June 26, 2003 DALLAS, June 24 – Researchers studying an inherited life-threatening heart disorder have mapped a new location for a genetic mutation that causes the problem, according to a report in today's rapid access issue of Circulation: Journal of the American Heart Association.
The finding may lead to early, life-saving treatment for familial thoracic aortic aneurysm and dissection (TAAD), in which the aorta enlarges until it eventually bursts or dissects.
The aorta is the large artery that receives oxygen-rich blood from the heart. Arteries that branch from the aorta distribute blood to the rest of the body.
TAAD is sometimes found in people with an inherited condition called Marfan syndrome, which is characterized by many anomalies including elongated bones. It is also associated with Turner syndrome, which results from a missing X chromosome and is associated with dwarfism and arrested sexual development in addition to aortic aneurysm. TAAD also can run in families independent of those two syndromes. Because it is difficult to diagnose victims often die young.
Researchers hope their finding means that "instead of people dying prematurely in their 40s, they could go on to lead near-normal lives," says lead researcher Dianna M. Milewicz, M.D., Ph.D., professor and vice chair, department of internal medicine, University of Texas Medical School at Houston.
Currently people with TAAD are unaware of the risk they face because the slowly enlarging aorta does not cause any symptoms until it has reached a critical diameter. At that point, the aorta dissects or ruptures, both of which are life-threatening. The patient develops chest pain and usually goes to an emergency department to seek treatment, Milewicz explains.
"Usually emergency room physicians will run a series of tests designed to detect heart attack and those tests will be negative. So the patient frequently is sent home with a diagnosis of heart burn or anxiety," she says. "If these patients are sent back out, they will die."
Milewicz and other researchers have been searching all the human genes (the human genome) to identify the genes responsible for TAAD. But they first needed to identify the chromosome sites of the genes. The team had already identified two chromosome sites: 5q13-15 (TAAD1) and 11q23.2-q24 (FAA1) – but some families had disease that could not be linked to these sites.
In this study, researchers examined four generations of one family of Swiss-German heritage. The family had a history of TAAD unlinked to the previously identified chromosome locations. Researchers collected and analyzed DNA samples from 52 family members and identified a new location for familial TAAD at 3p24-25, and named it TAAD2.
Other families with familial TAAD don't have the link to any of these three chromosome locations, so "there is at least one more unmapped location for familial TAAD," she says.
As Milewicz and her colleagues continue to search for other sites, they are also trying to pinpoint the exact mutant gene. Once the mutation is identified, researchers may develop tests to identify people who are at risk for familial TAAD. Then these high-risk people can be closely monitored so that they can undergo surgery to correct the disorder before the aorta is at risk for dissection, she says.
Co-authors are Sumera N. Hasham, M.D.; Marcia C. Willing, M.D.; Dong-chaun Guo, M.D.; Ann Muilenburg, M.D.; Rumin He, M.D.; Van T. Tran, M.D.; Steven E. Scherer, M.D.; and Sanjay S. Shete, M.D.
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