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Advances in Experimental Medicine and... 2021Marfan syndrome (MFS) is a systemic connective tissue disorder that is inherited in an autosomal dominant pattern with variable penetrance. While clinically this disease... (Review)
Review
Marfan syndrome (MFS) is a systemic connective tissue disorder that is inherited in an autosomal dominant pattern with variable penetrance. While clinically this disease manifests in many different ways, the most life-threatening manifestations are related to cardiovascular complications including mitral valve prolapse, aortic insufficiency, dilatation of the aortic root, and aortic dissection. In the past 30 years, research efforts have not only identified the genetic locus responsible but have begun to elucidate the molecular pathogenesis underlying this disorder, allowing for the development of seemingly rational therapeutic strategies for treating affected individuals. In spite of these advancements, the cardiovascular complications still remain as the most life-threatening clinical manifestations. The present chapter will focus on the pathophysiology and clinical treatment of Marfan syndrome, providing an updated overview of the recent advancements in molecular genetics research and clinical trials, with an emphasis on how this information can focus future efforts toward finding betters ways to detect, diagnose, and treat this devastating condition.
Topics: Aortic Dissection; Aorta; Fibrillin-1; Humans; Marfan Syndrome; Transforming Growth Factor beta
PubMed: 34807420
DOI: 10.1007/978-3-030-80614-9_8 -
Revista Portuguesa de Cardiologia Apr 2020Marfan syndrome is an autosomal dominant connective tissue disease with an estimated incidence of 1 in 5000 individuals. In 90% of cases it is caused by mutations in the... (Review)
Review
Marfan syndrome is an autosomal dominant connective tissue disease with an estimated incidence of 1 in 5000 individuals. In 90% of cases it is caused by mutations in the gene for fibrillin-1, the main constituent of extracellular microfibrils. Studies on animal models of Marfan syndrome have revealed that fibrillin-1 mutations interfere with local TGF-β signaling, in addition to impairing tissue integrity. The cardinal features involve the cardiovascular, ocular and skeletal systems. The diagnosis of Marfan syndrome is made according to the revised Ghent nosology. Early identification and appropriate management are critical for patients with Marfan syndrome, who are prone to the life-threatening cardiovascular complications of aortic aneurysms and aortic dissection. The standard treatment includes prophylactic beta-blockers in order to slow down dilation of the ascending aorta, and prophylactic aortic surgery. The success of current medical and surgical treatment of aortic disease in Marfan syndrome has substantially improved mean life expectancy, extending it above 72 years. This review aims to provide an overview of this hereditary disorder.
Topics: Adrenergic beta-Antagonists; Aortic Dissection; Animals; Aorta; Aortic Aneurysm; Fibrillin-1; Marfan Syndrome; Mutation; Transforming Growth Factor beta
PubMed: 32439107
DOI: 10.1016/j.repc.2019.09.008 -
Nature Reviews. Disease Primers Sep 2021Marfan syndrome (MFS) is an autosomal dominant, age-related but highly penetrant condition with substantial intrafamilial and interfamilial variability. MFS is caused by... (Review)
Review
Marfan syndrome (MFS) is an autosomal dominant, age-related but highly penetrant condition with substantial intrafamilial and interfamilial variability. MFS is caused by pathogenetic variants in FBN1, which encodes fibrillin-1, a major structural component of the extracellular matrix that provides support to connective tissues, particularly in arteries, the pericondrium and structures in the eye. Up to 25% of individuals with MFS have de novo variants. The most prominent manifestations of MFS are asymptomatic aortic root aneurysms, aortic dissections, dislocation of the ocular lens (ectopia lentis) and skeletal abnormalities that are characterized by overgrowth of the long bones. MFS is diagnosed based on the Ghent II nosology; genetic testing confirming the presence of a FBN1 pathogenetic variant is not always required for diagnosis but can help distinguish MFS from other heritable thoracic aortic disease syndromes that can present with skeletal features similar to those in MFS. Untreated aortic root aneurysms can progress to life-threatening acute aortic dissections. Management of MFS requires medical therapy to slow the rate of growth of aneurysms and decrease the risk of dissection. Routine surveillance with imaging techniques such as transthoracic echocardiography, CT or MRI is necessary to monitor aneurysm growth and determine when to perform prophylactic repair surgery to prevent an acute aortic dissection.
Topics: Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Microfilament Proteins; Mutation
PubMed: 34475413
DOI: 10.1038/s41572-021-00298-7 -
International Journal of Medical... 2021Marfan syndrome (MFS) is a complex connective tissue disease that is primarily characterized by cardiovascular, ocular and skeletal systems disorders. Despite its... (Review)
Review
Marfan syndrome (MFS) is a complex connective tissue disease that is primarily characterized by cardiovascular, ocular and skeletal systems disorders. Despite its rarity, MFS severely impacts the quality of life of the patients. It has been shown that molecular genetic factors serve critical roles in the pathogenesis of MFS. is associated with MFS and the other genes such as , transforming growth factor beta (TGF-β) receptors ( and ), latent TGF-β-binding protein 2 () and , amongst others also have their associated syndromes, however high overlap may exist between these syndromes and MFS. Abnormalities in the TGF-β signaling pathway also contribute to the development of aneurysms in patients with MFS, although the detailed molecular mechanism remains unclear. Mutant FBN1 protein may cause unstableness in elastic structures, thereby perturbing the TGF-β signaling pathway, which regulates several processes in cells. Additionally, DNA methylation of and histone acetylation in an MFS mouse model demonstrated that epigenetic factors play a regulatory role in MFS. The purpose of the present review is to provide an up-to-date understanding of MFS-related genes and relevant assessment technologies, with the aim of laying a foundation for the early diagnosis, consultation and treatment of MFS.
Topics: Animals; DNA Mutational Analysis; DNA-Binding Proteins; Disease Models, Animal; Fibrillin-1; Fibrillin-2; Genetic Testing; Humans; Latent TGF-beta Binding Proteins; Marfan Syndrome; Mutation; Proto-Oncogene Proteins; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II
PubMed: 34220303
DOI: 10.7150/ijms.60685 -
Current Rheumatology Reports Nov 2021Marfan syndrome (MFS) is an autosomal dominant heritable disorder of fibrillin-1 (FBN1) with predominantly ocular, cardiovascular, and musculoskeletal manifestations... (Review)
Review
PURPOSE OF REVIEW
Marfan syndrome (MFS) is an autosomal dominant heritable disorder of fibrillin-1 (FBN1) with predominantly ocular, cardiovascular, and musculoskeletal manifestations that has a population prevalence of approximately 1 in 5-10,000 (Chiu et al. Mayo Clin Proc. 89(1):34-42, 146, Dietz 3, Loeys et al. J Med Genet. 47(7):476-85, 4).
RECENT FINDINGS
The vascular complications of MFS still pose the greatest threat, but effective management options, such as regular cardiac monitoring and elective surgical intervention, have reduced the risk of life-threatening cardiovascular events, such as aortic dissection. Although cardiovascular morbidity and mortality remains high, these improvements in cardiovascular management have extended the life expectancy of those with MFS by perhaps 30-50 years from an estimated mean of 32 years in 1972 (Dietz 3, Gott et al. Eur J Cardio-thoracic Surg. 10(3):149-58, 147, Murdoch et al. N Engl J Med. 286(15):804-8, 148). The musculoskeletal manifestations of MFS, which to date have received less attention, can also have a significant impact on the quality of life and are likely to become more important as the age of the Marfan syndrome population increases (Hasan et al. Int J Clin Pract. 61(8):1308-1320, 127). In addition, musculoskeletal manifestations are often critically important in the diagnosis of MFS. Here, we review the main clinically relevant and diagnostically useful musculoskeletal features of MFS, which together contribute to the "systemic features score" (referred to hereafter as systemic score), part of the revised Ghent nosology for MFS. We discuss current treatment strategies and highlight the need for a multidisciplinary approach to diagnosis and management. Finally, we review new pharmacological approaches that may be disease modifying and could help to improve the outcome for individuals with this syndrome.
Topics: Cardiovascular Diseases; Humans; Marfan Syndrome; Quality of Life
PubMed: 34825999
DOI: 10.1007/s11926-021-01045-3 -
Zhongguo Dang Dai Er Ke Za Zhi =... Jul 2022Marfan syndrome (MFS) is a multisystem connective tissue disease with autosomal dominant inheritance. It is mainly caused by gene mutation and often has different... (Review)
Review
Marfan syndrome (MFS) is a multisystem connective tissue disease with autosomal dominant inheritance. It is mainly caused by gene mutation and often has different clinical manifestations. Neonatal MFS is especially rare with severe conditions and a poor prognosis. At present, there is still no radical treatment method for MFS, but early identification, early diagnosis, and early treatment can effectively prolong the life span of patients. This article reviews the latest advances in the diagnosis and treatment of MFS.
Topics: Fibrillin-1; Humans; Infant, Newborn; Marfan Syndrome; Mutation
PubMed: 35894201
DOI: 10.7499/j.issn.1008-8830.2203099 -
Circulation May 2021Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the (fibrillin-1) gene encoding a large glycoprotein in the...
BACKGROUND
Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the (fibrillin-1) gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm. To date, no effective pharmacologic therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms.
METHODS
Combining transcriptomics and metabolic analysis of aortas from an MFS mouse model () and MFS patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMC) by conditional depleting Tfam (mitochondrial transcription factor A; mice). We used a mouse model of MFS to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration.
RESULTS
The main canonical pathways highlighted in the transcriptomic analysis in aortas from mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial DNA content, were reduced in aortas from young mice. In vitro experiments in -silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient VSMC mice lose their contractile capacity, showed aortic aneurysms, and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside rapidly reverses aortic aneurysm in mice.
CONCLUSIONS
Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.
Topics: Animals; Aortic Aneurysm; Disease Models, Animal; Humans; Marfan Syndrome; Mice; Mitochondria
PubMed: 33709773
DOI: 10.1161/CIRCULATIONAHA.120.051171 -
JAMA Cardiology Jan 2021Women with aortopathy conditions are at risk for pregnancy-related aortic dissection, and these conditions may not be recognized until after the aortic dissection occurs.
IMPORTANCE
Women with aortopathy conditions are at risk for pregnancy-related aortic dissection, and these conditions may not be recognized until after the aortic dissection occurs.
OBJECTIVE
To examine the clinical characteristics, imaging features, and outcomes in women with pregnancy-related acute aortic dissection.
DESIGN, SETTING, AND PARTICIPANTS
A cohort study, comprising data from the International Registry of Acute Aortic Dissection (IRAD) (February 1, 1998, to February 28, 2018). The multicenter referral center study included 29 women with aortic dissection during pregnancy or less than 12 weeks post partum in IRAD from 1998 to 2018.
MAIN OUTCOMES AND MEASURES
Clinical features of pregnancy-related aortic dissection to be studied included underlying aortopathy, aortic size, type of aortic dissection, timing of dissection, hypertension, and previous aortic surgery.
RESULTS
A total of 29 women (mean [SD] age, 32 [6] years) had pregnancy-related aortic dissection, representing 0.3% of all aortic dissections and 1% of aortic dissection in women in the IRAD. Among women younger than 35 years, aortic dissection was related to pregnancy in 20 of 105 women (19%). Thirteen women (45%) had type A aortic dissection, and 16 women (55%) had type B. Aortic dissection onset was known in 27 women (93%): 15 during pregnancy, 4 in the first trimester, and 11 in the third trimester; 12 were post partum, occurring a mean (SD) of 12.5 (14) days post partum. At type A aortic dissection diagnosis, the mean (SD) aortic diameters were sinus of Valsalva, 54.5 (5) mm and ascending aorta, 54.7 (6) mm. At type B aortic dissection diagnosis, the mean (SD) descending aortic diameter was 32.5 (5) mm. Twenty women (69%) had an aortopathy condition or a positive family history: 13 women (65%) with Marfan syndrome, 2 women (10%) with Loeys-Dietz syndrome, 2 women (10%) with bicuspid aortic valves, 2 women (10%) with a family history of aortic disease, and 1 woman (5%) with familial thoracic aortic aneurysm. Aortopathy was not recognized until after aortic dissection in 47% of the women. Twenty-eight women (97%) survived aortic dissection hospitalization.
CONCLUSIONS AND RELEVANCE
Aortic dissection complicating pregnancy is rare. Most pregnancy-related aortic dissection is due to an aortopathy often not diagnosed until after aortic dissection. In this study, type A aortic dissections were associated with a dilated aorta, and type B aortic dissections often were not. Recognition of underlying conditions and risks for aortic dissection may improve management of pregnancy in women with aortopathy.
Topics: Adult; Aortic Dissection; Aorta; Aorta, Thoracic; Aortic Aneurysm; Aortic Diseases; Bicuspid Aortic Valve Disease; Female; Hospital Mortality; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Organ Size; Pregnancy; Pregnancy Complications, Cardiovascular; Puerperal Disorders; Registries; Sinus of Valsalva; Undiagnosed Diseases; Young Adult
PubMed: 33052376
DOI: 10.1001/jamacardio.2020.4876 -
Journal of the American College of... Jun 2021
Topics: Cardiovascular System; Humans; Marfan Syndrome; Phenotype
PubMed: 34140104
DOI: 10.1016/j.jacc.2021.04.073