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Duke Geneticists Unraveling The Tangled Web Of Autism

January 28, 2000
Duke University Medical Center
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.

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 environment.

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 Genomics).

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 opinions."

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 both."

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.

"I think there has always been some doubt, even until recently, that this is truly a biological disease," said Cuccaro. "This will hopefully be the science that puts to rest the idea that parenting style contributes to the development of the disorder. We can say now that autism is definitively a neurobiological disorder."

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