More threads by David Baxter PhD

David Baxter PhD

Late Founder
Gene Mutation Linked to Schizophrenia
October 24, 2005
HealthDay News

Schizophrenia appears to be inherited about 70 percent of the time, with a small percentage of schizophrenia cases connected to a gene mutation in one of the body's two copies of the 22nd chromosome. About 30 percent of children with the rare mutation become schizophrenic or develop another psychotic disorder.

Heredity seems to play a major role in schizophrenia, since the disease runs in families, and now new research sheds light on exactly how a genetic mutation disrupts the brain and makes people develop the condition.

The findings could eventually result in better drugs for schizophrenia, which is difficult to treat. For now, however, they're helping scientists understand the development of the disease, says Dr. Doron Gothelf, a child psychiatrist at Stanford University and co-author of a study in the Oct. 23 online issue of Nature Neuroscience.

Schizophrenics -- an estimated 1 percent of the population -- have trouble comprehending reality and are often prone to hallucinations and delusions. Some schizophrenics have memory and thinking problems, too.

"It's a disorder of thought," explains Wendy R. Kates, an associate professor of psychiatry at the State University of New York Upstate Medical University. "People hear voices that aren't necessarily there, and they experience delusions."

However, contrary to depictions in movies and on television, schizophrenia and split personality or multiple-personality disorder -- now known as dissociative identity disorder -- are different conditions.

According to Gothelf, schizophrenia appears to be inherited about 70 percent of the time, with a small percentage of schizophrenia cases connected to a gene mutation in one of the body's two copies of the 22nd chromosome. About 30 percent of children with the rare mutation become schizophrenic or develop another psychotic disorder; some have unusual facial features and cleft problems that make their speech very nasal.

According to Gothelf, "we wanted to know why one-third develop schizophrenia, and two-thirds do not."

Gothelf and a team of American and Swiss researchers studied 24 young children who had the genetic mutation to figure out why it causes schizophrenia. Then they checked on the children five years later when they were adolescents; schizophrenia often develops in young adulthood.

In the new study, the researchers report that seven of the children developed psychotic disorders. The worst cases of cognitive difficulties -- such as the inability to think clearly -- were among those whose brains had the most difficulty processing the neurotransmitter chemical known as dopamine.

Scientists have linked dopamine to a variety of emotions, including desire and pleasure, along with memory and the ability to plan and organize.

The findings could lead to genetic screening for schizophrenia among children, Kates says. But there's controversy over whether to give drugs to those children or wait until they have symptoms, she says. "At the very least, though, (the patient) can be monitored, and the family and patient can be given more support."

What does this mean in terms of changes in medical treatment?

Currently, schizophrenics are treated with anti-psychotic drugs, but they aren't always effective.

Gothelf says the future on the drug front isn't clear. "In general, in psychology the path from genes to biochemistry to a new medication is not straightforward," he says.

David Baxter PhD

Late Founder
Genetic Trigger Behind Some Schizophrenia Cases

Genetic Trigger Behind Some Schizophrenia Cases
October 24, 2005

( - 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."

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.

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. None of the children in either group had yet 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. 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's interesting about this finding is that the disease course in the individuals with low-activity COMT looked remarkably like idiopathic schizophrenia," said Reiss, who 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," said Reiss. "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."

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

The research was funded by the National Institute of Mental Health, the National Institute of Child Health and Human Development and the Swiss National Science Foundation.
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