By David N. Leff
Abraham Lincoln was awkwardly tall, thin and gangly. That is why modern physicians have speculated that he suffered from Marfan's syndrome.
Lincoln was shot and killed in 1865. Thirty-one years later, in 1896, French pediatrician Antoine Marfan described the first case of the genetic syndrome that now bears his name. That founder patient was a five-year-old girl, known to medical history as Gabrielle P., who displayed striking skeletal abnormalities.
It's not certain that either she or Lincoln actually had Marfan's. Gabrielle died, probably of tuberculosis, in early adolescence. Lincoln's death at 55 years of age was rather advanced, compared to the usual mortality of what is now known of Marfan's syndrome. Efforts to analyze the DNA in his blood, bone and hair are still pending.
For the past three decades, Marfan victims have survived, on average, into their 70s, up from death before 50 in earlier years.
What usually — and suddenly — kills most of them is a ruptured aorta.
Just such a dissecting aneurysm took the life 10 years ago of U.S. Olympic volleyball star Flo Hyman, who didn't even know she had Marfan's syndrome.
Natural Elasticity Not Always Enough
What causes this multifaceted malady to cause the aorta to swell up like a balloon and burst? "Throughout our lifetime," explained molecular geneticist Francesco Ramirez, of Mt. Sinai Medical Center, in New York, "we subject our ascending aorta — from the moment the adult circulation starts after birth — to something like one billion insults. So that hard-pressed blood vessel has to be a fairly good elastic system, which must do two things.
"First," Ramirez went on, "it has to absorb the insult of the hemodynamic stress of the pulsating heart. And second, it has to convert that insult into a positive force, to push the blood into the bloodstream." He noted that in an individual with Marfan's syndrome, a dissecting aneurysm can dilate the ascending aorta up to 10 cm in diameter — five to 10 times its normal size.
Marfan's syndrome isn't the only cause of aortic aneurysms, which account for two percent of all deaths in industrialized countries. The syndrome itself, Ramirez told BioWorld Today, has an estimated frequency of from one in 5,000 to one in 10,000 people. "Of these," he added, "30 percent are sporadic cases that arise from de novo mutations. That leaves, say, 70 percent that are familial."
Besides its spidery, scarecrow-like skeletal appearance, Marfan's syndrome has other bodily signs to answer for. Among the most striking, and a diagnostic hallmark, is distortion of the lens of the eye, which hangs loose, suspended by fragile ligaments. This connective-tissue weakness is systemic, but except for the wall of the aorta, not life-threatening.
Mutations in the gene for fibrillin result in Marfan's. "The fibrillin protein's normal function," Ramirez explained, "is to produce extracellular proteins, which polymerize and give rise to structures called microfibrils. These, we believe, hold the body's organs in place — like the lens of the eye.
"And in association with elastin," he continued, "fibrillin forms elastic fibers. These are responsible for the coil and recoil under stress of several tissues, like the aorta, the lungs when we breath, the diaphragm, and so on."
The 25-kilobase fibrillin gene, discovered a decade ago, resides on the long arm of human chromosome 15. "What its mutations do," Ramirez said, "is impair fibrillin polymerization in the microfibrils."
He is senior author of a research article in the October issue of Nature Genetics titled: "Targeting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan's syndrome."
That research, he told BioWorld Today, aimed to develop mouse models for Marfan's syndrome, "which can be used to generalize about dissecting aneurysms and their pathogenesis. So we need to know first," he pointed out, "whether or not the murine mutation — like the human mutation — can be replicated as a valid model in the mouse."
The first lesson the team learned from its transgenic animals was a surprise: "We found," Ramirez recounted, "that you can have a mouse going through embryogenesis with no normal fibrillin, which is supposed to be a major contributor to elastic fibrin morphogenesis."
On the other hand, those Marfan-mutated mice died soon after birth, too early in life to develop full-blooded signs and symptoms of the syndrome. "That," he continued, "is where the second line of mice we are working up comes in — animals that develop dissecting aneurysms during their life span.
"The question is: How does the wall of the aorta respond to the insult? We know the end result, breaking of the structural system, but we don't know how that initiates. Is it just mechanical failure, or is there some cellular determinant that favors increased stress?
"What we tried to do," Ramirez observed, "was make, and keep alive, a mouse that makes less fibrillin, but not so little that it dies before birth. That's the aim of our game." He and his colleagues are now analyzing the results obtained from these late-model transgenics.
Envisioning Gene Therapy
Next, it's on to the third-generation murine models. "We are trying next to make a mouse that has a more subtle mutation, rather than the large ones we did before. These should develop, according to the human situation, a milder form of Marfan's, and express it heterozygotically [with one gene variant], rather than the homozygotic [double-gene dose], in the previous mice."
Ramirez made the point, "If you envision gene therapy, you don't have to introduce a new good gene into the organism. You have just to block the bad one, because you can go fine with half of the good one. And since this will be a single-point mutation," he continued, "we will try to use it as a model for gene therapy, because we would know exactly what the abnormal transcript is.
"Conceptually," he went on, "you would need only to block the expression of this gene by any genetic means, which may be a ribosome or antisense codon specific for the mutation. But the important concept here," he emphasized, "is that you'd have to do it only in the cardiovascular system, because all the other manifestations of Marfan's don't lead to the death of the individual." *