When Dr. Hal Dietz arrived at Johns Hopkins University in the 1980s, he became obsessed with helping children with Marfan syndrome, a rare and often fatal disorder that can cause the aorta, the large blood vessel that carries blood from the heart, to grow and grow until it bursts.
“Nothing we were doing seemed to make a difference in their lives,” he said.
These doomed children had a distinctive look that clearly had a genetic basis. They were typically very tall and thin, with long arms, legs and fingers. They often had unusually flexible joints, flat feet and teeth that were crowded in their mouth.
“I decided to study genetics with the sole incentive to identify the gene for Marfan syndrome and ultimately to understand the mechanism,” said Dr. Dietz, now director of the William S. Smilow Center for Marfan Syndrome Research at Johns Hopkins.
That journey has led to surprising discoveries about Marfan’s causes and a soon-to-be published clinical trial of a drug that may help its sufferers.Continue reading the main story
Dr. Dietz’s work also inspired research that may lead to a blood test that detects enlarged aortas, potentially saving thousands of lives, even among those who do not have Marfan syndrome.
Every year about 10,000 Americans die from ruptured aortas; two victims were the actor John Ritter and the diplomat Richard C. Holbrooke. The hope is that such a test will allow doctors to operate before the aorta bursts, or to quickly identify aortas that have ruptured so surgery can be performed without delay.
Time is of the essence. Patients whose aortas are breaking apart “all need immediate treatment,” said Dr. Scott A. LeMaire, a professor of surgery and of molecular physiology and biophysics at the Baylor College of Medicine. “The longer you delay the diagnosis, the greater the chance their aorta will rupture while you are trying to figure out what is going on.”
A Slow, Frustrating Hunt
For families who have recently learned that a child has Marfan syndrome, Dr. Dietz’s discoveries and the clinical trial he designed have divided their world into before and after, dread and hope.
Daniel Speck of Knoxville, Md., was given a diagnosis of Marfan six years ago, when he was 8, after his pediatrician noticed his spine was curved and suggested a test for scoliosis. It turned out that the curvature was caused by Marfan syndrome.
“We were blindsided,” said his mother, Amy Speck. Daniel was furious when he couldn’t play basketball anymore.
By then, Dr. Dietz and his colleagues had finally found the gene mutation that causes Marfan. It had been a slow and frustrating process: The sequencing machines now used to quickly map DNA had not been invented. Researchers had to sort through every gene in large regions of DNA shared by members of families in which someone had the syndrome.
Yet when the researchers first found the mutation, in 1990, it seemed to lead to a dead end. The mutation was in fibrillin-1, a protein in connective tissue, suggesting that the tissue was falling apart because its molecular rivets did not work. And if that was true, Dr. Dietz said, “there was nothing you could do to alter the course of the disease.” Or as Dr. David Altshuler of the Broad Institute of Harvard and M.I.T., who was not part of the research team, put it, “How can we fix the rivets when every rivet in the body is broken?”
Those were “the dark days of Marfan research,” Dr. Dietz said. But then he began to question the rivet hypothesis. It did not explain some of Marfan’s most notable features: the strikingly long bones of the children’s arms, legs and fingers, their deeply set eyes that slanted downward, their flat cheekbones, small chins, extremely low muscle mass and small amount of body fat.
About 10 years ago, he and his colleagues discovered the answer in another protein, T.G.F.-beta, short for transforming growth factor beta, which tells cells how to behave during development and is used in repairing wounds.
The protein’s function depends on fibrillin-1, the very protein that is altered in Marfan syndrome. Normally, fibrillin-1 hooks T.G.F.-beta to connective tissue. But in someone with Marfan, the researchers discovered, the fibrillin-1 is defective, and the process goes awry. Instead of attaching to the connective tissue, T.G.F.-beta drifts away from it. Floating free in the bloodstream, it makes cells behave abnormally, leading to many of the problems caused by Marfan, including excessive growth of the aorta.
In short, the rivet model was entirely wrong. “That,” Dr. Dietz said, “was one of the few ‘aha’ moments in my life.”
He tested his theory in mice, giving them the mutated fibrillin-1 gene. Sure enough, levels of the T.G.F. protein were very high. The mice showed Marfan symptoms, including emphysema, weak skeletal muscles and a thickening of the mitral valve in the heart.
He sought a way to block the function of T.G.F.-beta and found a widely used blood pressure drug, losartan, that did just that.
In the mice, the drug prevented features of the syndrome, including ballooning of the aorta. Instead of dying of aortic aneurysms by three months of age, the mice lived a normal life span of two years.
In 2006, the National Heart, Lung, and Blood Institute started a randomized trial based on Dr. Dietz’s work in which some children with Marfan got the drug and others got the standard treatment, with a beta blocker that slows the heart rate.
But Dr. Dietz worried about the children who were most severely affected. Most died in the first few years of life. By the time he finished the clinical trial, they would be dead.
“They had an unrelenting growth of the aorta,” he said. “If the drug worked, it could save their lives immediately. I felt compelled to treat them.”
The Beginnings of a Solution
One morning in 2006, Kari Dostalik of Urbandale, Iowa, whose daughter, Haley, has the disorder, went to a lecture by Dr. Dietz at the annual Marfan syndrome conference. He showed a slide of a boy who had a severe form of Marfan and had been given losartan outside the clinical trial. Ms. Dostalik had met the child and his family at a previous conference.
Before treatment, the boy looked weak and tired. But after having taken the drug, she said, “he was grinning ear to ear.”
Even better, Dr. Dietz told the group, as soon as the boy and other children took the drug, their aortas stopped growing. And losartan appeared to reverse some of the disease’s effects.
“When we heard the word ‘reversed,’ ” Ms. Dostalik said, “our first gut reaction was, ‘How soon can we get Haley enrolled?’ ”
The study was just beginning, and children would be in it for three years. Neither the families nor the doctors would know which drug they were taking, losartan or the beta blocker.
As tempting as it was to just give Haley losartan, Ms. Dostalik said, she and her husband worried about possible side effects, and they wanted to help science find an answer. “This was our chance to help the Marfan community,” she said.
Two years later, Dr. Dietz and his colleagues published data in The New England Journal of Medicine on 17 severely affected children who were given the drug outside the clinical trial. Before they took it, their aortas were growing about three and a half millimeters a year; afterward, the rate slowed to half a millimeter a year.
Some researchers worried that publishing the data might doom efforts to persuade parents to enroll children in the trial when they could get a drug like losartan on their own. But over the next three years, 604 families joined the study, with results expected in the coming months.
The Specks enrolled Daniel, and suspect he got losartan. His mother said the family saw “wonderful changes — everything started to stabilize.” Daniel’s aorta had been “growing astronomically,” she said, and that growth slowed so much that he would not qualify if he tried to enter the trial today. He also developed better muscle tone and more body fat.
When his time in the trial ended, the Specks were told Daniel could take losartan or the older drug, whichever they preferred. Ms. Speck did not want to take any chances. They chose both.
Daniel, now 15, continues to do well.
“It really is amazing,” his mother said.
Help for Those Without Marfan
The Marfan discoveries are starting to affect a bigger group — those without Marfan but whose aortas have bulged and torn, a life-threatening emergency.
Symptoms of a torn aorta can vary enormously, depending on which of the arteries branching from it are disrupted. The aorta begins at the heart and runs all the way down to the abdomen, feeding blood to more than a dozen major arteries. If a tear interferes with branches that deliver blood to the heart, it can look like a heart attack. If it interferes with branches that deliver blood to the brain, it can look like a stroke.
“People come in with this life-threatening condition and are either misdiagnosed or there is a long delay in diagnosis,” Dr. LeMaire said. Once the vessel ruptures, the operation to fix it is risky. Patients have to be put on a heart-lung machine, and their torn aortas repaired with a piece of synthetic fabric. The stretched and torn aorta has become something akin to tissue paper. Even the most experienced surgical teams lose as many as a quarter of their patients.But it appears that these patients may have the same telltale molecular signals as Marfan patients. When an aorta ruptures, it releases high levels of the Marfan protein, fibrillin-1, into the blood. That led Lynn Sakai, a biochemist at the Shriners Research Centerin Portland, Ore., to suggest using fibrillin-1 levels as a blood test for aortic ruptures.
She, Dr. LeMaire and their colleagues studied blood and tissue samples, stored at the Baylor College of Medicine, that belonged to patients with ballooning or ruptured aortas.
In a recent paper, they reported that fibrillin-1 levels in the blood of patients with bulging aortas were two and a half times higher than in those who did not have enlarged aortas. And high fibrillin-1 levels were three times as common in those with tears in their aortas as in those whose aortas were bulging but not torn.
Dr. LeMaire and his colleagues say they need to validate their results with blood tests from many more emergency room patients. They hope that such tests can be used to predict who is at risk for an aortic aneurysm or needs emergency surgery.
“We’d like to round up all the people who come to an emergency room with some symptom of chest pain,” Dr. Sakai said, “people like John Ritter, who died because the emergency room guy did not recognize that he was having an aortic dissection.” Steve Marpman, of Queens, 42, director of social work for a managed care company, could have used a blood test when he went to an emergency room and almost died of an aortic aneurysm.
He was training to be a policeman and passed several physical exams without trouble. Then one day he was dizzy and had a hollow feeling in his chest. His vision blurred. His speech became incoherent. By the time he got to an emergency room, he was near death — vomiting blood, going in and out of consciousness, with a weak pulse and rapid heartbeat. The doctors were baffled.
A cardiology intern came in, looked at Mr. Marpman’s long legs and fingers, and said, “Marfan.” Mr. Marpman had never heard of the syndrome.
An adult aorta is normally three to four centimeters, or 1.2 to 1.6 inches, in diameter. When it reaches five centimeters, doctors often suggest elective surgery. Mr. Marpman’s aorta was 10 centimeters wide, and had split open. His heart was spilling blood into his abdominal cavity and lungs.He had emergency surgery and awoke from the 12-hour operation intubated and strapped to a bed.
Losartan, the blood pressure drug, has not been tested on adults with Marfan, but Mr. Marpman has begun taking it. His baby boy inherited the Marfan gene. And if the clinical trial turns out to prevent excessive growth of the aorta, son will join father in taking the drug.
“It’s been a wild ride,” Mr. Marpman said.Continue reading the main story