Marfan Syndrome
Introduction
Marfan syndrome (MF) is a condition that is caused by a genetic disorder. The gene that enables the body to produce proteins that provides connective tissue its strength and elasticity becomes defective. Due to the fact connective tissue helps make up or structure many parts in the body, MF can affect almost any part of the body and cause a wide variety of complications. One of the most dangerous complications involve the heart and to be more specific the aorta; whether it leads to an aneurysm or a dissection. Other common severe complications occur in the heart valves, retinas, and lens. Physical appearances commonly associated with MF include tall, slender build, curved or altered spine, disproportionately long arms, legs, and fingers.
This disease is caused by the up regulation of the TGF-b pathway, leading to over expression of collagen (connective tissue) synthesis proteins and matrix degradation proteins. The dysregulation of both pathways is the reason for the variety of symptoms for each individual patient.
Unfortunately, there is no cure for this disorder, but with early diagnosing and proper education of what to watch out for, and routine doctor visits the patient can maintain a fairly normal lifestyle.
Symptoms
Symptoms vary greatly for patients diagnosed with Marfan MF, even members of the same family experience the condition differently. Physical attributes associated with MF include: tall and slender build, flat feet, disproportionately long arms, legs, and fingers, extreme nearsightedness, abnormally curved spine, heart murmurs, and a breastbone that protrudes outward or dips inward. The more severe complications arise in the eyes and cardiovascular system and both tend to worsen with age.
The most dangerous complications involve the heart, more specifically the aorta and the valves due to defective connective tissue caused by MF. The weakened wall of the aorta begins to bulge out from pressure of the blood leaving the heart resulting in what is called an aortic aneurysm. Over time an aortic dissection may occur, which a small tear in the innermost layer causing blood to flow between the layers. This causes severe pain in the chest or back and may result in a rupture, which could be fatal. Lastly are valve malformations, it is where they become overly elastic or just plain malformed. With bad valves, your heart has to work harder to compensate causing irregular blood pressure, possibly leading to heart failure.
As for the eyes, lens dislocation can occur. The medical term for this is ectopia lentis and is when your lens moves out of place due to its supporting structure weakening. More than half of the patients diagnosed with MF have this problem. Detachment or tears in the retina also occur more frequently in MF patients as well as early-onset glaucoma or cataracts.
So, it is critical to keep an eye out for these conditions involving the heart and eyes at a much younger age to help prevent any long-term complications or damage.
The only diseased portion of this pathway is the overexpression of TGF-b and upregulation of this pathway due to the inability of latency-associated peptide(LAP) to bind with the TGF-b homodimer and inactivate it. The mechanism is not well known as to what causes this, but it is said to be associated with the abnormalities in fibrillin-1 leading to impaired latent TGF-b complexes.
The TGF-b pathway can signal through a classical and non-canonical pathway. The classical pathway consists of a bound TGF-b ligand to TGF-bR2, which recruits TGF-bR1 forming a heteromeric complex. This activated receptor phosphorylates a receptor-Smad, which then binds co-Smad and translocates into the nucleus leading to collagen and elastin proliferation. In the non-canonical pathway, TRAF6 associates with TGF-bR1, which recruits TGF-b associated kinase-1 (TAK1), which in turn activates p38MAPK. This kinase initiates a signaling cascade leading to enhanced matrix degradation, but also can crosstalk with the classical pathway and activate that as well.
The overexpression of these different pathways and their variable results is what leads to the inconsistent malformations of connective tissue in the body.
Signaling Pathway
Treatments
Due to the fact the heart provides the greatest complications with regards to MFS, it only makes sense initial treatments start there. Early on the standard of care began with beta-blockers (propranolol) because of their ability to slow aortic root dilatation, ultimately decreasing the chances of an aneurysm. However, because beta-blockers present with many difficult to manage side effects, especially at high doses, extensive research was performed to pursue other therapeutics. Finally, research proved that angiotensin converting enzyme (ACE) inhibitors (losartan) provide benefit over the standard of care (beta-blockers). It was reported to reduce stiffness, improve aortic distensibility, allow for a smaller root diameter, and provided more manageable side effects.
Unfortunately, there is no treatment for the eye issues MFS causes. Early onset glaucoma, cataracts, or lens dislocation may occur, but the treatment is the same as any other patient. Which is why patients with MFS should have their eyes checked at least once a year to keep a close watch on any possible complications. Furthermore, studies have shown blocking TGF-b receptors had no effect on Smad activation and treatment with Losartan or a p38MAPK inhibitor still induced Smad phosphorylation.
Side Effects
Side effects from beta-blockers include: slower heart rate, changes in blood sugar, sudden weight gain, and nausea. As for ACE inhibitors side effects include: hyperkalemia, fatigue, dizziness, dry cough, and sometimes angioedema, which could be life threatening depending on the area of occurrence.
References
Will add hyperlinks and references after completing :) (and more pictures!)