Publications (10)0 Total impact
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Chapter: Ophthalmological Aspects
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ABSTRACT: The eye is involved in a majority of patients affected by Marfan syndrome. Morphological changes essentially affect the microfibrillar elements of the corneosderal envelope, the iris, and the ciliary zonules, giving rise to clinically and diagnostically significant characteristics.07/2011: pages 35-44; -
Chapter: Cardiovascular Aspects of the Marfan Syndrome: A Systematic Review
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ABSTRACT: The Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue caused by mutations of the fibrillin-1 gene, which codes for fibrillin, a major component of the extracellular microfibrils. The mean life expectancy in untreated MFS is 32 years with aortic dissection, aortic rupture or cardiac failure accounting for at least 90 percent of all fatalities. In severely affected patients with neonatal MFS, patients are likely to survive a few months only. According to our literature database analysis aortic dilatation is present in 83 percent, aortic regurgitation in 53 percent, mitral valve prolapse in 57 percent, and mitral valve regurgitation in 31 percent of adult males with classic MFS. We put a special focus on the pathogenesis and natural course of cardiovascular disease in MFS, including complications such as arrhythmia, sudden death, and endocarditis or complications during pregnancy. With optimal management, patients may have an acceptable life quality and almost normal life expectancy.07/2011: pages 45-69; -
Chapter: Familial Thoracic Aortic Aneurysms and Dissections
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ABSTRACT: Ascending aortic aneurysms leading to type A aortic dissections are the major cardiovascular complication of the Marfan syndrome (MFS). MFS is a major genetic syndrome predisposing individuals to these aortic conditions but other genetic syndromes also have similar aortic problems. In addition, ascending thoracic aortic aneurysms and dissections can be inherited in an autosomal dominant manner with decreased penetrance and variable expression, and the locations of the genes contributing to familial thoracic aortic aneurysms and dissections are beginning to be mapped in the human genome.07/2011: pages 113-122; -
Chapter: Microfibril-Associated Glycoprotein-1 (MAGP-1) and Other Non-Fibrillin Macromolecules Which May Possess a Functional Association with the 10 nm Microfibrils
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ABSTRACT: There is growing evidence that fibrillin-containing microfibrils are not just fibrillin polymers but that a variety of additional macromolecules may be associated with these structures. The functions of these molecules may be envisioned to include (a) structural support to stabilize the interaction of fibrillin molecules within the microfibril; (b) mediation of the interaction of adjacent microfibrils within bundles; (c) assembly of elastin on the surface of the microfibrils; (d) interfacing between the microfibrils and other structural elements of different matrices; (e) modulation of the interaction of the microfibrils with cells to influence the deposition, orientation and organization of microfibrils and elastic fibers in different tissue environments; (f) provision and modulation of nonstructural functions of the microfibrils e.g., TGF-beta storage; (g) enzymatic activity e.g., lysyl oxidase; and (h) specific interactions with fibrillin-2-containing microfibrils. In recent years many candidate microfibril-associated macromolecules have been identified. Some of these molecules appear to be found in extracellular matrices associated exclusively with the fibrillin-containing microfibrils indicating that their function(s) are likely to be specific to some aspect of microfibril biology. Other candidates clearly have association with additional structural matrix components and thus they must possess some microfibril-independent functions. The best-characterized matrix macromolecule which is exclusively associated with fibrillin-containing microfibrils is Microfibril-Associated Glycoprotein-1, or MAGP-1, a small glycoprotein with an apparent molecular weight of 31 kDa.1,2 MAGP-1 was first identified as a component of the elastic-fiber rich tissue, developing bovine nuchal ligament. MAGP-1 was shown to be resistant to chaotropic extraction from tissue homogenates, unless a reducing agent was included in the extraction buffer. Such reductive treatment had been shown to selectively solubilize the microfibrillar component of developing elastic fibers, later to become known as fibrillin-containing microfibrils.1 MAGP-1 is the strongest candidate for a ubiquitous component of fibrillin-1-containing microfibrils since it extensively and specifically codistributes with these structures in tissues,3–6 and is localized periodically along these microfibrils in association with the bead regions.7 A structurally related molecule, MAGP-2 (apparent molecular weight 25 kDa) was later identified in fibrillin-1 enriched extracts of the same tissue along with MAGP-1 and two polypeptides of 78 and 70 kDa.8,9 MAGP-2 was also found to be exclusively associated with the microfibrils but it exhibited a more restricted distribution than MAGP-1.5 The 78 kDa and 70 kDa polypeptides, later referred to as MP78 and MP70, were identified as forms of βig-h3,9 a protein which appears to be associated with type VI collagen microfibrils rather than the fibrillin-containing structures,10 and thus these two polypeptides are not discussed further in this chapter.07/2011: pages 161-177; -
Chapter: Cardiovascular Surgery: Surgical Management of the Marfan Patient at the Johns Hopkins Hospital
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ABSTRACT: Over the past 25 years, there has been remarkable progress in surgical management of the Marfan patient with aortic root aneurysm. The introduction in 1966 of the composite graft procedure by Mr. Hugh Bentall in London was a major step forward in the successful treatment of these aneurysms and was complemented later by use of homograft aortic roots. More recendy, valve-sparing procedures introduced by Sir Magdi Yacoub in London and Tirone David in Toronto, Canada have provided new options for Marfan patients that eliminate life-long anticoagulation.07/2011: pages 70-80; -
Chapter: Insights into Fibrillin-1 Structure and Function from Domain Studies
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ABSTRACT: Structural information is required to understand the assembly of fibrillin-1 into 10–12 nm microfibrils and to gain insight into the consequences of Marfan syndrome (MFS)-causing mutations. Since fibrillin-1 is a modular protein (Fig. 1), a dissection approach has been used to generate structural information for individual or small numbers of domains, where an analysis of the complete protein is unlikely to be feasible due to its physicochemical properties (size, disulphide-rich, post-translational modifications, rapid macromolecular association). From these data, one can begin to produce a homology model of fibrillin-1. Figure 1.Schematic illustration of the module organisation of fibrillin-I showing domain fragments re-ferred to in the text.07/2011: pages 188-198; -
Chapter: Genetics of Marfan Syndrome in Mouse Models
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ABSTRACT: Tensile strength and resilience are critically important properties of the connective tissue that are afforded by the assembly of specialized collagenous and elastic fiber networks. In addition to conferring integrity to virtually every organ system, these extracellular macroaggregates are also involved in modulating several developmental programs and cellular activities through direct or indirect interactions with the surrounding tissues. To a large extent, our current understanding of the multiple functions of the extracellular matrix (ECM) is based on information acquired through comprehensive phenotypic characterization of human patients and mutant mice. Owing to the integrated nature of extracellular networks and cell-matrix interactions, these studies have underscored the need of placing linear genotype-phenotype correlations within the broader context of organismal function. Relevant to Marfan syndrome (MFS), a new paradigm has therefore emerged whereby causative mutations of fibrillin-1 have the capacity to interfere with microfibril assembly and stability, elastic fiber integrity, and cellular performance (or a combination thereof). This chapter reviews the evidence supporting this novel paradigm of MFS pathogenesis which has been gathered through the analysis of genetically engineered mice. It also discusses the implications of animal findings for the clinical management of the human condition. In order to provide a full account of elastic fiber contribution to tissue formation and homeostasis, the review includes a brief description of the components of the elastic fiber and their contribution to the assembly and function of the network.02/2011: pages 199-208; -
Chapter: Fibrillin-2 Mutations in Congenital Contractural Arachnodactyly
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ABSTRACT: Congential contractural arachnodactyly (CCA) or Beals syndrome is characterized by a marfanoid habitus. In addition to the tall, slender, asthenic appearance, most individuals with CCA have “crumpled” ears, flexion contractures, severe kyphoscoliosis, and muscular hypoplasia (Figs 1 and 2)1–4. The ear abnormalities are characterized as a folded upper helix of the external ear. Although significandy less frequent, additional craniofacial abnormalities include mild micrognathia, high arched palate, scaphocephaly, brachycephaly, dolichocephaly, and frontal bossing. In most patients, contractions of major joints (knees, elbows, ankles) are present at birth. The proximal interphalangeal joints display flexion contractures (i.e., camptodactyly). The toes are similar. Contractures of the hip, adducted thumbs, and clubfoot may also occur. Bowed long bones and muscular hypoplasia are additional musculoskeletal findings in CCA. Contractures usually resolve with time. Arachnodactyly (long slender fingers and toes) is present in most individuals with CCA. The greatest morbidity in CCA is caused by progressive kypho/scoliosis that can begin in early infancy. It is present in about half of all affected individuals. The spinal abnormalities are progressive. Severe thoracic cage abnormalities with associated scoliosis may cause restrictive pulmonary disease.5 Figure 1.Patient with congenital contractural arachnodactyly. A)Face at three years. B)Profile at three years. C) Left elbow at three years (note contracture). D) Left ear at three years (note crumpled upper pinna). E) Hands at three years (note arachnodactyly and carnptodactyly). F) Total body (note bandaged hand after surgery for carnptodactyly and also the thin legs below the knees) .(Reprinted with permission from: Belleh et al. Am J Med Genet 2000.) Figure 2.Patient with congenital contractural arachnodactyly at eight years. A) Profile (note the crumpled upper pinna). B) Face. C) Anterior aspect oflower extremities. (Note thin legs below the knees). D) Lateral aspect of lower extremities. (Reprinted with permission from: Belich et al . Am J Med Genet 2000.)02/2011: pages 123-129; -
Chapter: Mutation Analysis of the FBN1 Gene in Individuals with Marfan Syndrome: Sensitivity, Methods, Clinical Indications
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ABSTRACT: Since the discovery of the FBN1 gene as the gene responsible for the Marfan syndrome (MFS), molecular testing for this condition has become possible. Although MFS is a clinical diagnosis, certain situations may occur in which molecular analysis of the FBN1 gene is wanted, either for diagnostic, management or genetic counseling purposes.02/2011: pages 93-100; -
Chapter: Introduction
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ABSTRACT: In 1876, E. Williams,1 an ophthalmologist in Cincinnati, Ohio, described ectopia lentis in a brother and sister who were exceptionally tall and had been loosejointed from birth. Although there is a Williams syndrome that has aortic manifestations (supravalvar aortic stenosis), the name Williams was never associated with the disorder we now call Marfan syndrome. The reason is clear: Williams was geographically removed from the leading medical centers and published in the Transactions of the American Ophthalmological Society; surely his report attracted little attention and the non-ocular features were not emphasized.02/2011: pages 1-12;
Top co-authors
Institutions
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2011
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Humboldt-Universität zu Berlin
- Institute of Medical Genetics and Human Genetics
Berlin, Land Berlin, Germany -
Howard Hughes Medical Institute
Chevy Chase, MD, USA -
University of Nebraska Medical Center
Omaha, NE, USA
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