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SEVERAL YEARS AGO, internationally known autism expert Isabelle Rapin, M.D., professor of Neurology and Pediatric Neurology at the Albert Einstein College of Medicine in New York, worked with a young brother and sister who were both autistic.
“The boy, who was about six at the time, was very mildly affected — going to a regular school and doing well,” she recalls. “His younger sister, however, was profoundly impaired.”
Dr. Rapin has cared for literally thousands of children with autism in her career, but this family sticks out in her mind as a particularly dramatic example of the complexity of the genetic and environmental factors that affect autism.
There's little doubt, experts say, that genetics play a role in autism spectrum disorders. It is considered a spectrum disorder because the symptoms and characteristics of children with autism can present themselves in a wide variety of combinations, from mild to severe. Children with autism can have difficulties with social interaction, display problems with verbal and nonverbal communications and exhibit repetitive behaviors or narrow, obsessive interests.
Twin studies have found that the “concordance rate” — which is the chance that if one twin has the disorder, the other will have it as well — is between 60 percent and 90 percent for identical twins, while the concordance rate for fraternal twins appears to be the same as for non-twin siblings. Because identical twins share 100 percent of their genes, and fraternal twins share only about 50 percent, the higher concordance rate among identical twins points toward genetic influence.
Unlike other disorders like Huntington's disease — in which one mutated gene clearly determines whether individuals with a family history will inherit the disease and pass it along to their children — autism involves multiple genes. It has a “complex” inheritance that can't be traced to a single gene, explains Nancy Minshew, M.D., associate professor of Psychiatry and Neurology at the University of Pittsburgh School of Medicine.
“Maybe two or three interacting genes are involved in a particular child with autism — but it's probably not always the same two or three genes in each child. There are probably up to 15 or 20 genes involved.”
“I believe strongly that autism is multifactorial, from a genetic point of view,” agrees Darryl DeVivo, M.D., Sidney Carter Professor of Neurology and a professor of Pediatrics at Columbia University Medical Center in New York. “The genes that are fundamental to our ability to think and to learn are all tightly linked. There probably are primary sets of genes that, when disturbed, are expressed as disturbances in behavior. These genes may alter how individuals relate to their environment and interpret what's going on around them.”
The challenge for autism genetics researchers, then, is not only to identify these genes, but also to figure out how they interact with one another — and with environmental factors — to produce the behavioral and cognitive impairments found all along the spectrum of autism.
As much as half of the human genome may be associated with brain development. That's a pretty big pond to be fishing in — but investigators are catching some promising fish.
In July 2004, The National Alliance for Autism Research launched the NAAR Autism Genome Project, the largest study ever conducted to find the genes associated with inherited risk for autism. Over 150 of the world's leading genetics researchers have pooled their resources. They have data on some 1,400 families in which more than one person has been diagnosed with autism and plan to probe the human genome for possible genetic “suspects” in this disorder.
“Previous studies on the genetics of autism just didn't have enough power because too few families were studied in each individual study,” explains Margaret Pericak-Vance, Ph.D., director of the Duke University Center for Human Genetics and the principal investigator of Duke's autism genetics research program (part of the NAAR consortium). “If you have pockets of different genetic effects, and you're only looking at 200 families, it's hard to tease out different genes’ involvement. Now, with this large data set, we're seeing some exciting early results, not only in terms of new places to look for genes but in terms of confirming the regions where we're already looking.”
Promising candidate areas of the genome identified so far include sections of chromosomes 2, 7, 15, 17 and 19. For example, a recent analysis of chromosomes 2 and 7 suggests that certain regions on these chromosomes may be involved with autism in a way that can't be detected if the regions were studied separately.
Chromosomes are the microscopically visible carriers of the genetic materials — or genes — that we inherit. Each of our cells contains a complete set of genes encoded into 46 chromosomes: 22 numbered pairs, one each inherited from our mother and father. When scientists look for genetic “coding errors” that might lead to a disorder such as autism, an important step is to find out which areas of which chromosomes might be involved. For example, if an area of a particular chromosome carries some instruction for brain development, an error in that area could lead to a disorder like autism.
“We're particularly intrigued by the genes that work with GABA (gamma aminobutyric acid),” says Dr. Pericak-Vance. GABA is a neurotransmitter — a chemical that one neuron, or brain cell, fires at receptors on another neuron to trigger a response. Some researchers are examining genes related to different chemical pathways, and others are studying genes that regulate how the brain is formed during fetal development. “These are all good candidates; now we need to find out what the mechanism is, and how they interact,” she adds.
Will discoveries about these genetic factors for autism lead to new treatments for the disorder? Probably not right away.
“Theoretically, mapping these genetic pathways could give us the information we need to design new drugs or chemicals that alter gene expression, restore brain development or prevent the problem from arising in the first place,” says Dr. Minshew. “It may also help us develop tools for early diagnosis in families that are at higher risk, with a history of autism.”
Our evolving understanding of the genetics of autism is already changing how doctors and families think about the disorder, Dr. Rapin says. “When we talk to families who have one child with autism, we owe it to the parents to warn them that they are at risk having another child with the disorder. There's not necessarily a very high risk, but there is a risk — and the severity of the disorder in one child doesn't necessarily predict the severity in another. These families need good, clear information about these factors.”
Autism Society of America
(800) 3 AUTISM (328-8476)
Cure Autism Now Foundation
(800) 8-AUTISM (828-8476)
National Alliance for Autism Research
(888) 777-NAAR (6227)
National Institute of Mental Health
(301) 443-4513, (301) 443-8431
TTY: (866) 625-NIMH
National Institute of Neurological Disorders and Stroke
TTY: (301) 468-5981