A genetic defect that predisposes its bearer to aortic aneurysms--blood-vessel swellings that can rupture fatally--has been discovered in a family with a history of the disease, researchers reported Thursday.
Researchers from Thomas Jefferson University in Philadelphia have developed a simple saliva test for the presence of the gene and have identified five members of the family who are at risk of developing aneurysms.
Molecular biologist Darwin J. Prockop and his colleagues are now studying nearly 100 other families in hopes of finding similar defects before aneurysms develop, and they believe that within two years the test can be expanded to cover a large segment of the population.
Aortic aneurysms kill more than 15,000 Americans annually and at least 2 million people are thought to be at risk. Identifying susceptibility to the aneurysms will enable physicians to monitor those at risk so that the aneurysms can be surgically repaired before they burst.
"It's a very important discovery . . . a milestone in the understanding of this problem," said surgeon M. David Tilson of Columbia University.
Prockop and his colleagues discovered the gene in 37-year-old Michele Hegler, a former Air Force captain who is currently healthy but was referred to them because of a family history of aneurysms. Five of her relatives, including a 15-year-old cousin and her 34-year-old mother, died suddenly from ruptured aneurysms in their aortas. The aorta is the largest artery in the body.
The team quickly focused on a protein called collagen III. Collagen is the fibrous material that holds together skin, tendons and most other tissues in the body, and collagen III is the major form found in the aorta. "We also knew that a few rare diseases . . . were caused by mutations in collagen III and that many people with these diseases developed aortic aneurysms in addition to other symptoms," Prockop said.
The gene that codes for collagen III contains 30,000 chemicals, called bases, arrayed in a specific sequence. The Philadelphia team reports in today's issue of the Journal of Clinical Investigation that one of those 30,000 bases in Hegler's gene had been mutated so that the collagen III it produced had a subtly altered shape.
"Each collagen molecule is like a brick that sticks to other collagen molecules and forms long, tough fibers," Prockop said. "Because each collagen molecule sticks to other molecules on all sides, the structure must be almost perfect." The alteration in Hegler's collagen III "is enough to slightly change the shape of the molecule and interfere with its ability to adhere to other molecules properly."
After years of pounding from the blood pressure of the heart, he added, the aorta wall can stretch and form a weak bubble that can very easily rupture, causing the patient to bleed to death.
Study of preserved tissue samples from Hegler's deceased mother and aunt showed that their collagen III genes carried the same defect.
After discovering the defective gene, the researchers developed a simple test for it that requires only a teaspoonful of saliva. They then tested 10 other members of the family and found that four of them--Hegler's 15-year-old son, 17-year-old daughter, brother, and aunt--all carried the defective gene.
"I was always concerned about my family's history of aneurysms because so many died," Hegler said. "I often wondered whether the same thing can happen to me. Now that I know, my family and I take precautions."
Among other things, the susceptible family members will have ultrasound, echocardiogram, and CT scan exams yearly to detect aneurysms at an early stage. Once detected, the aneurysms can be surgically repaired at relatively low risk, Prockop said. In contrast, 90% of patients die when their aneurysms proceed to the stage where they burst.
Her son has also stopped playing football and her daughter has given up gymnastics because the exertion increases the risk of an aneurysm forming.
The Philadelphia team does not expect precisely the same genetic defect to be present in other families with a history of aneurysms. Previous studies on much rarer genetic disorders that are also caused by collagen III defects suggest that each family will have its own unique defect, said Gerard Tromp, another member of the Philadelphia team.
But it is possible, he added, that a small group of genetic defects will account for most families, thereby making screening easier. Their saliva test is now being used by many other laboratories to determine if the same genetic defect is present in any other families, Tromp added, but they have not received any results yet.
Even if a very large number of defects are eventually found, he added, the team is developing techniques that would enable each family's unique defect to be discovered in a very short time. He predicted that the tests could be in wide use within as little as two years.