosed within an hour of each other,"
says Zoe. "It's something you never forget."

The Irelands feared both boys, Darcy, then 4, and Morgan,
2½, would be stigmatized, that the boys might be dependent on
them forever, never able to live independently. Thoughts raced
through their heads: What now? How will we cope? What about the
girls, Rachel, 10, and the infant Colleen?

To make matters worse, Dan's brother, Gregg and his wife,
Lori, also had a son, Vinnie, diagnosed with autism. To Zoe it
seemed like a curse. "We couldn't believe what we were
hearing," she says.

Most families can chuckle at their family traits, the pointy
ears or turned-up nose that grandpa passed down to junior. But
the Ireland family shares a more serious family bond. Between
the two Ireland brothers, Dan and Gregg, they have three
autistic sons. This was no mere coincidence: the boys inherited
a gene or genes that led to the disorder.

"Autism is the most mysterious disorder I know of in
medicine," says Dr. Robert DeLong, a Duke University Medical
Center pediatric neurologist.

Autism is a complex disease. It typically affects 15 of
every 10,000 people, making it the third most common
developmental disability -- more common than Down's syndrome.
But doctors know little about why the brains of autistic people
have such difficulty interpreting what they see and hear in the
outside world. Some forms of autism appear to be linked to
other brain disorders, such as fragile X syndrome, a type of
mental retardation. But most autistic children have no obvious
underlying disease.

Even among the Ireland children the severity of autistic
behavior is striking.

Darcy has mild autism. "He never had problems making eye
contact, and he is a very social child," says Zoe. "Morgan,
though, has more of the classical autistic behaviors:
wandering, trouble sleeping, repeating movements like hand
waving. He didn't talk until he was three years old."

Such bizarre behavior caused some psychiatrists to blame the
disease on poor mother-child bonding and called mothers of
autistic children "refrigerator mothers," even when families
had non-autistic children as well – a theory that has since
lost favor. Research on autism has been slow, with many false
starts and blind alleys. Only recently did doctors acknowledge
that the disorder has a physical basis.

After many frustrating years, research in the underlying
causes of autism is traveling light speed ahead. And the
Irelands are helping it happen. They are one of more than 125
families who opened up their homes, their lives and their
family histories to Duke geneticists seeking the gene or genes
that predispose people to autistic behaviors.

"Finding the gene is going to blow the whole thing wide
open," DeLong says. "Eventually it's going to reveal the
underlying biological defect and set us on a course to better
diagnosis and treatment."

Although the study has only been underway for a year, the
research team is within a hair's breadth of locating at least
one gene that contributes to autism in families like the
Irelands', where more than one family member is affected.
Scientists now know that gene is located in a tiny portion of
human chromosome 15, and are now searching for the exact

Such fast results would have been unthinkable only a couple
of years ago, when the human genome was still mostly uncharted
territory. But the worldwide human genome initiative has
changed all that by creating at least a rough map of the entire
genome mapped in increments comparable to neighborhoods in a
road atlas.

This gene atlas is a valuable tool for human geneticists who
know how to read it – but geneticists experienced enough to
link human diseases to the still sparse genetic road map are
few and far between. Even more rare is the geneticist who can
track down the inherited components of complex diseases, such
as autism, that may have many interacting genes and may also be
dependent on environmental factors such as diet and chemical

The new genetic science, with its power to revolutionize our
understanding of disease processes, has arrived. Reflecting
that shift, last year the Duke department of medicine created
the section of medical genetics. Section members include
genetic epidemiologists, biostatisticians, genetic counselors,
physician's assistants, molecular biologists and technicians.
The lead geneticist behind the Alzheimer's disease finding and
a dozen others, Margaret Pericak-Vance, is at its helm.

"Duke has in its midst a top-caliber genetic research team
that has uncovered the genetics of a number of neurological
disorders," says Dr. Bart Haynes, chairman of medicine.
"Because they are willing to generalize their expertise to
begin to map genes for other diseases such as asthma,
osteoarthritis, and inflammatory bowel disease, we now have an
extraordinary resource for the Duke research community."

Pericak-Vance and her colleagues knew from experience that
to have the best chance of finding such genes, it would take
the backing of researchers like Robert DeLong, a doctor
passionate about his work, and who knows a network of
like-minded doctors around the country. So they created the
Center for Human Genetics, a medical center-wide program to
attract physicians and scientists interested in pursuing
genetic research. The section of medical genetics is designed
to be a resource to help get such studies up and running.

To track down the autism gene, the researchers extract the
DNA out of the blood samples, then catalogue and store it in
what is called the Pedigene database and DNA banking facility.
This storehouse at Duke is one of the world's largest
collections of DNA samples from family studies of genetic
diseases, containing more than 30,000 DNA samples from 3,000
families collected over more than 20 years of painstaking

For the autism project, Pericak-Vance's team of molecular
biologists might analyze hundreds of markers, or signposts,
along the 6 billion base pairs of DNA in the 46 human
chromosomes using the genotyping facility. Once they narrow the
search to a particular gene region, they will create
overlapping segments of DNA to fill in between molecular
signposts and locate the segment of DNA that differs among
diseased versus healthy people. When they find the responsible
gene, they can figure out what protein is made from the genetic
instructions, and from there make the connection to what might
be going wrong. But in the end, finding the gene requires the
practiced eye of an experienced geneticist.

"A lot of it is really more an art than a science, it's
having an intuitive feel for what's going on," says Marcy
Speer, assistant professor of medical genetics. "With someone
like Peggy [Pericak-Vance], that comes from years and years of
experience. There are not very many people like Peggy who have
years of experience in looking at things."

That art is now bringing the research team close to a gene
involved in autism as well as helping them find genes involved
in 21 other disorders now under study by center scientists and
collaborating physicians.

For Lori Ireland, the choice to participate in the study was
clear: "I want to know what's going on for my other children.
I'm hoping that by the time they are old enough to have
children, in another 10 years, they will have information we
didn't have," she says.

DeLong is thinking of the patients he may be able to help.
Brain imaging studies are beginning to show that in autistic
children, the part of the brain that controls language is
deprived of serotonin, an important brain communication signal.
He believes that drugs now available for treating other
psychiatric disorders may be able to help some autistic

"If we can test for the presence of a particular gene and we
know there is effective treatment for people with a particular
form of autism, it may be possible to intervene early enough to
prevent some of the deficits of autism," he says.

For now, the Irelands rely on the patient, individualized
instruction of teachers trained in the special needs of
autistic children. Despite their initial fears, Darcy is a
vivacious first grader, offering tutoring in use of the
classroom computer to his classmates. Zoe reports that his
teacher can't even tell he's autistic.

For Lori, knowing that doctors have gotten beyond labeling
women "refrigerator mothers" and knowing scientists are close
to understanding what is going on is a comfort.

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