scholarly journals Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome

2015 ◽  
Vol 112 (45) ◽  
pp. 14012-14017 ◽  
Author(s):  
Lior Zilberberg ◽  
Colin K. L. Phoon ◽  
Ian Robertson ◽  
Branka Dabovic ◽  
Francesco Ramirez ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Marfan Syndrome ◽  
Autosomal Dominant ◽  
Aortic Disease ◽  
Elastic Fibers ◽  
Thoracic Aneurysm ◽  
Tgfβ Signaling ◽  
Autosomal Dominant Disorder ◽  
Present Evidence ◽  
Fibrillin 1

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFβ signaling. TGFβ is secreted from cells as a latent complex consisting of TGFβ, the TGFβ propeptide, and a molecule of latent TGFβ binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGFβ levels, and has been hypothesized as an explanation for enhanced TGFβ signaling observed in MFS. We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that perturbed TGFβ signaling in MFS might be due to defective interaction of latent TGFβ complexes containing LTBP-3 with mutant fibrillin-1 microfibrils. To test this hypothesis, we genetically suppressed Ltbp3 expression in a mouse model of progressively severe MFS. Here, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms, reduced disruption and fragmentation of medial elastic fibers, and decreased Smad2/3 and Erk1/2 activation in their aortas. These data suggest that, in MFS, improper localization of latent TGFβ complexes composed of LTBP-3 and TGFβ contributes to aortic disease progression.

scholarly journals Early-Onset Marfan Syndrome: A Case Series

2018 ◽  
Vol 08 (02) ◽  
pp. 086-090
Author(s):  
Mohanageetha Ardhanari ◽  
Deborah Barbouth ◽  
Sethuraman Swaminathan
Keyword(s):  
Heart Failure ◽  
Connective Tissue ◽  
Marfan Syndrome ◽  
Early Onset ◽  
Autosomal Dominant ◽  
Case Series ◽  
Autosomal Dominant Disorder ◽  
Fibrillin 1 ◽  
Valvular Insufficiency ◽  
Multisystem Manifestations

AbstractMutations in fibrillin 1 cause Marfan syndrome (MFS), an autosomal dominant disorder of the connective tissue, with multisystem manifestations. In early-onset MFS, the physical characteristics are expressed much earlier than the classical MFS. Those affected by this form generally have their mutations restricted to the gene “hotspot” region of exons 24 to 32. Historically, affected individuals usually die within the first few years of life due to heart failure secondary to severe valvular insufficiency. We report three patients with early-onset MFS, whose clinical evolution has been remarkably positive, when compared with other reported cases in the literature.

Marfan syndrome and the evolving spectrum of heritable thoracic aortic disease: Do we need genetics for clinical decisions?

VASA ◽  
2010 ◽  
Vol 39 (1) ◽  
pp. 17-32 ◽  
Author(s):  
von Kodolitsch ◽  
Rybczynski ◽  
Bernhardt ◽  
Mir ◽  
Treede ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Autosomal Dominant ◽  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Clinical Implications ◽  
Thoracic Aortic Disease ◽  
Gene Coding ◽  
Autosomal Dominant Fashion ◽  
Fibrillin 1 ◽  
Work Up

Marfan syndrome (MFS) is a disorder of the connective tissue that is inherited in an autosomal dominant fashion and that is classically caused by mutations in the gene coding for fibrillin-1, FBN1. The high mortality of untreated MFS results almost exclusively from aortic complications such as aortic dissection and rupture. However, more than half of patients with Marfan-like features do not have MFS, but have other diseases including inherited aortic aneurysms and dissections (TAAD). We elucidate the increasing spectrum of syndromes associated with Marfan-like features and discuss the clinical implications of these diseases. We performed a systematic review to tabulate all known inherited diseases and syndromes carrying a risk for thoracic aortic disease. We discuss evidence that different syndromes with different causative genes and mutations have different prognoses and profiles of cardiovascular manifestations. We conclude that future decisions for optimized management of patients with inherited TAAD require a comprehensive clinical and genetic work-up.

Neuropsychiatric complications in a patient with Marfan syndrome

2013 ◽  
Vol 25 (4) ◽  
pp. 245-247 ◽  
Author(s):  
Chin-Pang Lee ◽  
Chun-Lin Chu ◽  
Chia-Yih Liu ◽  
Chia-Hsiang Chen
Keyword(s):  
Cerebral Infarction ◽  
Marfan Syndrome ◽  
Clinical Management ◽  
Autosomal Dominant ◽  
Gene Mutations ◽  
Autosomal Dominant Disorder ◽  
Neuropsychiatric Complications ◽  
Fibrillin 1 ◽  
Psychiatric Conditions ◽  
Psychiatric Complications

BackgroundMarfan syndrome (MFS) is an autosomal dominant disorder of fibrillin-1 gene mutations, with the involvement of cardiovascular, skeletal, and ocular systems. In addition to physical abnormalities, MFS patients are also found to be susceptible to schizophrenia and other psychiatric conditions.ObjectivesAwareness of the association between MFS and psychiatric conditions would improve the clinical management of MFS patients to reduce the risk or even to prevent the development of psychiatric complications in MFS patients.MethodsHere, we describe a male MFS patient who manifested incoherent speech and impaired cognitive and social function at the age of 40 years.Results and conclusionHis mental dysfunction could be attributed to his bilateral cerebral infarction, which is a neurovascular complication associated with MFS.

scholarly journals Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 128
Author(s):  
Keiichi Asano ◽  
Anna Cantalupo ◽  
Lauriane Sedes ◽  
Francesco Ramirez
Keyword(s):  
Marfan Syndrome ◽  
Single Gene ◽  
Gene Mutations ◽  
Aortic Disease ◽  
Connective Tissue Disorder ◽  
Tgfβ Signaling ◽  
Thoracic Aortic Disease ◽  
Molecular Determinants ◽  
Fibrillin 1 ◽  
Experimental Findings

About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein fibrillin-1 cause additional abnormalities in the heart, eyes, and skeleton. Mouse models of MFS have been instrumental in delineating major cellular and molecular determinants of thoracic aortic disease. In spite of research efforts, translating experimental findings from MFS mice into effective drug therapies for MFS patients remains an unfulfilled promise. Here, we describe a series of studies that have implicated endothelial dysfunction and improper angiotensin II and TGFβ signaling in driving thoracic aortic disease in MFS mice. We also discuss how these investigations have influenced the way we conceptualized possible new therapies to slow down or even halt aneurysm progression in this relatively common connective tissue disorder.

scholarly journals Cardiomyopathy in Genetic Aortic Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Laura Muiño-Mosquera ◽  
Julie De Backer
Keyword(s):  
Marfan Syndrome ◽  
Myocardial Dysfunction ◽  
Genetic Defect ◽  
Positive Family History ◽  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Aortic Diseases ◽  
Pathogenic Variants ◽  
Fibrillin 1

Genetic aortic diseases are a group of illnesses characterized by aortic aneurysms or dissection in the presence of an underlying genetic defect. They are part of the broader spectrum of heritable thoracic aortic disease, which also includes those cases of aortic aneurysm or dissection with a positive family history but in whom no genetic cause is identified. Aortic disease in these conditions is a major cause of mortality, justifying clinical and scientific emphasis on the aorta. Aortic valve disease and atrioventricular valve abnormalities are known as important additional manifestations that require careful follow-up and management. The archetype of genetic aortic disease is Marfan syndrome, caused by pathogenic variants in the Fibrillin-1 gene. Given the presence of fibrillin-1 microfibers in the myocardium, myocardial dysfunction and associated arrhythmia are conceivable and have been shown to contribute to morbidity and mortality in patients with Marfan syndrome. In this review, we will discuss data on myocardial disease from human studies as well as insights obtained from the study of mouse models of Marfan syndrome. We will elaborate on the various phenotypic presentations in childhood and in adults and on the topic of arrhythmia. We will also briefly discuss the limited data available on other genetic forms of aortic disease.

Genetics of vascular disease: Marfan syndrome and aortic disease

ESC CardioMed ◽  
2018 ◽  
pp. 713-715
Author(s):  
Dorien Schepers ◽  
Bart Loeys
Keyword(s):  
Extracellular Matrix ◽  
Marfan Syndrome ◽  
Transforming Growth Factor Beta ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Aortic Disease ◽  
Extracellular Matrix Protein ◽  
Genetic Defects ◽  
Fibrillin 1 ◽  
Growth Factor Beta

Marfan syndrome is an autosomal dominant, multisystemic disorder, presenting with skeletal, ocular, and cardiovascular symptoms. This connective tissue disease is caused by mutations in FBN1, encoding fibrillin-1, which is an important extracellular matrix protein. Marfan syndrome shows significant clinical overlap with Loeys–Dietz syndrome, which is caused by genetic defects in components of the transforming growth factor-beta pathway: TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, and SMAD3. Overlapping clinical features between Marfan syndrome and Loeys–Dietz syndrome include aortic root aneurysm, arachnodactyly, scoliosis, and pectus deformity.

scholarly journals Marfan Syndrome: A Case Report

2012 ◽  
Vol 2012 ◽  
pp. 1-4
Author(s):  
Rajendran Ganesh ◽  
Rajendran Vijayakumar ◽  
Haridoss Selvakumar
Keyword(s):  
Stainless Steel ◽  
Case Report ◽  
Connective Tissue ◽  
Blood Vessel ◽  
Marfan Syndrome ◽  
Autosomal Dominant ◽  
The Body ◽  
Tissue Protein ◽  
Fibrillin 1 ◽  
Systemic Disorder

Marfan syndrome is an autosomal dominant systemic disorder of the connective tissue. Children affected by the Marfan syndrome carry a mutation in one of their two copies of the gene that encodes the connective tissue protein fibrillin-1. Marfan syndrome affects most organs and tissues, especially the skeleton, lungs, eyes, heart, and the large blood vessel that distributes blood from the heart to the rest of the body. A case report of Marfan syndrome has been reported with oral features. The dental problems of the child were treated under general anesthesia and a one-month review showed intact stainless steel crowns' restorations and no signs of secondary caries.

scholarly journals Inhibition of HIPK2 Alleviates Thoracic Aortic Disease in Mice With Progressively Severe Marfan Syndrome

2021 ◽  
Author(s):  
Cristina I. Caescu ◽  
Jens Hansen ◽  
Brittany Crockett ◽  
Wenzhen Xiao ◽  
Pauline Arnaud ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Marfan Syndrome ◽  
Thoracic Aortic Aneurysm ◽  
Acute Aortic Dissection ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Aortic Disease ◽  
Computational Analyses

Objective: Despite considerable research, the goal of finding nonsurgical remedies against thoracic aortic aneurysm and acute aortic dissection remains elusive. We sought to identify a novel aortic protein kinase that can be pharmacologically targeted to mitigate aneurysmal disease in a well-established mouse model of early-onset progressively severe Marfan syndrome (MFS). Approach and Results: Computational analyses of transcriptomic data derived from the ascending aorta of MFS mice predicted a probable association between thoracic aortic aneurysm and acute aortic dissection development and the multifunctional, stress-activated HIPK2 (homeodomain-interacting protein kinase 2). Consistent with this prediction, Hipk2 gene inactivation significantly extended the survival of MFS mice by slowing aneurysm growth and delaying transmural rupture. HIPK2 also ranked among the top predicted protein kinases in computational analyses of genes differentially expressed in the dilated aorta of 3 MFS patients, which strengthened the clinical relevance of the experimental finding. Additional in silico analyses of the human and mouse data sets identified the TGF (transforming growth factor)-β/Smad3 signaling pathway as a potential target of HIPK2 in the MFS aorta. Chronic treatment of MFS mice with an allosteric inhibitor of HIPK2-mediated stimulation of Smad3 signaling validated this prediction by mitigating thoracic aortic aneurysm and acute aortic dissection pathology and partially improving aortic material stiffness. Conclusions: HIPK2 is a previously unrecognized determinant of aneurysmal disease and an attractive new target for antithoracic aortic aneurysm and acute aortic dissection multidrug therapy.

scholarly journals Simultaneous Occurrence of Duane Retraction Syndrome with Marfan Syndrome

2011 ◽  
Vol 2011 ◽  
pp. 1-3 ◽  
Author(s):  
Mihir Kothari ◽  
Florence Manurung ◽  
Bhavesh Mithiya
Keyword(s):  
Case Report ◽  
Connective Tissue ◽  
Marfan Syndrome ◽  
Autosomal Dominant ◽  
Simultaneous Occurrence ◽  
Autosomal Dominant Disorder ◽  
First Case ◽  
Retraction Syndrome ◽  
Congenital Cranial Dysinnervation Disorder ◽  
Duane Retraction Syndrome

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, while Duane retraction syndrome (DRS) is a congenital cranial dysinnervation disorder (CCDD) which can be transmitted as autosomal dominant disorder in 5–10% of patients. In this paper, we present an 8-year-old girl who presented with left eye DRS and bilateral subluxation of the lens associated with MFS in absence of familial involvement. To our knowledge this is the first case report of DRS with MFS. The occurrence of these syndromes together is very rare and appears to be coincidental.

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