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Gene Responsible for Cerebral Venous Abnormalities Found

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Duke Health News 919-660-1306

DURHAM, N.C. - A group of American researchers, led by geneticists at Duke University Medical Center, has found one of the genes known to be responsible for an inherited form of cerebral cavernous malformations, a difficult-to-detect condition that can cause massive brain hemorrhages.

The scientists said discovery of a cerebral cavernous malformations (CCM) gene could herald important medical advances for individuals and families with this condition - especially for the Mexican-American community, which appears to show a higher incidence of CCM than other ethnic groups.

"With DNA testing, we can now pick up the mutation in kids who are not showing symptoms and follow them closely," said Douglas A. Marchuk, lead geneticist of the Duke group. "This is the significance of the discovery. We can now help alleviate a great deal of the fear surrounding this condition by focusing our efforts on those children and adults who are truly at risk."

Initial genetic analysis of the Mexican-American families included in the study revealed evidence of a so-called "founder effect," which suggests most of the families are descended from a common ancestor. Of the 21 Mexican-American families included in the study, 16 had the same genetic mutation. Different mutations in the same gene were detected in non-Hispanic families who were also included in the study.

Cerebral cavernous mutations are lesions of large, abnormally shaped blood vessels in the brain. People with CCM often suffer from seizures (sometimes misdiagnosed as epilepsy) or recurrent, severe headaches usually beginning in their 20s or 30s. Sometimes, however, no symptoms present themselves until it is too late. Hemorrhagic stroke, caused by massive bleeding of the vascular lesions in the brain, can be fatal. A massive stroke is often the first and only symptom ever exhibited by those so afflicted.

The CCM Consortium reported the findings Thursday and the study results will be published in the November issue of Human Molecular Genetics. The consortium is comprised of researchers from 10 institutions throughout the United States, including the National Human Genome Research Institute, the National Center for Biotechnology Information division of the National Library of Medicine, and the Barrow Neurological Institute of St. Joseph's Hospital in Phoenix. The study was funded by the American Heart Association.

In the October issue of Nature Genetics, Elisabeth Tournier-Lasserve of Institut National de la Sante et de la Recherche Medicale (INSERM) and colleagues also reported finding the same mutation in the CCM gene responsible for the disorder.

Using DNA samples collected from CCM families, genetic researchers at Duke were able to accurately predict the approximate location of the genetic mutation on chromosome 7. With DNA sequencing of that chromosomal location made available through the Human Genome Project, they were then able to predict the genes that might be present. Research showed that the gene known as KRIT1 was mutated in the families they were studying.

Physicians will now be able to conduct DNA testing to determine which members of susceptible families are carriers of the mutation. The only way to detect CCM had been through the use of expensive magnetic resonance imaging, but even MRI has limitations in this type of detection because there are some areas of the brain where CCM lesions could reside that are undetectable even with the use of MRI. DNA testing will offer an accurate and less expensive method of detection, researchers said.

According to Dr. Trilochan Sahoo, a Duke researcher, "Many patients with CCM are completely treatable. Eighty percent of CCM lesions are usually located in an operable area of the brain. Although some lesions may not be removable, most of them are. Once skilled neurosurgeons can remove the dangerous abnormalities, a patient can become symptom-free often for life.

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