STANFORD, Calif. –A gene that regulates dopamine levels in the brain is involved in the development of schizophrenia in children at high risk for the disorder, say researchers at the Stanford University School of Medicine, Lucile Packard Children’s Hospital and the University of Geneva. 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.”
Gene therapy to restore COMT activity (see below) would probably be the ideal method for early intervention. More generally, as we discover the genetic contributors to more diseases we will need better gene therapy delivery techniques to make use of the discovered information.
30% of those with a deletion at a location on chromosome 22 will develop schizophrenia or a similar mental disorder.
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).
Note the point above about how some combinations of COMT variations confer a mild cognitive advantage. Quite possibly some of these COMT these variations which contribute to schizophrenia exist due to Darwinian natural selective pressure for higher cognitive ability. Some people get combinations of genes that boost their cognitive ability at the cost of higher risk of schizophrenia.
The researchers decided to see if excess levels of dopamine due to insufficient COMT activity perhaps acted as neurotoxins that brought on schizophrenia.
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.
Since chromisomes come in pairs deletion on one chromosome 22 still leaves another copy of the gene on the other copy of chromosome 22. So the scientists investigated variations of COMT on that other copy of chromosome 22 for those who have deletions on one of their chromosome 22 copies.
The surmise of the researchers turned out to be correct. Of those children missing one copy of COMT the children who had the lower activity version of their only copy of COMT had worse symptoms than children who had a higher activity version of COMT.
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. Of these seven, those with the low-activity version of COMT had 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. The psychotic symptoms of the low-activity subset were also significantly more severe.
In contrast, members of the control group experienced no significant differences in any of these categories, regardless of their COMT profiles.
What I want to know: are the COMT low activity and deletion mutations more examples of IQ "overclocking" mutations? The press release doesn't provide enough detail to tell. Which combinations of COMT variations resulted in the best cognitive performance? Also, are low activity versions of COMT or deletions of COMT more common among Ashkenazi Jews than among other populations?
|Share |||Randall Parker, 2005 October 30 12:49 PM Brain Disorders|