Pathophysiology and Japanese clinical characteristics in Marfan syndrome

Abstract

Marfan syndrome is an autosomal dominant heritable disorder of the connective tissue, caused by mutations of the gene FBN1, which encodes fibrillin-1, a major component of the microfibrils of the extracellular matrix. Fibrillin-1 interacts with transforming growth factor-β (TGF-β), and dysregulated TGF-β signaling plays a major role in the development of connective tissue disease and familial aortic aneurysm and dissection, including Marfan syndrome. Losartan, an angiotensin II blocker, has the potential to reduce TGF-β signaling and is expected to be an additional therapeutic option. Clinical diagnosis is made using the Ghent nosology, which requires comprehensive patient assessment and has been proven to work well, but evaluation of some of the diagnostic criteria by a single physician is difficult and timeconsuming. A Marfan clinic was established at the University of Tokyo Hospital in 2005, together with cardiologists, cardiac surgeons, pediatricians, orthopedists, and ophthalmologists in one place, for the purpose of speedy and accurate evaluation and diagnosis of Marfan syndrome. In this review, we discuss the recent progress in diagnosis and treatment of Marfan syndrome, and the characteristics of Japanese patients with Marfan syndrome.

Peripartum type B aortic dissection in patients with Marfan syndrome who underwent aortic root replacement: a case series study

“…Diagnostic criteria of MFS were revised in 2010 (revised Ghent nosology) to place more emphasis on causative genetic analyses, aortic root aneurysm/dissection, and ectopia lentis (EL) . Since the release of the revised Ghent nosology, there have been two cohort studies on pregnancy outcomes of MFS patients collected from multiple institutions and five case series .…”

“…8 Diagnostic criteria of MFS were revised in 2010 (revised Ghent nosology) to place more emphasis on causative genetic analyses, aortic root aneurysm/dissection, and ectopia lentis (EL). 2,9,10 Since the release of the revised Ghent nosology, there have been two cohort studies on pregnancy outcomes of MFS patients collected from multiple institutions 11,12 and five case series. [13][14][15][16][17] Collectively, these reports indicate that (1) pregnant MFS patients have a higher risk of AD compared with non-pregnant MFS patients, 11,12 and (2) pregnancy increases the risk of aortic complications in the long-term.…”

Congenital Contractural Arachnodactyly without <i>FBN1</i> or <i>FBN2</i> Gene Mutations Complicated by Dilated Cardiomyopathy

“…The prevalence of clinical or subclinical heart failure in CCA patients has not been reported, and further cardiovascular studies are needed in adults with CCA. Recent advances in molecular and genetic analyses have improved the pathophysiological understanding of the cardiovascular features of CTD, and it has become clear that the dysregulation of TGFβ signaling is profoundly involved in the pathogenesis of such disorders (12)(13)(14). In human patients and mouse models, the loss-of-function of fibrillin-1 results in the aberrant release of TGFβ into the extracellular matrix, thus inducing the overactivity of TGFβ signaling.…”

Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys–Dietz Syndromes

“…In addition, more than 3,000 mutations have been identified in the FBN1 gene, and these are mostly unique in families. 11,27) The revised nosology provides useful criteria for causative FBN1 mutations, 18) emphasizing the significance of altered conserved residues of cysteine and EGF consensus sequences. Most mutations are considered to act in a dominant negative way exemplified by missense mutations, or through haploinsufficiency due to nonsense-mediated mRNA decay (NMD) mostly caused by splice-site, frameshift, and nonsense mutations.…”

“…Although LDS patients present several characteristics of MFS, LDS is characterized by rapidly progressive aortic/arterial tortuosity and aneurysmal disease that is known to result in ruptures at an early age and at smaller dimensions, and by widely spaced eyes (hypertelorism) and bifid uvula or cleft palate. [9][10][11] Until recently, mutations in TGFB2, 12,13) TGFB3, 14) and SMAD3, 15,16) which encode main members of the TGF-β/SMAD signal transduction pathway, were also reportedly associated with diseases that resemble MFS. Fibrillin-1 also regulates TGF-β bioavailability, and thus traditional definitions for the pathogenesis of MFS and related diseases have been dramatically revised.…”