MARFAN SYNDROME

ABOUT AUTHORS:
Jyotirmoyee Patnaik
Kanak Manjari Institute of pharmaceutical Sciences.
Rourkela, Orissa
patnaik.jyotirmoyee@gmail.com

ABSTRACT:
Marfan syndrome is an inherited disease that affects the body's connective tissue, which provides the strength, support and elasticity to tendons, cartilage, heart valves, blood vessels, and other vital parts of the body. Marfan syndrome is a systemic, heritable connective tissue disorder that affects many different organ systems.

REFERENCE ID: PHARMATUTOR-ART-2103

INTRODUCTION:
Marfan syndrome (also called Marfan's syndrome) is a genetic disorder of the connective tissue. People with Marfan tend to be unusually tall, with long limbs and long, thin fingers.

The syndrome is carried by the gene FBN1, which encodes the connective protein fibrillin-1. Marfan syndrome is a dominant genetic trait, meaning that people who inherit only one copy of the Marfan FBN1 gene from either parent will develop Marfan syndrome and be able to transmit it to their children.

Marfan syndrome has a range of expressions, from mild to severe. The most serious complications are defects of the heart valves and aorta. It may also affect the lungs, the eyes, the dural sac surrounding the spinal cord, the skeleton and the hard palate.

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). TGF-β has deleterious effects on vascular smooth muscle development and the integrity of the extracellular matrix. Researchers now believe, secondary to mutated fibrillin, excessive TGF-β at the lungs, heart valves, and aorta weakens the tissues and causes the features of Marfan syndrome. Since angiotensin II receptor antagonists (ARBs) also reduce TGF-β, ARBs (losartan, etc.) have been tested in a small sample of young, severely affected Marfan syndrome patients. In some patients, the growth of the aorta was indeed reduced.

Marfan syndrome is named after Antoine Marfan, the French pediatrician who first described the condition in 1896. The gene linked to the disease was first identified by Hal Dietz and Francesco Ramirez in 1991.

CAUSES:
Marfan syndrome is caused by defects in a gene called fibrillin-1. Fibrillin-1 plays an important role as the building block for connective tissue in the body.

The gene defect also causes too much growth of the long bones of the body. This causes the tall height and long arms and legs seen in people with this syndrome. How this overgrowth happens is not well understood.

Other areas of the body that are affected include:

Lung tissue (there may be a pneumothorax, in which air can escape from the lung into the chest cavity and collapse the lung)
The aorta, the main blood vessel that takes blood from the heart to the body may stretch or become weak (called aortic dilation or aortic aneurysm)
The eyes, causing cataracts and other problems (such as a dislocation of the lenses)
The skin
Tissue covering the spinal cord

In most cases, Marfan syndrome is inherited, which means it is passed down through families. However, up to 30% of patients have no family history, which is called "sporadic." In sporadic cases, the syndrome is believed to be caused by a new gene change.

SYMPTOM:
Marfan syndrome affects different people in different ways. Some people have only mild symptoms, while others are more severely affected. In most cases, the symptoms progress as the person ages. The body systems most often affected by Marfan syndrome are:

Skeleton:People with Marfan syndrome are typically very tall, slender, and loose-jointed. Because Marfan syndrome affects the long bones of the skeleton, a person's arms, legs, fingers, and toes may be disproportionately long in relation to the rest of the body. A person with Marfan syndrome often has a long, narrow face, and the roof of the mouth may be arched, causing the teeth to be crowded. Other skeletal problems include a sternum (breastbone) that is either protruding or indented, curvature of the spine (scoliosis), and flat feet.

Eyes: More than half of all people with Marfan syndrome experience dislocation of one or both lenses of the eye. The lens may be slightly higher or lower than normal, and may be shifted off to one side. The dislocation may be minimal, or it may be pronounced and obvious. One serious complication that may occur with this disorder is retinal detachment. Many people with Marfan syndrome are also nearsighted (myopic), and some can develop early glaucoma (high pressure within the eye) or cataracts (the eye's lens loses its clearness).

Heart and blood vessels (cardiovascular system):Most people with Marfan syndrome have problems associated with the heart and blood vessels. Because of faulty connective tissue, the wall of the aorta (the large artery that carries blood from the heart to the rest of the body) may be weakened and stretch, a process called aortic dilatation. Aortic dilatation increases the risk that the aorta will tear (aortic dissection) or rupture, causing serious heart problems or sometimes sudden death. Sometimes, defects in heart valves can also cause problems. In some cases, certain valves may leak, creating a "heart murmur," which a doctor can hear with a stethoscope. Small leaks may not result in any symptoms, but larger ones may cause shortness of breath, fatigue, and palpitations (a very fast or irregular heart rate).

Nervous system: The brain and spinal cord are surrounded by fluid contained by a membrane called the dura, which is composed of connective tissue. As someone with Marfan syndrome gets older, the dura often weakens and stretches, then begins to weigh on the vertebrae in the lower spine and wear away the bone surrounding the spinal cord. This is called dural ectasia. These changes may cause only mild discomfort; or they may lead to radiated pain in the abdomen; or to pain, numbness, or weakness in the legs.

Skin: Many people with Marfan syndrome develop stretch marks on their skin, even without any weight change. These stretch marks can occur at any age and pose no health risk. However, people with Marfan syndrome are also at increased risk for developing an abdominal or inguinal hernia, in which a bulge develops that contains part of the intestines.

Lungs: Although connective tissue problems make the tiny air sacs within the lungs less elastic, people with Marfan syndrome generally do not experience noticeable problems with their lungs. If, however, these tiny air sacs become stretched or swollen, the risk of lung collapse may increase. Rarely, people with Marfan syndrome may have sleep-related breathing disorders such as snoring, or sleep apnea (which is characterized by brief periods when breathing stops).

PATHOGENESIS:
Marfan syndrome is caused by mutations in the FBN1 gene on chromosome 15, which encodes the glycoprotein fibrillin-1, a component of the extracellular matrix. Fibrillin-1 protein is essential for the proper formation of the extracellular matrix, including the biogenesis and maintenance of elastic fibers. The extracellular matrix is critical for both the structural integrity of connective tissue, but also serves as a reservoir for growth factors. Elastin fibers are found throughout the body, but are particularly abundant in the aorta, ligaments and the ciliary zonules of the eye; consequently, these areas are among the worst affected.

A transgenic mouse has been created carrying a single copy of a mutant fibrillin-1, a mutation similar to that found in the human gene known to cause Marfan syndrome. This mouse strain recapitulates many of the features of the human disease and promises to provide insights into the pathogenesis of the disease. Reducing the level of normal fibrillin 1 causes a Marfan-related disease in mice.

Transforming growth factor beta (TGFβ) plays an important role in Marfan syndrome. Fibrillin-1 directly binds a latent form of TGFβ, keeping it sequestered and unable to exert its biological activity. The simplest model of Marfan syndrome suggests reduced levels of fibrillin-1 allow TGFβ levels to rise due to inadequate sequestration. Although it is not proven how elevated TGFβ levels are responsible for the specific pathology seen with the disease, an inflammatory reaction releasing proteases that slowly degrade the elastin fibers and other components of the extracellular matrix is known to occur. The importance of the TGFβ pathway was confirmed with the discovery of the similar Loeys-Dietz syndrome involving the TGFβR2 gene on chromosome 3, a receptor protein of TGFβ. Marfan syndrome has often been confused with Loeys-Dietz syndrome, because of the considerable clinical overlap between the two pathologies.

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TREATMENT: There is no cure for Marfan syndrome. To develop one, scientists may have to identify and change the specific gene responsible for the disorder before birth. However, a range of treatment options can minimize and sometimes prevent complications. The appropriate specialists will develop an individualized treatment program; the approach the doctor’s use depends on which systems have been affected.

Skeletal. Annual evaluations are important to detect any changes in the spine or sternum. This is particularly important in times of rapid growth, such as adolescence. A serious malformation not only can be disfiguring, but also can prevent the heart and lungs from functioning properly. In some cases, an orthopedic brace or surgery may be recommended to limit damage and disfigurement.

Eyes. Early, regular eye examinations are essential for identifying and correcting any vision problems associated with Marfan syndrome. In most cases, eyeglasses or contact lenses can correct the problem, although surgery may be necessary in some cases.

Heart and blood vessels. Regular checkups and echocardiograms help the doctor evaluate the size of the aorta and the way the heart is working. The earlier a potential problem is identified and treated, the lower the risk of life-threatening complications. Those with heart problems are encouraged to wear a medical alert bracelet and to go to the emergency room if they experience chest, back, or abdominal pain. Some heart-valve problems can be managed with drugs such as beta-blockers, which may help decrease stress on the aorta. In other cases, surgery to replace a valve or repair the aorta may be necessary.

Surgery should be performed before the aorta reaches a size that puts it at high risk for tear or rupture. Because blood clots can form around artificial heart valves, people who have a valve replaced must take the blood-thinning drug warfarin for the rest of their lives. They must also take extreme care to prevent endocarditis (inflammation of the lining of the heart cavity and valves). Dentists should be alerted to this risk; they are likely to recommend that the patient be prescribed protective medicines before they perform dental work. Because warfarin carries a risk of some serious side effects, including excessive bleeding, and because it is dangerous to unborn babies, doctors are increasingly opting for a newer aortic root replacement procedure that enables people to keep their own valves. The procedure involves removing and replacing the enlarged part of the aorta with a Dacron tube, and re suspending the natural valve into the tube so that the tube supports the valve. The procedure is often performed at an earlier stage than traditional valve replacement. It may also be offered to women with aortic enlargement who are considering becoming pregnant, because it can prevent the rapid aortic growth and possible tearing that sometimes occur during pregnancy.

Nervous system. If dural ectasia (swelling of the covering of the spinal cord) develops, medication may help minimize any associated pain.
Lungs. It is especially important that people with Marfan syndrome not smoke, as they are already at increased risk for lung damage. Any problems with breathing during sleep should be assessed by a doctor.

Pregnancy poses a particular concern due to the stress on the body, particularly the heart. A pregnancy should be undertaken only under conditions specified by obstetricians and other specialists familiar with Marfan syndrome. In some cases, valve surgery prior to pregnancy may be warranted. The pregnancy should be monitored as a high-risk condition. Women with Marfan syndrome may also seek genetic counseling concerning the likelihood that they will pass the disease on to their children.

Although eating a balanced diet is important for maintaining a healthy lifestyle, no vitamin or dietary supplement has been shown to help slow, cure, or prevent Marfan syndrome.

For most people with Marfan syndrome, engaging in moderate aerobic exercise is important for promoting skeletal and cardiovascular health and a sense of well-being. However, because of the risk of aortic dissection, people with the syndrome should not engage in contact sports, competitive athletics, or isometric exercise.

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