The finding adds to mounting evidence of dopamine's link to psychiatric and neurological disorders. It may also allow physicians to pinpoint a subset of these children for treatment before symptoms start.
"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," said Allan L. Reiss, MD. "As we gain a much better understanding of these disorders, we can design treatments that are much more specific and effective."
Reiss is the Robbins Professor of Psychiatry and Behavioral Sciences at Stanford and director of the school's Center for Interdisciplinary Brain Sciences Research. He is also a child and adolescent psychiatrist at Packard Children's Hospital at Stanford. The research, which will be published online Oct. 23, will appear in print in the November issue of Nature Neuroscience.
Dopamine levels have been implicated in many neurological conditions, including Parkinson's disease and psychosis. Data from this and other studies suggest a kind of Goldilocks effect for this important chemical messenger: too little or too much can dramatically interfere with normal cognition, behavior and motor skills. Nudging these levels back into the "just-right" range may help treat or cure some conditions.
Schizophrenia is a brain disease that affects about 1 percent of people in this country and can manifest itself through agitation, catatonia and psychosis. Although the disorder sometimes runs in families, it can also occur spontaneously. Scientists have suspected for many years that dopamine was involved, 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 schizophrenia has remained elusive.
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 this country despite its link to schizophrenia.
"We have strong evidence that this deletion is a major risk factor for the development of schizophrenia or related psychotic disorders," said 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 doesn't usually 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. Reiss and Gothelf, who is also an assistant professor at Tel Aviv University in Israel, 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 if the clinical course of the children with deletions who developed schizophrenia varied with the version of the COMT protein they had.