Genetic researchers eventually may be able to develop a model for predicting shizophrenia in some high-risk individuals allowing treatment to begin before symptoms manifest.

The finding may allow physicians to identify a subset of children for treatment before symptoms start.

Schizophrenia is a brain disease that affects about 1 percent of people in the United States. It can manifest as agitation, catatonia and psychosis. Although the disorder sometimes runs in families, it also can occur spontaneously.

"The hope is that we will one day be able to identify the highest-risk groups and intervene early to prevent a lifetime of problems and suffering," says Allan L. Reiss, MD, director of the Stanford University School of Medicine's Center for Interdisciplinary Brain Sciences Research.

Velocardiofacial Syndrome

The latest finding adds to mounting evidence of dopamine's link to many psychiatric and neurological disorders, including Parkinson's disease and psychosis. There may be a kind of "Goldilocks effect" for this important chemical messenger: Too little or too much can interfere dramatically with normal cognition, behavior and motor skills, researchers suggest. Nudging these levels back into the "just-right" range may help treat or cure some conditions.

Scientists have suspected for many years that dopamine was involved in schizophrenia, due in part to the success of older psychiatric drugs that function by interacting with dopamine receptors in the brain. But the root cause of the disorder has remained elusive.

Dr. Reiss and the study's first author, Doron Gothelf, MD, a child psychiatrist and postdoctoral scholar at Stanford, studied 24 children with a small deletion in one copy of chromosome 22. About 30 percent of children with this deletion -- which occurs in about one in 4,000 births -- will develop schizophrenia or a related psychotic disorder.

These children also often have special facial features, cardiac defects and cleft anomalies that often make their speech hypernasal. Although these characteristics make it possible to identify them before psychiatric disorders develop, the disorder, called velocardiofacial syndrome, is under-diagnosed and under-recognized in the US despite its link to schizophrenia.

Not Enough Dopamine?

"We have strong evidence that this deletion is a major risk factor for the development of schizophrenia or related psychotic disorders," says Dr. Reiss. "We asked, 'What is it about this deletion that causes such an increase in risk?'"

The answer lay in the fact that one of the missing genes encodes a dopamine-degrading protein called COMT. Natural variations in the gene generate two versions of the protein: one with high activity, one with low.

Because most people have two copies of the gene, it usually doesn't matter which versions of COMT they inherit; high-high, high-low and low-low all seem to provide enough COMT activity to get the job done (though some combinations confer a mild advantage for some cognitive tasks).

But children with the deletion have only the one copy that remains on their intact chromosome 22. Drs. Reiss and Gothelf surmised that a single copy of the low-activity COMT might not dispose of enough dopamine to produce optimal brain function.

They set out to determine whether the clinical course of the children with deletions who developed schizophrenia varied with the version of the COMT protein they had.

Genetic Deletion, Low-Activity COMT

The researchers matched the age, gender, ethnicity and IQ of the 24 children with the deletion with 23 children with developmental disabilities of unknown causes. They then tested their subjects' verbal IQ and cognitive abilities. At that point, none of the children in either group had experienced any psychotic symptoms.

They also measured the size of the children's prefrontal cortex -- an area of the brain where COMT activity is particularly important and that is strongly associated with schizophrenia. They repeated the same tests after about five years, when their subjects reached late adolescence or early adulthood.

As expected, about 29 percent, or seven, of the children with the deletion had developed a psychotic disorder by the second round of testing, compared with only one child in the control group.

Among the seven, those with the low-activity version of COMT experienced a significantly greater drop in their verbal IQ and expressive language skills and a markedly greater decrease in the volume of their prefrontal cortex than did their peers with the more highly active version of COMT. Also, the psychotic symptoms of the low-activity subset were significantly more severe.

In contrast, members of the control group experienced no significant differences in any of these categories, regardless of their COMT profiles.

Important Contributory Factor

"What's interesting about this finding is that the disease course in the individuals with low-activity COMT looked remarkably like idiopathic schizophrenia," says Dr. Reiss. He hopes to use this and future data to develop a model for other causes of schizophrenia.

"Although this deletion probably causes less than 5 percent of schizophrenia cases, it's the only well-defined genetic risk factor we have right now," he notes.

"In the future, researchers will likely discover multiple causes of this disorder, with complex interactions between genetic and environmental risk factors. But COMT activity appears to be an important contributory factor for the development of psychosis in the chromosome 22 deletion syndrome," Dr. Reiss concludes.

The researchers next plan to extend their studies to younger children, and to repeat the above study using multiple time points to observe the ongoing development of the disorder more precisely.