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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 -
Sao Paulo Medical Journal = Revista... Dec 2010Marfan's syndrome is an autosomal dominant condition with an estimated prevalence of one in 10,000 to 20,000 individuals. This rare hereditary connective tissue disorder... (Review)
Review
Marfan's syndrome is an autosomal dominant condition with an estimated prevalence of one in 10,000 to 20,000 individuals. This rare hereditary connective tissue disorder affects many parts of the body. The diagnosis of Marfan's syndrome is established in accordance with a review of the diagnostic criteria, known as the Ghent nosology, through a comprehensive assessment largely based on a combination of major and minor clinical manifestations in various organ systems and the family history. Aortic root dilation and mitral valve prolapse are the main presentations among the cardiovascular malformations of Marfan's syndrome. The pathogenesis of Marfan's syndrome has not been fully elucidated. However, fibrillin-1 gene mutations are believed to exert a dominant negative effect. Therefore, Marfan's syndrome is termed a fibrillinopathy, along with other connective tissue disorders with subtle differences in clinical manifestations. The treatment may include prophylactic β-blockers and angiotensin II-receptor blockers in order to slow down the dilation of the ascending aorta, and prophylactic aortic surgery. Importantly, β-blocker therapy may reduce TGF-β activation, which has been recognized as a contributory factor in Marfan's syndrome. The present article aims to provide an overview of this rare hereditary disorder.
Topics: Humans; Marfan Syndrome
PubMed: 21308160
DOI: 10.1590/s1516-31802010000600009 -
Lancet (London, England) Dec 2005Marfan's syndrome is a systemic disorder of connective tissue caused by mutations in the extracellular matrix protein fibrillin 1. Cardinal manifestations include... (Review)
Review
Marfan's syndrome is a systemic disorder of connective tissue caused by mutations in the extracellular matrix protein fibrillin 1. Cardinal manifestations include proximal aortic aneurysm, dislocation of the ocular lens, and long-bone overgrowth. Important advances have been made in the diagnosis and medical and surgical care of affected individuals, yet substantial morbidity and premature mortality remain associated with this disorder. Progress has been made with genetically defined mouse models to elucidate the pathogenetic sequence that is initiated by fibrillin-1 deficiency. The new understanding is that many aspects of the disease are caused by altered regulation of transforming growth factor beta (TGFbeta), a family of cytokines that affect cellular performance, highlighting the potential therapeutic application of TGFbeta antagonists. Insights derived from studying this mendelian disorder are anticipated to have relevance for more common and non-syndromic presentations of selected aspects of the Marfan phenotype.
Topics: Adrenergic beta-Antagonists; Animals; Clinical Trials as Topic; Diagnosis, Differential; Female; Fibrillin-1; Fibrillins; Humans; Male; Marfan Syndrome; Mice; Microfilament Proteins
PubMed: 16325700
DOI: 10.1016/S0140-6736(05)67789-6 -
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 -
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 -
BMJ Case Reports Dec 2013Marfan syndrome is a rare autosomal dominant disorder of the connective tissue, with skeletal, ligamentous, orooculofacial, pulmonary, abdominal, neurological and the...
Marfan syndrome is a rare autosomal dominant disorder of the connective tissue, with skeletal, ligamentous, orooculofacial, pulmonary, abdominal, neurological and the most fatal, cardiovascular manifestations. It has no cure but early diagnosis, regular monitoring and preventive lifestyle regimen ensure a good prognosis. However, the diagnosis can be difficult as it is essentially a clinical one, relying on family history, meticulous physical examination and investigation of involved organ systems. Patients of Marfan syndrome portray very typical physical and orofacial characteristics, suggesting obvious recognition, but due to variable phenotypic expression, cases often go unnoticed unless a full range of attributing features is apparent. Dental practitioners are very likely to encounter patients of Marfan syndrome at an early age as they frequently present for dental treatment. The present case report illustrates the preliminary screening of Marfan syndrome in a dental office followed by timely diagnosis and appropriate referrals.
Topics: Adolescent; Diagnosis, Differential; Diagnosis, Oral; Female; Humans; Malocclusion; Marfan Syndrome; Physical Examination; Referral and Consultation; Tooth Extraction; Toothache; Treatment Outcome
PubMed: 24336584
DOI: 10.1136/bcr-2013-201632