A multi-centered team of researchers has found the first link between a specific gene abnormality and autism, a common neurobiological disorder. The discovery should speed the search for additional genes that increase susceptibility to autism and enhance understanding of this complex disorder. It could eventually result in more precise diagnosis and possibly better treatments.
The finding is reported by scientists from the University of Chicago Medical Center, Children's Hospital Research Center in San Diego and the University of California at San Diego, in the May issue of Molecular Psychiatry.
"This is just one of at least three to five genes whose interactions result in autism," says Ed Cook, M.D., associate professor of psychiatry and pediatrics at the University of Chicago and lead author of the report. "But nailing the first one confirms the value of the genetic approach and may provide clues about where to look for others."
Autism affects nearly one child in 1,000, 80 percent of them male. People with autism usually have difficulty forming relationships with others. They are slow to acquire speech, resistant to change and prone to repetitive behaviors such as hand flapping. About half are mentally retarded.
The severity of the disorder can vary enormously. About one-sixth of autistic children learn to function independently as adults, but the majority require special care throughout life and many spend most of their lives in institutions. There is no cure. Treatments tend to focus on specific symptoms and on providing social support, special schooling, and counseling for parents and families.
The researchers studied 86 families consisting of at least one autistic child and both parents, looking for genetic markers that tended to be inherited by children with the disorder.
Because elevated blood levels of the neurotransmitter serotonin have long been associated with this disorder, the researchers focused on the genes that regulate the production and function of this powerful chemical messenger. They zeroed in on the serotonin transporter gene (HTT), which codes for a protein that re-absorbs serotonin into the nerve cell after it has been released. Although the researchers found no change in the coding region of the gene, they did find that autistic children were much more likely to have inherited a shortened form of the gene's promoter -- the DNA sequence that serves as the "on ramp" for the cellular machinery that will express the gene.
A previous clinical study, led by Cook and published in 1992, also points to this protein. Cook and colleagues demonstrated that drugs, such as Prozac (fluoxetine), that inhibit serotonin transport, can reduce the repetitive behaviors exhibited by some children with autism.
"The short form of the serotonin transporter gene promoter does not explain autism," insists Cook, who heads a nationwide consortium of researchers looking for the genetic underpinnings of this disease, "but it does appear to play a significant role, perhaps in concert with other abnormalities which we've not yet uncovered."
In fact, the short version is quite common. About 16 percent of people have two copies of that version of the gene.
"It may have just a subtle influence," suggests Cook, "but if we find two more autism-associated genes with the same prevalence -- possibly additional hits along the same pathway -- 16 percent cubed comes to four in a thousand, close to the frequency of autism."
The genetics of psychiatric disorders have been notoriously difficult to trace. One problem has been the difficulty of making a precise diagnosis of the study subjects. Cook and colleagues were able to confine their study to patients who unquestionably had autism, based on an unusually thorough evaluation of each study patient by a multi-disciplinary clinical team that specializes in this disorder.
Several research teams, studying different groups of patients, are already trying to replicate the team's discovery of a link between autism and the HTT promoter.
Other members of the research team include Shuya Yan, Nancy Cox, Richard Haas, Catherine Lord and Bennett Leventhal of the University of Chicago Medical Center; Alan Lincoln and Rachel Courchesne of the Children's Hospital Research Center, La Jolla, California; and Eric Courchesne from the University of California at San Diego.