Scientists begin to trace autism's genetic roots
BY TINA HESMAN
St. Louis Post-Dispatch
ST. LOUIS - (KRT)
- Most 11-year-olds don't react to their first trip to the zoo the way Alex Richie did.
"I shouldn't have come. I shouldn't have come."
The Ferguson, Mo., boy's family hears that whenever Alex goes someplace new.
A visit to IHOP would have been all right. Alex had been there.
But even Disney World was traumatic. They don't serve Dr. Pepper there.
"Alex wants out of his room and he wants to enjoy life," said his mother, Jessica Cooper, 32.
But he is imprisoned in a world constricted by autism.
Autism is a spectrum of developmental disorders that disrupts social interaction, delays or destroys language, and causes people to repeat behaviors, such as hand-flapping or rocking, or to focus on specific topics to the exclusion of all else.
Scientists are beginning to trace the deep genetic roots that keep children like Alex locked in boxes of their brains' own making. Researchers are linking rare changes in common brain chemicals and networks of genes with some of the symptoms that plague children with autism and their families. Scientists at Washington University and the University of Missouri are learning that people with autism are simply at one end of a continuum that encompasses us all.
"With autism, I think somebody takes a salt shaker and everybody gets a little dusting of traits," Cooper said.
She has firsthand experience. Four of Cooper's five children have been diagnosed with Pervasive Developmental Disorder Not Otherwise Specified, or PDD-NOS, a mild form of autism.
Her daughter, Emilee, 8, and son Max, 5, are no longer classified as autistic, although both display strong symptoms. Emilee bangs her head and rocks back and forth, talking incessantly for hours about the same topic. Max's voice has one volume - loud. He didn't start speaking until he was almost 4 and transitions are still tough for him.
Emilee and Max will be fine in the real world, Cooper says, but her two older boys, Alex, 11, and Nick, 10, have a hard time navigating life.
"In their little world they can function just fine, but our world is hard for them," Cooper said.
No one knows for sure what causes autism, though theories abound. Researchers have yet to prove a connection between the disorder and any environmental trigger.
What is known is that autism is a genetic disorder. The identical twin of a child with autism has about a 65 percent chance of having autism and about a 90 percent chance of having one of the autism spectrum disorders, including Aspberger's syndrome and PDD-NOS, said Dr. Eric Hollander, director of the Seaver Autism Center at Mount Sinai School of Medicine in New York. And siblings of autistic children, especially male siblings (boys are four times more likely than girls to have autism), have a higher risk of autism.
Toni Ayers and her husband, Ronald, of St. Louis County, discovered that fact when their two sons, Nicholas, 13, and Ronnie, 10, were diagnosed with autism. Doctors told Toni Ayers that she and her husband had a mix of genes more likely to produce children with the disorder.
Researchers are working to uncover the genes that lead Ronnie to strip off his clothes and hang naked from doors, make him restrict his diet to Pizza Hut pizza and french fries, and impair his language development so that he speaks more like a toddler than a 10-year-old.
Scientists also want to know what combination of genes makes Nick Richie so insistent on order that "things that don't even matter" can tip him into a frenzy. At a restaurant, Nick was distressed to find four pieces of chicken on his plate instead of three. "He was yelling at the waitress to take back the chicken. `I can't have four pieces,'" Cooper said.
Many genes have been implicated in causing autism. But "to date there has not been a single gene with a major effect," Hollander said.
That is changing as scientists take a closer look at genes that affect specific symptoms of autism and probe interactions between groups of genes.
The first challenge is to recognize autism for what it is, and eliminate disorders that look like autism but have different roots. Dr. Judith Miles, director of the Division of Medical Genetics at the University of Missouri at Columbia, says she can recognize the essence of autism now.
Some children get autism because their genes guide their brains to develop in a nontypical way. Miles calls the genetically based disorder "essential autism."
But environmental insults, such as toxins, and developmental missteps caused by hormone surges or other factors may also push a child into autism, Miles says. She calls this type of disorder "complex autism."
Children with complex autism may have physical signs that something else went wrong during development, Miles said. About 20 percent of autistic children in a study conducted by Miles and T. Nicole Takahashi had abnormally small heads or malformed facial features, ears or hands. Children with complex autism also were more likely to have seizures and low IQs, and remain nonverbal past age 8.
Autism actually may be multiple different genetic syndromes, suggested Dr. John Constantino of Washington University. He and colleague Dr. Richard Todd are leading an effort to find the similarities and differences between autistic disorders. That could make it easier to narrow down the gene or genes that are responsible for the delay in language development or hand-flapping.
Autism is not a "you have it or you don't" disorder, Todd said. Instead, it is a highly inheritable continuum of traits, much like height or high blood pressure. The cutoff for being tall or short or having high or low blood pressure is somewhat arbitrary, he said. So is the diagnosis of autism.
The measure of autism is usually the inability to cope in the real world, said NYU's Hollander.
"People can be different without having a pathology," Hollander said. "It's only a disorder if it causes stress or interferes with function."
Constantino's research found that a child's place on the social continuum was as inheritable as autism itself. That is, if parents fell toward the gregarious end of the scale, so did the child - just as tall parents often have tall children.
That information is important, not to place blame on parents for causing their children's autism, but to give genetic studies more power, Constantino said. In most gene searches, scientists only consider people with the disease or disorder of concern. But Constantino and Todd were able to use information from nonautistic family members to help narrow their search for genes that contribute to autism.
Such searches may help scientists understand which genes amplify the anxiety of children like Alex Richie when confronted with something new. One gene that might contribute to a number of different autism symptoms is the serotonin transporter gene, SERT, according to new research from Vanderbilt University.
Serotonin is a brain chemical that helps neurons communicate with each other. It has been implicated in brain disorders such as depression. About 25 percent of children with autism have high levels of serotonin in their blood.
Researchers have linked autism to the serotonin receptor before, but the Vanderbilt group and others couldn't find associations with autism and the two forms of the gene that are common in the population.
That means there are two possibilities, said James Sutcliffe, who headed the investigation along with Randy Blakely. Either the scientists were investigating the wrong gene, or the source of the problem is not a common variation of the gene. But the researchers were convinced that the biological evidence was strong enough to justify a closer look at the serotonin genes.
They examined 120 families with multiple children with autism, who also seemed to have a strong association with the serotonin receptor gene. The strategy paid off in the identification of 19 different mutations in families with multiple affected boys.
Only four of those mutations change the protein produced from the gene. The rest alter possible regulatory regions of the gene. The researchers reported the find in the August issue of the American Journal of Human Genetics. One of the protein-changing mutations affects the same part of the protein as an alteration found in people with obsessive-compulsive disorder, and all four of the changes were associated with severe rigid-compulsive behaviors.
Ronnie Ayers sometimes gets overwhelmed by loud sounds and the feel of things against his skin, his mother says. Ronnie's response is a high-pitched scream, which causes even him to clap his hands over his ears. The boy also hits himself in the head when the world gets too loud or confusing, or when too much change happens too fast.
Now, Duke University researchers have pinned down a couple of genes that may interact and lead to such overstimulation in children with autism.
The Duke researchers, led by Margaret Pericak-Vance, director of the Duke Center for Human Genetics, have implicated a pair of faulty neural off-switches in autism. The genes, known as GABRA4 and GABRA1, are part of the GABA system. GABA is the nickname of gamma aminobuttyric acid, a neurotransmitter responsible for inhibiting nerve cell function. It also is involved in early brain development.
Pericak-Vance and her colleagues reported the interaction in the September issue of the American Journal of Human Genetics.
Parents needn't feel guilty for passing autism-related genes on to their children, Pericak-Vance said.
"Every family has something," she said.
