Gene Is a Factor in Hyperactivity, Researchers Say

UC Irvine researchers say they have discovered the first abnormal gene associated with attention deficit hyperactivity disorder, the syndrome that causes as many as 5% of children to be restless, inattentive and often disruptive in the classroom.

The identification promises to help in the understanding and diagnosis of hyperactivity, which affects an estimated 2 million children in the United States. The scientists say that the gene by itself does not cause the disorder, commonly known as ADD or ADHD, and that other as yet unknown factors contribute to its onset.

The discovery also provides the first direct evidence of how the controversial hyperactivity drug Ritalin works and, according to the researchers, opens the door for the development of more effective medications.

Not all hyperactive children carry the aberrant gene, but those who do carry it have a more severe form of the disorder, Dr. Gerald J. LaHoste and his colleagues report today in the journal Molecular Psychiatry.

“If this holds up, it will be a significant first step in understanding the genetics of ADHD,” said Dr. F. Xavier Castellanos of the National Institute of Mental Health. “What’s likely is that there will be more than one gene--it’s almost certain. This is certainly not the whole story.”

ADHD is the most common psychiatric disorder of childhood, affecting, on average, one child in every classroom in the country. Symptoms usually begin before the child reaches school age and affect boys at least twice as often as girls.

Nearly a quarter of children with the disorder have specific learning disabilities, and 40% exhibit a pattern of starting fights, stealing, lying and disobedience. As many as 60% of hyperactive children continue to display symptoms in adulthood.

Those symptoms can be controlled in the majority of cases with Ritalin, a stimulant that, paradoxically, calms the hyperactive child. Nearly 1 million people in the United States now take the drug, experts say. This wide use has been a source of controversy, with many critics charging that Ritalin is prescribed indiscriminately to children who do not have a definitive diagnosis of the disorder.

Hyperactivity has long been known to run in families, but LaHoste’s work is the first to purport to show why. His group focused on the dopamine D4 receptor, one of five types of dopamine receptors in the brain.

Dopamine is a hormone used by brain cells to transmit messages among themselves. The receptors are docking sites on the cell surface to which dopamine binds, stimulating the cell to take a specific action.

LaHoste and his colleagues at UC Irvine and the University of Toronto studied 39 children with the disorder between the ages of 7 and 12 and compared them to a similar number of healthy children. The researchers found that about half of the children with the disorder had a D4 gene containing a unique segment that repeats itself seven times. This aberrant form of the gene was found in only 21% of children in the control group.

Furthermore, those children who had the sevenfold repeat had, on average, a more severe form of the disorder than children who had other forms of the gene. The researchers link this observation to other work showing that the receptor with the sevenfold repeat is less sensitive to dopamine than those with fewer repeats.

Intriguingly, researchers in Israel and at the National Institute of Mental Health independently reported earlier this year that they had found the same sort of association in people with “novelty-seeking behavior.” Such individuals are characterized as excitable, fickle, thrill-seeking and quick-tempered--characteristics that are clearly similar to those of individuals with the disorder.

The novelty-seekers were found in both studies to have a much higher proportion of the sevenfold repeat in the dopamine D4 gene.

The new findings shed light on the activity of Ritalin, which is known to stimulate dopamine release in the brain. That excess dopamine may overcome the inefficiency of the abnormal receptor associated with the sevenfold repeat.

However, LaHoste said, “Ritalin causes the release of other chemicals in the brain that may not have anything to do with ADHD,” and may produce adverse reactions.

Now that researchers may have “a biological mechanism” at least partially explaining how Ritalin works, he added, they may be able to devise better drugs. Such a drug would be aimed specifically at the D4 receptor, he said.

Tests for the aberrant gene, he added, could also assist diagnosis of the disorder in many children, a task that is often very difficult now.