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Fragile X Syndrome Marfans syndrome Marfan syndrome is a disorder that weakens the connective tissue of the body. Connective tissue is not a single entity, but a catch-all term for everything in your body that keeps you from falling apart. The familiar tendons and ligaments keep bones and muscles together, but other connective tissue is more obscure, like the elastic fibers in the aorta that keep it soft and rubbery. Even bone is a connective tissue. Marfan syndrome affects all of these structures. People with Marfan syndrome have loose tendons and ligaments, less elasticity in the aorta, and longer arms and legs. All of these seemingly unrelated characteristics are caused by a mutation in a single gene on chromosome 15. The gene is named FBN1 for the protein it encodes, fibrillin-1. The precise order of the A's, C's, T's, and G's in the gene determines the composition of the protein. The cell's protein-production machinery embodied by the funny green guy reads the code in the gene and then adds the proper amino acid to the growing protein. Each amino acid is encoded by a different 3-letter code. The gene produces lots of copies of the fibrillin protein, and these join together with other components to form a long, stringy structure called a microfibril. In people with Marfan syndrome, a mutation (a misspelling) in the gene changes the shape of the fibrillin protein. There are many mutations that can cause Marfan syndrome, but most are single letter changes that lead to a single amino acid change in the protein. The change in the amino acid alters the shape of the fibrillin proteins. The irregularly-shaped proteins then assemble into an irregularly-shaped microfibril. The change in the amino acid alters the shape of the fibrillin proteins. The irregularly-shaped proteins then assemble into an irregularly-shaped microfibril. Microfibrils show up in all kinds of connective tissues, but for people with Marfan syndrome, the microfibrils in the aorta are most important. In the wall of the aorta (the large blood vessel that carries blood out of the heart), microfibrils combine with elastic fibers to make the aorta stretchy. When the heart ejects blood into the aorta, the force of the propelled blood causes the vessel to expand, stretching the elastic fibers. The elastic fibers then return to their original size, bringing the aorta back to its unstretched diameter. In people with Marfan syndrome, the microfibrils do not help the elastic fibers spring back, and the aorta gets stretched out over time (like an old rubber band) by the force of the blood. As it widens, the aorta also weakens. This puts people with Marfan syndrome at risk for aortic dissection, a tear in the vessels inner layer. In a dissection, blood flows into the space between the layers of the aorta. The blood pools and may block normal blood flow through the vessel. An untreated dissection will form an aneurysm, weakening the outer wall and leading to a complete rupture of the aorta. A complete rupture is usually fatal. Mitral valve prolapse, a type of heart murmur, is another common cardiovascular condition in people with Marfan syndrome. In mitral valve prolapse, the flaps between the left atrium and the left ventricle are too big and floppy. The flaps normally keep blood from flowing backward into the left atrium when the heart contracts. When the flaps are too big and floppy, they dont close properly, and some blood can flow back into the left atrium. This is called regurgitation. When the backflow is large, blood flow to the rest of the body decreases, and the heart may pump harder to compensate. If the heart is working too hard, it can eventually fail. Cardiovascular health is the main health concern of people with Marfan syndrome, but skeletal problems can also be debilitating. People with Marfan syndrome are frequently tall and skinny, with disproportionately long arms and legs, from faster bone growth. As bones grow, they pull on the ligaments that connect one bone to another. The combination of fast bone growth and weak microfibrils in people with Marfan syndrome stretches their ligaments out. The ligaments become too loose to keep vertebrae in place, and the vertebrae get out of line. (Similar loose ligaments in the fingers cause "double-jointedness"). A side-to-side curve to the spine is called scoliosis. The spine may also bend forward or backward away from its natural curvature. When the curve is severe, the spine can impinge on the lungs and impair breathing. People with Marfan syndrome are also frequently near-sighted due to elongated eyeballs that move the retina away from the focused image. A more unique problem is lens dislocation, where the ligaments centering the lens weaken and the lens moves off center. This is usually corrected by glasses or contacts, but the lens may be replaced if it detaches completely. Three out of every four people with Marfan syndrome inherit the disorder from a parent who also has the disorder. The disorder can be inherited from the mother if she passes the Marfan mutation to the child, or from the father if he passes the mutation to the child. The child only needs to inherit one copy of the Marfan mutation to develop the syndrome, because the mutation is dominant. Even though normal fibrillin is made from the second copy of the gene, the irregular Marfan fibrillin interferes with it during microfibril production. This weakens ALL of the microfibrils, and the child develops the symptoms of Marfan syndrome. Though they share the same mutation, the affected child and parent may have different characteristics of the syndrome. For example, this child may develop scoliosis, even though her affected parent never had skeletal problems. Researchers believe other genes and environmental differences account for the wide variability of symptoms among people with Marfan. In the remaining quarter of people with Marfan syndrome, neither parent has the disorder. These people develop the disorder when one of their fibrillin genes spontaneously mutates before birth. In this example, a gene mutates during the production of one of the mother's eggs and is passed to the child Every unborn child in the world has a 1 in 10,000, or 0.01%, chance of getting Marfan syndrome through a spontaneous mutation. When one parent has a mutated "Marfan" gene, the chance of his/her child inheriting the disorder is 50%. In this couple, the father has the Marfan-causing mutation (M) and the normal gene (m), while the mother has two copies of the normal gene. A Punnett Square illustrates their possible children, and lets us calculate the chance each child has of inheriting the disorder. First, we arrange each parent's genes on the outer edges of the square. Each parent donates one of their two fibrillin genes to the child, so we place one of the father's genes and one of the mother's genes into each box. Each completed box shows a potential combination (or genotype) in the child, and the entire square contains all possible combinations. Next, we count the boxes that contain a Marfan-causing genotype (the Mm combo). 2 out of 4 boxes contain this combo, so the chance of this couple's child inheriting Marfan syndrome is also 2 out of 4, or 50%. The same chance applies in the opposite situation when the woman has the Marfan mutation and the man does not. Two out of four boxes contain the Marfan-causing combo (Mm or mM), so the chance of this couple's child inheriting Marfan syndrome is also 2 out of 4, or 50%. The most important thing to remember about these odds is that they apply to every child this couple has. It may be useful to think of the Punnett Square as a roulette wheel. Each child is a separate "spin of the wheel," so each child has a 50% chance of receiving the mutation. In this family, one in four children has Marfan syndrome. Other couples with the mutation may have two, three, four, or even no children with Marfan syndrome. What is it? What causes it? How is it inherited? How is it diagnosed? How is it treated? What is it like to have it? For more information
Acknowledgments Facts and Theories Many people think that Abraham Lincoln had Marfan syndrome based on his lanky body and the fact that a distant relative had the disorder. DNA tests are not yet good enough to confirm or refute this suspicion. Symptoms People with Marfan syndrome have weak connective tissues in the heart, skeletal system, eyes and other organs. The aorta may enlarge, the spine may curve and the eye lens may dislocate. These symptoms are quite variable among people with Marfan syndrome and can range from mild to severe. Marfan syndrome affects both sexes and all ethnic groups, but it is relatively rare. About 1 in 5,000 people are born with the disorder. Physicians familiar with marfan syndrome make a diagnosis based on the co-existence of several features. There are no DNA- based tests for diagnosis, because nearly every family with Marfan syndrome has their own unique mutation in the fibrillin gene. Marfan syndrome is a genetic disorder caused by a mutation in the fibrillin gene. The misshapen fibrillin produced fom the mutated gene weakens the tendons, ligaments, and other connective tissues in the body. Treatment for cardiovascular problems is critical, and the aorta must be monitored for weakness. Drugs can help reduce the stress experienced by the aorta, but surgery may be needed eventually to replace the vessel. Variability of Symptoms Dr. Richard Devereux is a cardiologist at the New York Presbyterian Hospital. He talks about the variability of symptoms among people with Marfan syndrome. Physical characteristics. Dr. Devereux lists some of the physical characteristics associated with Marfan syndrome. Diagnosis Dr. Devereux talks about how he would proceed with a Marfan syndrome diagnosis. DNA Diagnosis Since the fibrillin gene has been cloned, Dr. Devereux discusses the development and use of DNA tests for diagnosis. Diagnosis in Children Dr. Devereux talks about how to diagnose children with Marfan syndrome, specifically comparing the length of growing bones. Aortic Dissections Dr. Richard Devereux is a cardiologist at the New York Presbyterian Hospital. He talks about the dangers of aortic dissections and the various treatment options. Elective Heart Surgery Dr. Devereux discusses surgery as an option for those who have enlarged aortas. Preventing Heart Problems Dr. Devereux talks about ways to reduce stress on the aorta and the heart. Eye Conditions Dr. Devereux discusses the possibility of eye problems, such as lens displacements, in people with Marfan syndrome. Skeletal Problems Dr. Devereux talks about skeletal problems common among people with Marfan syndrome. Skeletal Treatments Dr. Devereux talks about different ways to deal with skeletal problems. Medication Joe Gagliano, president of the National Marfan Foundation (NMF), and Julie Kurnitz talks about adjusting to the medications they take. Exercise Joe Gagliano talks about the need to balance the level of exertion and physical activity with quality of life. Managing Healthcare Joe Gagliano and Julie Kurnitz talk about the need for extra specialists to treat Marfan syndrome. A team of doctors is necessary for this multi-system disorder. Educating Others Julie Kurnitz talks about the need for people to be aware of the serious health risks of Marfan syndrome, and what she has done to try to raise awareness. Post-diagnosis Feelings 1 Joe Gagliano and Julie Kurnitz talks about how they felt after being diagnosed with Marfan syndrome. Post-diagnosis Feelings 2 Joe Gagliano and Julie Kurnitz talks about how they dealt with their feelings after being diagnosed with Marfan syndrome. Support Julie Kurnitz talks about Marfan support groups: the information and the emotionl support they can provide. Parental Guilt Joe Gagliano talksabout how his father felt knowing that his children inherited Marfan syndrome from him. Abraham Lincoln Richard Devereux, professor of medicine at Cornell University, talks about evidence that historical figures, like Abraham Lincoln, had Marfan syndrome. Alzheimer Disease
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Fragile X Syndrome ...
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