Marfan Syndrome?

What causes the Marfan syndrome?

HEY "DOCTOR," IT'S POLITE TO GIVE A CITATION WHEN CUTTING AND PASTING FROM eMEDICINE
http://www.emedicine.com/ped/topic1372.h...

It's a genetic mutation in the FBN1 gene on chromosome 15. FBN1 codes the synthesis of a proteine called fibrillin. Fibrillin is important for connective tissue strength. If you have Marfan Syndrome, your ability to produce fibrillin is impaired, so you can get weakness in the aorta.

It's a genetic disorder

Background: Marfan syndrome is an inherited connective tissue disorder transmitted as an autosomal dominant trait. It is noteworthy for its worldwide distribution, relatively high prevalence, clinical variability, and pleiotropic manifestations, some of which are life threatening. The disorder results from molecular defects in the fibrillin gene that are responsible for the impaired structural integrity of the skeletal, ocular, and cardiovascular systems. Cardinal features of the disorder include tall stature, ectopia lentis, mitral-valve prolapse, aortic-root dilatation, and aortic dissection. About three quarters of patients have an affected parent; new mutations account for the remainder. Marfan syndrome is fully penetrant with marked interfamilial and intrafamilial variability.

Pathophysiology: Marfan syndrome is caused by mutations in the fibrillin-1 (FBN1) gene located on chromosome 15q21.1. The gene encodes the glycoprotein fibrillin, a major building block of microfibrils, which constitute the structural components of the suspensory ligament of the lens and which serve as substrates for elastin in the aorta and other connective tissues. Abnormalities involving microfibrils weaken the aortic wall. Progressive aortic dilatation and eventual aortic dissection occur because of tension caused by left ventricular ejection impulses. Likewise, deficient fibrillin deposition leads to reduced structural integrity of the lens zonules, ligaments, lung airways, and spinal dura.

Production of abnormal fibrillin-1 monomers from the mutated gene disrupts the multimerization of fibrillin-1 and prevents microfibril formation. This pathogenetic mechanism has been termed dominant-negative because the mutant fibrillin-1 disrupts microfibril formation though the other fibrillin gene encodes normal fibrillin. This proposed mechanism is evinced by the fact that cultured skin fibroblasts from patients with Marfan syndrome produce greatly diminished and abnormal microfibrils.

Three other proposed pathophysiologic mechanisms are a disturbance of tissue homeostasis of elastic fibers, increased susceptibility of fibrillin to proteolysis, and marked dysregulation of transforming growth factor-beta (TGF-beta) activation and signaling resulting in apoptosis, as shown in the developing lung of mice deficient in fibrillin-1. Identification of mutations in TGFBR2 (gene encoding TGF-beta receptor type II) in type II Marfan syndrome (MFS2 mapped at 3p24.2-p25) was a major step that provided direct evidence of abnormal TGF-beta signaling in the pathogenesis of Marfan syndrome.

Abnormalities of TGFBR2 and TGFBR1 were also reported to cause a new syndrome associated with aortic aneurysm and congenital anomalies (Loeys-Dietz aortic aneurysm syndrome, Online Mendelian Inheritance in Man [OMIM] 609192). These results define a new group of Marfan syndrome-related connective-tissue disorders, namely, TGF-beta signalopathies.

Nice to have a doctor here to explain it. Hey doc, could you please see about educating other doctors? I am tired of being a Guinea Pig!
I am a 3rd generation Marfan with 11 surgeries in the past 16 years. Some of them not too bad but the TAAA was a *****! Still need more surgery, but on my knees instead of aorta!