Marfan Syndrome

By: Urmika Balaji, Contributing Writer

Edited by: Fauzia Haque, Editor; Elias Azizi, Editor in Chief

Introduction:

Abraham Lincoln, the tallest American president standing at 6 foot and 4 inches, is believed to have had Marfan syndrome (Time). This was due to his height, but also due to his disproportionately long arms. However, there is no way of proving this as It was only after Lincoln’s death that Marfan Syndrome was discovered by the French pediatrician, Antoine-Bernard Marfan, in 1896 (HGV). Marfan Syndrome is a rare autosomal-dominant genetic disorder that affects connective tissue in the body, resulting in cardiovascular, ocular, or skeletal complications (Mayo Clinic). It is usually characterized by abnormally long fingers, arms, and legs, crowded teeth, protruding breastbone, an abnormally curved spine, flat feet, and extreme nearsightedness. Marfan Syndrome appears from 1 in every 3000 births to 1 in 5000 births (AHA). Going down to the molecular level, this article will examine how the mutation that causes Marfan Syndrome results in certain medical complications and how these conditions are treated.

Molecular Effects:

Marfan Syndrome is inherited in the autosomal dominant pattern, meaning that an individual only needs one copy of the gene to have the condition, and if one parent has it, there is at least a 50% chance the child will have it (HGV). Marfan Syndrome is caused by over 1,300 mutations in the fibrillin 1 gene located on chromosome 15, and many of these mutations are overlapped with other conditions, such as Loeys-Dietz Syndrome (LDS), Shprintzen-Goldberg Syndrome (SGS) and the MASS (Mitral valve, Aorta, Skeletal, Skin) Syndrome. Therefore, Marfan Syndrome can be difficult to distinguish especially in the younger years (HGV). The fibrillin 1 gene codes for an extracellular matrix glycoprotein that plays a role in the formation of microfibrils. The formation of microfibrils affects the elasticity and structure of many types of tissues. Mutations in the fibrillin 1 gene can decrease the production of fibrillin by the cell, alter the structure of the fibrillin 1 protein, or prevent the transport of fibrillin outside of the cell. This affects the formation and the amount of microfibril in tissues, as there is significantly less fibrillin to produce the microfibril. The microfibril stores a growth factor called Transforming Growth Factor Beta (TGF-β), a protein that regulates cell division, cell differentiation, cell movement, and apoptosis (programmed cell death). When TGF-β binds to a receptor, its signal activates the production of CDK (cyclin dependant kinase) inhibitors, which stop the progression of cell division. TGF-β remains inactivated when stored inside the microfibril, but is activated when released, making it available to bind to cellular receptors and inhibit cell proliferation. With less functional microfibril to store it, more TGF-β is activated, allowing them to bind to receptors. This reduces the elasticity of tissues, leading to many of the symptoms of Marfan Syndrome (HGV).

Specific Conditions and Treatment:

Aortic Aneurysm

Aortic Aneurysms are a common and life-threatening symptom of Marfan Syndrome. With the combined effect of blood pressure and weak vessel tissue, individuals with Marfan Syndrome have a higher chance of dilating and rupturing their blood vessels, most commonly in the aortic root, where oxygenated blood is carried out to the rest of the body. The ruptured vessels can leak and clot in other vessels, causing further complications. After the vessel dilates to 4.7 centimeters or more, most individuals with Marfan Syndrome undergo a surgery where the dilated section of the aorta is replaced with a tissue or mechanical valve (Mayo Clinic). To prevent aortic aneurysms, individuals with Marfan Syndrome take blood pressure medications, regular echocardiograms to monitor the heart and aorta, and avoid strenuous exercise, because it increases blood flow and pressure (Escardio, JTD).

Mitral Valve Prolapse

The mitral valve is located between the left atrium and left ventricle. Mitral Valve Prolapse occurs when the cusps collapse, as an effect of weak connective tissue, into the left atrium instead of closing during systole, when the heart contracts. This causes some of the blood to leak into the left atrium instead of flowing into the aorta, causing a characteristic “murmur” (NORD). Mitral Valve Prolapse can be asymptomatic during its initial stages, but it can eventually lead to congestive heart failure and chest pain. Individuals with damaged valves are often susceptible to bacterial infections, so antibiotics are initially prescribed. However, the valves are eventually replaced by surgery (NORD).

Ectopia Lentis (Lens Dislocation)

Ectopia Lentis is found in 60 to 68% of all individuals with Marfan Syndrome (Open Ophthalmology Journal). It is characterized by the dislocation of the crystalline lens on the eye, which can cause nearsightedness, irregular curving of the lens, and blurred vision in the individual (MedlinePlus). The lens is located in the front of the eye and helps focus light. The dislocation of the lens occurs due to the weak ocular connective tissue, as a result of lower amounts of fibrillin proteins, which prevents the lens from being properly attached to the cornea, the outer layer of the eye. The dislocation occurs independently on each eye, and disalines more over time (MedlinePlus). This condition is typically treated through the use of eyeglasses, contact lenses, or if severe, surgical intervention (NORD). Additionally, individuals also avoid playing sports that may result in head trauma (soccer, football, diving, etc.) (NORD).

Skeletal Malformations

Skeletal malformations caused by Marfan Syndrome can include overgrowth of the ribs, curving of the spine (scoliosis), and other elongated effects on bone structures (long and bent fingers, flexible joints, etc.) (NORD). The lack of connective tissue as a result of the mutated fibrillin gene causes the overgrowth of bones, resulting in these malformations. The overgrowth of the ribs causes a protruded or sunken chest, which is usually corrected surgically. These malformations can worsen during puberty, when individuals undergo rapid growth (NORD). For scoliosis, braces may be used to correct the curving, but if the curve exceeds ten degrees and continues to worsen, the curve may be surgically corrected.

Conclusion

The life expectancy of individuals with Marfan Syndrome is nearly 70 years, despite their heavy risk for cardiovascular, skeletal, and ocular issues (Medicine Net). Though Marfan Syndrome is molecularly incurable, most of the conditions associated with it can be treated, which allows for this extended life expectancy. Due to the advancement of medical technology in the past 50 years, life expectancy has seen an increase of more than 25 percent (Medicine Net). In the near future, we can hope to see new technology for targeting specific mutations and proteins to cure or regulate the symptoms of Marfan Syndrome.