Acute health events in adult patients with genetic disorders: The Marshfield Epidemiologic Study Area
Gene Causing Marfan Syndrome Discovered Hopkins Scientists Help Find Cause Of Inherited Disorder. - Baltimore Sun
Discovery of the Marfan syndrome gene, whose existence was predicted 35 years ago by Dr. Victor A. McKusick, a Johns Hopkins cardiologist, is reported in today's issue of Nature, a British journal.
Scientists from Johns Hopkins and the Portland (Ore.) Shriners Hospital have proved that the gene responsible for making a connective tissue protein causes the syndrome, a potentially fatal, inherited disorder affecting one in 10,000 Americans, the journal reports.
The tall and long-armed Abraham Lincoln is believed to have had it. Olympic volleyball player Flo Hyman and University of Maryland basketball player Chris Patton died of it when their aortas — the heart's major blood vessel — burst despite apparently excellent health.
The finding is expected to have immediate use in early diagnosis of patients before symptoms appear and in prenatal diagnosis where the gene, which is altered in Marfan patients, can be tracked through families, says Dr. Harry C. Dietz, lead author of the Hopkins-Shriners Hospital paper, one of three related articles in Nature.
The gene is on chromosome 15 and normally makes the protein fibrillin, a component of connective tissue, the scaffolding that holds together skin, muscles and organs.
The mutated gene in Marfan's patients either makes too little of this scaffolding or makes weak or broken scaffolding. Since connective tissues exist everywhere in the body, a defective gene can affect a number of organs, but most commonly the heart, eyes, bones and skin.
The Hopkins-Shriners Hospital report shows that a particular alteration in the gene was present in patients with Marfan's and not in people without the syndrome.
"That was the final proof that the fibrillin gene was the gene responsible for Marfan syndrome," Dietz says.
The clustering of abnormalities that McKusick, a pioneer and world authority on Marfan syndrome and other connective tissue diseases, saw in some of his heart patients in the 1950s at Hopkins led him to determine that a single genetic defect in connective tissue must be behind the long arms and long legs, dangerous weakening of the aorta and dislocated eye lenses — all characteristic of Marfan's.
The stretched, fragile aorta can rupture and cause sudden death and the dislocated eye lenses can lead to blindness.
Evidence suggests that the earlier a patient is diagnosed and started on medication, the better his or her chances of long-term, quality survival, says Dietz, a research geneticist.
"The real use for early diagnosis is in the individual who only has subtle features of the disease, but does have a family history," he says. "There are infants and children who don't show any signs of Marfan's syndrome, but they are from a family where the syndrome is passed along and then you have to make the decision: Is the child affected or not?
"In those individuals where it is not easy to make the diagnosis in early childhood, we can now make these diagnoses earlier."
To diagnose individuals who have a family history of the disorder, scientists identify a genetic marker in a family member who is known to have the syndrome and then determine whether it exists in other family members.
The discovery of the gene also will allow diagnosis in a fetus before birth, Dietz says.
"The precise indication for doing in utero diagnosis would be for families who are seeking family planning options," he says. "Basically, some people would decide to terminate a pregnancy if they knew they were carrying a child with Marfan's syndrome."
An offspring of a Marfan syndrome patient has a 50-50 chance of inheriting the disorder. However, spontaneous or non-inherited gene alterations are reported to account for 25 percent of cases. Scientists suspect that many more people have the disorder than are diagnosed.
The discovery of the gene is the culmination of almost 100 years of study of the disorder, which bears the name of a Paris pediatrician who first described skeletal abnormalities in a 5 1/2 -year-old girl in 1896.
Last year, a New England Journal of Medicine study by a Hopkins-Shriners team found that fibrillin is lacking in 90 percent of the Marfan syndrome cases. Later, a Finnish study mapped the Marfan syndrome gene to chromosome 15 and the Hopkins team placed it at a more specific location. Dr. Lynn Sakai and colleagues at Shriners cloned a portion of the gene that makes fibrillin, and localized it to chromosome 15, but its role had remained unclear.
"The next step is to look for more mutations or alterations and assess their role in the individual variation of the disease between and within families," says Dr. Reed Pyeritz, clinical director of the Hopkins Center for Medical Genetics. This will allow scientists to pursue new ways of rapidly screening families for all Marfan syndrome mutations.
McKusick, now university professor of medical genetics at Hopkins, is a key force behind the Human Genome Project, the international effort to map the human genome — the genetic blueprint for a complete human being.
He is on a scientific panel that is interested in determining if President Lincoln had Marfan. The current plan is to use blood samples from the cuffs of the surgeon who dressed Lincoln's wounds in 1865, Dietz says.
"Those materials are available in the archives," he says. "The issue right now is whether those samples should be made available for this kind of an analysis." Government agencies will have to make that decision, he added.
Originally Published: July 25, 1991 at 12:00 AM EDT
What Is Marfan Syndrome? - News-Medical.net
Marfan syndrome occurs in approximately 1 in every 5000 individuals. It is an autosomal dominant disorder therefore the majority of people with Marfan syndrome have a 50% chance of inheriting the defective gene from whichever parent who suffers from the disorder. Alternatively, in approximately 25-30% of those with Marfan syndrome the condition has developed due to a spontaneous mutation yielding the defective gene.
Marfan syndrome affects the body's connective tissues – these are required for the body to maintain its structure and provide necessary structural support to other tissues and organs. Connective tissue is usually strong and resilient – it is made up of a number of proteins which include collagen, elastin and fibrillin.
In people with Marfan syndrome, a defect in the FBN1 gene located on chromosome 15 affects the production of the glycoprotein fibrillin (specifically fibrillin-1). Normally, molecules of fibrillin-1 bind together and form structures called microfibrils. The microfibrils are required to provide elasticity and support to connective tissues such as bones, tissues, muscles, and lenses of the eyes.
Microfibrils also store transforming growth factor beta (TGF-β), a protein which has a function in numerous cellular processes including the growth, differentiation and proliferation of cells. In this way, microfibrils are considered as the regulatory switch for TGF-β availability - TGF-β is inactivated when stored in microfibrils and is activated upon its release.
In Marfan syndrome, a defect in FBN1 results in irregularly-shaped microfibrils which cannot bind transforming growth factor beta (TGF- β). This results in an elevated level of tissue TGF- β and eventually problems in connective tissues throughout the body.
Connective tissue is widely distributed throughout the body as part of the bones, muscles, ligaments, blood vessels. Therefore it should be unsurprising that the symptoms are similarly dispersed. Fortunately, Marfan syndrome does not impact intelligence but it can affect the following areas and with variable degrees of severity:
Skeletal systemLong bones are affected and grow longer than they should. People become tall with unusually long fingers, toes, arms and legs (arachnodactyly).
EyesLens dislocation (ectopia lentis) in one or both eyes occurs in more than 50% of those with the disorder. This happens because the connective tissue holding the lens in place becomes weak. As a result, the lens of the eye is held in an abnormal position so that the person is no longer looking through the center of the lens. Complications may occur i.E. Retinal detachment, early onset cataracts or glaucoma, or extreme myopia (short-sightedness).
Cardiovascular systemThe most serious effects occur when the connective tissue in blood vessels become weakened and stretched. The aorta can become widened (aortic dilation) due to this which in turn increases the likelihood of tears (aortic dissection) and ruptures that allow leakage of blood into the atria of the heart.
Overly elastic valves may also result - in mitral valve prolapse, the valve between the left atrium and ventricle collapses backward and cannot close properly which can allow leakage of blood into the left atrium (regurgitation). The workload of the heart increases to prevent this backflow and can eventually lead to heart failure.
Respiratory systemDecreased elasticity of the alveoli in the lungs could increase the likelihood of lung collapse should the alveoli become stretched.
References: Further ReadingMarfan Syndrome In The Third MillenniumEuropean Journal Of Human Genetics - Nature
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