MEDICINE / DISEASE : Gene Discovery Raises Hope for Marfan Syndrome Test

Two teams of researchers have independently found the gene that causes Marfan syndrome, a potentially fatal disorder that affects one in 10,000 people worldwide and perhaps as many as 40,000 Americans.

The disorder involves the connective tissue that holds together skin, muscles and organs and is characterized by impaired vision, weakened arteries, a lanky appearance and enlarged hands and feet--the latter traits often being found in athletes.

At least two star athletes, Olympic volleyball player Flo Hyman and University of Maryland basketball player Chris Patton, have died during competition when their Marfan-weakened coronary arteries burst, and many others have been sidelined.

Some researchers believe that Abraham Lincoln suffered from the disorder, and the discovery of the gene, reported today in the British journal Nature by researchers in Portland, Ore., Baltimore and New York, will accelerate efforts to test Lincoln’s stored tissue samples for a definitive diagnosis.

“We are optimistic that the discovery of gene mutations responsible for this syndrome will help to develop a definitive test to identify people at risk,” said Jennifer Howse, president of the March of Dimes, which helped fund the research.

Identifying people at risk is crucial, said Cheryl Williams, president of the National Marfan Foundation. “The sooner a person is aware of the risk,” she said, “the sooner care can be taken to decrease the likelihood of catastrophic occurrences,” such as an aneurysm in the aorta, the large blood vessel that leads to the heart.

The syndrome is treated with drugs that lower blood pressure, thereby decreasing the pounding that blood vessels take. In some cases, surgery is performed to replace weakened aortas before they can burst.

Marfan syndrome was discovered in 1896 by Parisian pediatrician Antonin Marfan, who diagnosed it in a 5 1/2-year-old girl with severe skeletal abnormalities. It has a very broad spectrum of symptoms. In the most severe cases, heart abnormalities can be present at birth, but in the mildest cases, symptoms may not be apparent even in old age.

A child has a 50% chance of inheriting the syndrome if one parent has it. In about 25% of cases, however, neither parent has the syndrome and the disorder arises from a spontaneous genetic mutation. Diagnosis is now made strictly from the appearance of the patient’s skeleton, echocardiograms of heart functions and examination of the eyes. With the discovery, physicians will be able to diagnose the syndrome before symptoms appear, and even before birth.

Two of the three papers appearing in today’s Nature were from a team headed by cardiologist Harry C. Dietz of the Johns Hopkins School of Medicine and molecular biologist Lynn Y. Sakai of the Shriners Hospital for Sick Children in Portland, Ore. The third was from a team headed by Francesco Ramirez of the Mt. Sinai School of Medicine in New York City.

Both teams reported that the defective gene that causes Marfan syndrome is found on chromosome 15--one of the 23 pairs of chromosome in humans--and that it serves as the blueprint for a protein called fibrillin.

Fibrillin, which is widespread in the body’s connective tissues, is especially important in the aorta, bones and the suspensory ligament of the eye lens--all the sites most affected by Marfan syndrome.

By studying blood samples from Marfan patients and their families, the scientists have shown that individuals who have a defective form of the fibrillin gene all have Marfan and that those who have an intact form of the gene do not have the syndrome. They observed several different defects in the gene in different patients, which may explain the varying severity of the disorder.

Ramirez’s team has also found a second gene for fibrillin on chromosome 5 and have linked it to a rare Marfan-related syndrome called congenital contractual arachnodactyly. Victims of that syndrome display skeletal abnormalities, such as arachnodactyly (literally, “spider fingers”), but do not have vision and aortic problems.

Discovery of the Marfan gene has whetted the interest of scientists who want to determine whether Lincoln suffered from the disorder. A special panel headed by molecular biologist Victor McKusick of Johns Hopkins recommended earlier this year that Lincoln’s dried blood and bone tissue, stored at the National Museum of Health and Medicine in Washington, be analyzed to search for the Marfan defect once the gene was identified. That time has arrived, McKusick said.