Marfan Syndrome

Author: beatrice boido
Date: 05/07/2010


Flora Jean Hyman (1954-1986) was an American volleyball player and Olympic silver medalist. She collapsed while sitting on the sidelines after being substituted out in a game against Hitachi. She told her team to keep fighting, then moments later slid to the floor and died. At first, the cause of her death was stated to be a heart attack, but an autopsy, discovered that her death was due to an aortic dissection resulting from previously undiagnosed Marfan syndrome.

It is sometimes inherited as a dominant trait. It is carried by a gene called FBN1, which encodes a connective protein called fibrillin-1. People have a pair of FBN1 genes. This syndrome can run from mild to severe. Sometimes a new gene defect occurs during the formation of sperm or egg cells, but two unaffected parents have only a 1 in 10,000 chance of having a child with Marfan syndrome. Possibly 25 percent of cases are due to a spontaneous mutation at the time of conception. A person with Marfan syndrome is born with the disorder, even though it may not be diagnosed until later in life. Although everyone with Marfan syndrome has a defect in the same gene, the mutation is specific to each family and not everyone experiences the same characteristics to the same degree (variable expression).

People with Marfan's are typically tall, with long limbs and long thin fingers. The most serious complications are the defects of the heart valves and aorta. Leaks in valves that control blood flow through the heart can cause shortness of breath, fatigue, and an irregular heartbeat felt as skipped or extra beats (palpitations). If leakage occurs, it usually affects the mitral valve or the aortic valve. The aorta can weaken and stretch, which may lead to a bulge in the blood vessel wall (an aneurysm). Aortic aneurysm and dissection can be life threatening. It may also affect the lungs, eyes, the dural sac surrounding the spinal cord, skeleton and the hard palate.


is a large protein, extracellular matrix glycoprotein that serve as a structural component of 10-12 nm calcium-binding microfibrils. These microfibrils provide force bearing structural support in elastic and nonelastic connective tissue throughout the body.
Researchers have identified more than 600 FBN1 mutations that cause Marfan syndrome. More than 60 percent of these mutations change one of the amino acids used to make fibrillin-1. The remaining FBN1 mutations produce an abnormally small fibrillin-1 protein that cannot function properly. FBN1 mutations reduce the amount of fibrillin-1 produced by the cell, alter the structure or stability of fibrillin-1, or impair the transport of fibrillin-1 out of the cell. As a result, the amount of fibrillin-1 available to form microfibrils is severely reduced. Decreased microfibril formation probably weakens the elastic fibers and causes overactivation of TGF-beta growth factors, which leads to the signs and symptoms of Marfan syndrome.
A mutation in the FBN1 gene has also been identified in one family with Weill-Marchesani syndrome. This mutation deletes part of the gene, leading to the production of an unstable version of the fibrillin-1 protein. The unstable protein likely interferes with the assembly of microfibrils. Abnormal microfibrils weaken connective tissue, which causes the eye, heart, and skeletal abnormalities associated with Weill-Marchesani syndrome.
Mutations in the FBN1 gene cause other disorders known as type 1 fibrillinopathies. Fibrillinopathies are disorders involving a deficiency of fibrillin proteins. Although Marfan syndrome is the most common type 1 fibrillinopathy, FBN1 mutations also cause a spectrum of disorders that vary in the age of onset and severity of symptoms.

  • Some FBN1 mutations cause an adult-onset disorder called isolated ectopia lentis, in which dislocation of the lens of the eye causes vision problems.
  • Other FBN1 mutations can cause an early-onset disorder known as Shprintzen-Goldberg craniosynostosis syndrome. The features of this syndrome are quite variable, but the main characteristics include premature fusion of certain bones of the skull that affects the shape of the head and face; heart defects; long, slender fingers and toes (arachnodactyly); hydrocephalus and intellectual disability.

In addition to being a connective protein that forms the structural support for tissues outside the cell, the normal fibrillin-1 protein binds to another protein, transforming growth factor beta (TGF-β) and have similarity to epidermal growth factor (EGF) so the fibrillin domain forms a calcium-binding, EGF-like module. As the putative calcium-binding sites are found at the amino-terminal end of the modules, has been proposed that calcium ions may bind in the interfaces between domains, affecting the overall structure of the protein. The Arg to Pro mutation, for instance, blocks domain folding in vitro, suggesting that lack of proper domain folding in vivo may contribute to the molecular defects responsible for Marfan syndrome.

The role of TGF- β

What is that factor?

TGF-β has deleterious effects on vascular smooth muscle development and the integrity of the extracellular matrix. Researchers now believe that secondary to mutated fibrillin there is excessive TGF-β at the lungs, heart valves, and aorta, and this weakens the tissues and causes the Marfan syndrome.

Some researchers believe that a small percentage of Marfan syndrome cases are caused by mutations in the TGFBR2 gene. These cases are called Marfan syndrome type II. The TGFBR2 gene provides instructions for making a protein that transmits signals from the cell surface to other signaling molecules inside the cell. These molecules then relay signals to the nucleus to either turn on or turn off specific genes. Through this signaling process, the environment outside the cell affects activities inside the cell such as division and growth. Mutations in the TGFBR2 gene alter the signaling activity of the protein, which disturbs the growth and development of cells and tissues.
To carry out its signaling function, the TGF-beta type II receptor spans the cell membrane, so that one end of the protein projects from the outer surface of the cell (the extracellular domain) and the other end remains inside the cell (the intracellular domain). The extracellular domain of the TGF-beta type II receptor associates with a similar receptor to form a receptor complex (type I receptor).

Signals triggered through the TGF-beta type II receptor complex prompt various responses by the cell. One such response is to inhibit cell growth and division. Based on this action, the TGF-beta type II receptor is sometimes called a tumor suppressor. Tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled way. The TGF-beta type II receptor also helps to control the process by which cells mature to carry out special functions (differentiation), and it plays a role in the formation of the extracellular matrix, an intricate lattice of proteins and other molecules that forms in the spaces between cells.
More than 10 mutations in the TGFBR2 gene have been identified. Almost all the mutations change one of the amino acids. Another type of mutation leads to a shortened version of this receptor. All of these mutations disrupt the signaling activity of the receptor, which probably disturbs the growth and development of cells and tissues. These disturbances lead to features of Marfan syndrome, such as skeletal abnormalities and heart problems.
Some TGFBR2 mutations are acquired during a person's lifetime and are present only in certain cells (somatic mutations). People appear to have an increased risk of developing various cancers. Unchecked cell division can lead to the formation of tumors, particularly when TGFBR2 mutations occur in the colon, rectum, and esophagus. It is estimated that 30 percent of cancerous (malignant) colon tumors have TGFBR2 mutations in their cells.

What about heart problems?
One disorder, known as familial thoracic aortic aneurysm and dissection (TAAD), involves problems with the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). The aorta can weaken and stretch, causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can be life threatening. TGFBR2 mutations that cause TAAD change a protein building block at a particular point (known as position 460; replace the amino acid arginine with the amino acids cysteine or histidine written as Arg460Cys or Arg460His, respectively).
Researchers have also identified several TGFBR2 mutations (increased signaling disturbs the formation of elastic fibers in the extracellular matrix, which in turn disrupts the function of flexible structures such as blood vessels) that cause a disorder called Loeys-Dietz syndrome (LDS). It is characterized by aortic aneurysms and dissections at a young age,arterial tortuosity, hypertelorism, cleft palate, scoliosis.


Unfortunately, no remedy or cure has evolved in medical science for doing away with this illness for good. What best can be done is to take up medical treatments and surgery which can help patients lead an improved and longer life spans.
If the disease has affected the cardiovascular systems of the body, then there might occur serious complications which might be fatal. So, in such a case, the Marfan syndrome treatment would involve annual heart exams. Medications to lower blood pressure are prescribed with an aim to keep the aorta from enlarging. These medications also reduce the risk of dissection, a fatal condition wherein a small tear in the innermost layer of the aorta's wall allows blood to squeeze in between the inner and outer layers of the wall. The drugs are used basically to make the heart slower and with less force. This in turn reduces the complications of any damage to the heart. The enlargement of aorta may attain a dangerous size which may result in a life-threatening rupture. So, this can be managed by a surgery to replace a portion of the aorta with an artificial material.
Researchers of the Johns Hopkins University School of Medicine tried to use Losartan to reduce the aortic aneurism, because the elevated levels of TGF-beta, which blocks activation of satellite cells—preventing them from proliferating and fusing into damaged myofibers to regenerate the muscle cells. A key regulator of latent TGF- activation is thrombospondin-1 (Tsp-1), which is produced in response to activation of the angiotensin II type 1 receptor (AT1) by angiotensin (AT). Losartan is a potent inhibitor of AT1 activation, thus blocking TGF-beta activation by inhibiting Tsp-1 production. After 12/47 months therapy they have noticed a significant reducing progression of aortic enlargement.

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