Marfan syndrome and genetics
Marfan syndrome is a rare genetic disorder characterized by defects in the body's connective tissue, impacting various organ systems including the skeleton, heart, lungs, eyes, and blood vessels. This condition is primarily caused by mutations in the FBN1 gene, leading to reduced production of fibrillin-1, a protein essential for maintaining the structure and elasticity of connective tissue. Inheritance of Marfan syndrome is typically autosomal dominant, meaning that an affected individual has a 50% chance of passing the mutation to their children. Approximately 25% of cases arise from spontaneous mutations, which occur in individuals without a family history of the disorder.
Symptoms of Marfan syndrome can vary widely and may include cardiovascular issues such as mitral valve prolapse and aortic aneurysms, along with skeletal features like tall stature and long limbs. Eye problems like myopia and lens dislocation are also common. Diagnosis is often challenging and relies on a combination of clinical evaluation and family medical history, supported by tests like echocardiograms and comprehensive eye exams. Although there is no cure, treatment focuses on managing symptoms and preventing complications, which may involve regular monitoring, medications, or surgical interventions. Individuals at risk or with a family history of Marfan syndrome are encouraged to consult with a genetic counselor for guidance and risk assessment.
Marfan syndrome and genetics
DEFINITION: Marfan syndrome is a rare disorder that causes a defect in the body’s connective tissue. This tissue is common throughout the body; it holds the body together and supports many of its structures. As a result, Marfan syndrome affects many organ systems, including the skeleton, particularly the joints, lungs, eyes, and the heart and blood vessels.
Risk Factors
Individuals who have family members with Marfan syndrome are at risk of getting the disorder. The child of a parent with Marfan syndrome has a 50 percent chance of inheriting the condition. Children whose parents were at an advanced age at the time of their births are also at risk.
Etiology and Genetics
Classic Marfan syndrome is an autosomal dominant disorder that results from mutations in the FBN1 gene, found on the long arm of chromosome 15 at position 15q21.1. In autosomal dominant inheritance, a single copy of the mutation is sufficient to cause full expression of the syndrome. An affected individual has a 50 percent chance of transmitting the mutation to each of his or her children. About 25 percent of cases of Marfan syndrome, however, result from a spontaneous new mutation, so in these instances, affected individuals will have unaffected parents.
The FBN1 gene encodes a large protein called fibrillin-1. This protein is excreted by cells into the extracellular matrix, where it binds to other molecules of fibrillin-1 and some other proteins to form long, thin structural fibers called microfibrils. These in turn become part of the molecular lattice that provides strength and flexibility to connective tissue, allowing the skin, ligaments, and blood vessels to stretch. Mutations that cause a drastically reduced amount of fibrillin-1 to be produced will result in weakened and inflexible connective tissue that will lead to the clinical symptoms associated with Marfan syndrome.
A small percentage of cases of Marfan syndrome are caused by mutations in a different gene, known as TGFBR2. Located on the short arm of chromosome 3 at position 3p22, this gene specifies a protein called transforming growth factor-beta type II receptor. This is an integral cell membrane protein that serves to receive and transmit chemical signals to the inside of the cell at times when cell division and growth are needed. It also plays a role in the formation of the extracellular matrix, and it is this function that is disrupted in cases where mutations in the gene lead to the development of Marfan syndrome. Inheritance of mutations in this gene also occurs in an autosomal dominant fashion.
Symptoms
Symptoms of Marfan syndrome range from mild to severe. The disorder can affect one or many parts of the body. Some symptoms may be evident at an early age; others may develop later in life. Some symptoms may worsen with age.
Symptoms that affect the heart and blood vessels include abnormalities of the heart valves and blood vessels; mitral valve prolapse, which can lead to leakage of the mitral valve or irregular heart rhythm; and a weakened or stretched aorta, the artery that leads from the heart, which can lead to an aortic aneurysm. People with Marfan syndrome are also at increased risk of aortic dissection, a dangerous condition that occurs when the layers of the aorta seperate because of a tear in the inner layer. There are two types of aortic dissection, including type A dissections that occur in the ascending aorta and type B dissections that occur in the descending aorta. While people with Marfan syndrome can be prone to both types of aortic dissections, the incidence of type B dissections is increasingly outpacing that of type A dissections. A 2023 study published in the Journal of the American College of Cardiology concluded that Marfan syndrome patients who experience type B aortic dissections are part of a cohort with a more severe overal phenotype
Symptoms affecting the eyes include dislocated eye lenses; myopia (nearsightedness), which sometimes is severe; glaucoma; cataracts; and a detached retina.
Symptoms affecting the bones include having a tall, slender build; loose joints; unusually long legs, arms, fingers, and toes; crowded teeth; a malformed breastbone; a curved spine; a high, arched palate in the mouth; and the risk of bone thinning (osteoporosis) in adult life. Symptoms affecting the back include back pain and a weakening of the supportive tissue of the spine with age. In rare cases, lung collapse can also be a symptom of Marfan syndrome.
Screening and Diagnosis
Marfan syndrome is difficult to diagnose. There is no specific test for the condition. A doctor can diagnose Marfan syndrome by observing the symptoms, performing a complete physical exam, and carefully studying the medical histories of the patient and the patient’s family. The doctor can also perform tests, such as an echocardiogram, a test that uses high-frequency sound waves to examine the size, shape, and motion of the heart. A complete eye examination is another test for the disorder. The first-degree relatives (parents, brothers, and sisters) of individuals who have Marfan syndrome should be screened for the disorder.
Treatment and Therapy
There is no cure for Marfan syndrome. Treatment is aimed at preventing or reducing complications or symptoms. Treatment for heart and blood vessels may include regular monitoring of the heart and aorta with regular check-ups and echocardiograms. Patients may also avoid strenuous exercise or contact sports, as directed by their doctors. Preventive antibiotics may be administered before medical procedures or dental cleaning for patients with valvular or aortic problems. Patients may also be given heart medications, such as beta blockers. Losartan is currently being investigated for use in aortic aneurysm prevention. Pregnant women with Marfan syndrome may be particularly closely monitored. In addition, patients may receive surgery to repair or replace a defective heart valve or aorta.
Treatment for the eyes may include regular eye examinations to check for eye problems, eyeglasses or contact lenses to correct myopia or problems with the eye lens, and eye surgery for severe problems.
Treatment for the bones may include regular physical exams to monitor for bone problems, especially during adolescence. In severe cases, treatment may include an orthopedic brace or surgery. A patient’s back can be treated with exercises or medication to relieve the pain caused by spinal weakness. Patients with lung problems may have to avoid smoking.
Prevention and Outcomes
There are no guidelines for preventing Marfan syndrome. Individuals can contact a genetic counselor to determine the risk of passing the condition on to their children.
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