Síndrome de Marfán en la edad adulta / Marfan's Syndrome

El síndrome de Marfán es una enfermedad que integra el grupo de las llamadas colagenopatías no autoinmunes. Etiológicamente consiste en la mutación del gen que codifica la fibrilina 1, que se encarga junto con otras proteínas como la elastina de formar los microfilamentos de sostén de la matriz celular. Este defecto genera diversas manifestaciones clínicas por trastornos en diferentes sistemas (esquelético, cardiovascular, gastrointestinal, ocular). Se presenta un paciente de 43 años de edad, de raza negra, que llegó a la edad adulta sin un diagnóstico de la enfermedad. Incidentalmente sospechamos el diagnóstico al tratar una neumonía adquirida en la comunidad. Se trató su cuadro de neumonía con piperacilina y tazobactam por 7 días. Se recomendó la valoración por parte de cirugía cardiovascular por hallazgos de aneurisma de la aorta ascendente, pero el paciente decidió no continuar con los estudios de su enfermedad. Se aconsejó cambios en el estilo de vida y ejercicios físicos y se diagnosticó alta probabilidad de muerte por el problema vascular descrito(AU)

Marfan's syndrome is a disease that is included in the group of the no autoimmune collagen diseases, the ca use of this syndrome is a mutation in the gen FBN1 that translate the protein fibrillin 1, that is fundamental besides other proteins like elastin to form a part of the extracellular matrix. This defect generates multiple clinical manifestations due to defects in different systems (skeletal, cardiac, big vessels, gastrointestinal, ocular). The reported case is of a patient who reached adulthood without a diagnosis of the diseases, which we incidentally suspect in the context of community acquired pneumonia(AU)

Ischemic stroke caused by Marfan syndrome: A case report / 中国脑血管病杂志

Marfan syndrome is a common connective tissue disease with cardiovascular,ocular and skeletal menifestations, but combination with cerebral infarction is rare. Marfan syndrome is also a rare cause of youth stroke with undetermined cause. Early cardiac color doppler ultrasound and comprehensive vascular assessment can improve clinical diagnosis and treatment effect, and early intervention can obtain the good prognosis and life quality of patients. A case of ischemic stroke caused by Marfan syndrome was reported in this article. Combined with relevant literature, the possible mechanisims of vascular events associated with Marfan syndrome was analyzed.

Study on the FBN1 gene mutation spectrum and association between genotype and clinical phenotype in 300 Marfan syndrome patients and their relatives / 中华胸心血管外科杂志

Objective To investigate the correlations between the FBN1 gene mutation types and the clinical phenotype . Methods 87 probands with Marfan or Marfan-like syndromes and their family members were enrolled in this study ( total 300 cases).The clinical manifestations of each patients involving the ocular, cardiovascular system, skeletal system and other im-plicated systems were collected and evaluated .According to the clinical manifestations , these patients were divided into two groups, namely aortic dissection group and aortic root aneurysm group.Blood samples were taken from patients and DNA se-quencing was performed on each patient by the genetic aortic disease gene Panel .The detected single nucleotide variants ( SNVs)/indel were interpreted according to the ACMG guidelines, and the pathogenic variation was confirmed through Sanger sequencing.The aortic wall tissue was obtained from MFS patients who underwent surgery .The correlations between genotypes and clinical phenotypes were further explored by comparing the aortic wall tissue histological specimens of each genotype pa-tient.Results A total of 92 FBN1 mutations(31％) were detected in 300 people with Marfan syndromes or Marfan-like syn-dromes, 18 of which were undiscovered mutations.There were 49 missense mutations(53.26％), 13 splicing mutations (14.13％), 17 frameshift mutations(18.48％), and 13 nonsense mutations(14.13％).In this cohort, 24 cases had aortic dissection and 25 cases were aortic root aneurysm.Statistical analysis revealed that patients with aortic dissection mostly ap-peared in frameshift mutations(29.17％ vs.4.00％, P =0.017).However, patients with aortic root aneurysm mostly ap-peared in missense mutations(72.00％ vs.37.50％, P =0.015), and accompanied with ectopia lentis(41.67％ vs. 8.33％, P=0.008).Pathological specimens staining found that elastic fibers in the aortic wall of patients with frameshift mu-tations are sparser, and the smooth muscle cells are more deficient and more disorganized than patients with missense muta-tions.Conclusion FBN1 gene frameshift mutations result a lack of elastic fibers and disorganized smooth muscle cells in aor-tic wall and are presented more in patients with aortic dissection than aortic root aneurysm .

Genotype-phenotype analysis of five families with congenital ectopia lentis accompanied with cardiovascular abnormalities / 中华实验眼科杂志

Objective To analyze the genotype-phenotype correlation in 5 families with congenital ectopia lentis (CEL) accompanied with cardiovascular abnormal manifestation.Methods Detailed clinical data of 15 family members in 5 families were collected from August 2017 to March 2018 in Zhongshan Ophthalmic Center,including examination of the condition of lens before and after mydriasis by slit-lamp,evaluation of the cardiovascular system using transthoracic echocardiography,and evaluation of the degree of involvement of the subjects' skeletal system using X-ray images.Genomic DNAs were extracted from whole blood sample of the 5 probands and 10 relatives,and screened for FBN1 mutation by targeted exome sequencing.The possible genotype-phenotype correlation was analyzed by reviewing previous literatures into these mutation sites.The study followed the principles of the Helsinki Declaration and written informed consent was obtained from each subject prior to any examination.Results All of the five probands were diagnosed as CEL accompanied with cardiovascular abnormal manifestation.FBN1 gene mutations were identified in all of the five probands,including four missense mutations (c.2741G＞T,c.2585G＞T,c.1633C＞T,c.4260C＞G) and one splicing mutation (c.2114-1G＞C).It was predicted that all of the 5 mutations would alter the protein structure.Conclusions FBN1 gene has a high degree of clinical heterogeneity,and the early detection of ocular phenotypes combined with genetic screening is of great significance in the diagnosis of cardiovascular abnormalities.

Analysis of fibrillin-1 new mutations in patients with Marfan syndrome / 中华胸心血管外科杂志

Objective To detect 14 genes including fibrillin-1(FBN1) and so on mutations in 17 patients with Marfan syndrome(MFS) and family members of 2 patients and to investigate the correlation between FBN1 gene mutation and MFS.Methods Genomic DNAs were extracted from whole blood sample of 17 patients and 43 family members.After DNA samples were amplified by polymerase chain raction(PCR), we used capture panels to get target genes which would be sequenced by Illumina HiSeq2500 Analyzers(Illumina, SanDiego, USA).The target genes included ACTA2、CBS、FBN1、FBN2、MYH11、COL3A1、SMAD3、TGFBR1、TGFBR2、MYLK、MSTN、COLA2、TGFB2 and SLC2A10.The results of sequencing would be compared with multiple databases, including NCBI dbSNP, HapMap, 1000 human genome dataset and database of 100 Chinese healthy adults, to find gene mutation.Finally, these mutations would be validated using conventional Sanger sequencing methods.Results A total of 10 FBN1 mutations and 1 actin alpha2(ACTA2) mutation in 17 patients were identified, of which 8 FBN1 mutations and 1 ACTA2 mutation were novel.One FBN1 mutation was underwent family investigation and we found in this family, all patients had this mutation and others did not have it.Conclusion Missense mutation of c.7280G>A in the 59th exon of FBN1 gene is new pathogenic mutation for MFS.The other 8 novel mutations may be the pathogenic factors of MFS.

Expression of fibrillin-1 in atrium tissue and analysis on its relationship with atrial fibrosis in patients with valvular atrial fibrillation / 吉林大学学报(医学版)

Objective:To investigate the expression of fibrillin-1 (FBN-1) in the atrium tissue of the patients with rheumatic heart valve disease complicated with atrial fibrillation(AF), and to explore its relationship with atrial fibrosis in the patients with valvular atrial fibrillation.Methods:Eighty-four consecutive patients with rheumatic heart valve disease underwent cardiac surgery were enrolled in this study.The patients were divided into AF group(n=39) and sinus rhythm group(SR group, n=45).The clinical data of patients were collected before operation.The right atrium tissue (0.3-0.5 mm3) was disserted during operation.The degrees of right atrial fibrosis of the patients in two groups were observed by Masson staining.Western blotting method was used to measure the protein expressions of FBN-1 in atrium tissue of the patients in two groups.Results:There were no significant differences in the gender ratio, age, blood pressure, blood biochemical indicators and other aspects of medical history between two groups(P>0.05);the diameters of left and right atrium of the patients in AF group were significantly larger than those in SR group(P<0.05).The Masson staining results showed that there was obvious fibrosis in AF group, and the collagen volume fraction and collagen level in AF group were significantly higher than those in SR group (P<0.05).The expression level of FBN-1 in right atrium tissue in AF group was obviously higher than that in SR group(P<0.05).The expression level of FBN-1 protein in right atrium tissue of the patients with valvular atrial fibrillation was positively correlated with the collagen level(r=0.544,P=0.021).Conclusion:There is obvious atrium fibrosis in the patients with valvular atrial fibrillation;it is closely related to the up-regulation of the expression of FBN-1 gene.

Estudio y análisis comparativo de interacciones entre la proteina integrina con fragmentos de la proteína fibrilina-1 y fragmentos mutados de esta utilizando la metodología de docking molecular / Study and comparative analysis of interactions protein between the integrina with fragments fibrillin-1 and mutated fragments of this by using molecular docking

Resumen Objetivo: Evaluar las interacciones proteína-proteína que pueden generarse entre fragmentos de la proteína fibrilina-1, cuyas mutaciones causan el síndrome de Marfan (SM). Materiales y métodos: Se realizó una serie de cálculos docking proteína-proteína entre las macromoléculas de interés; se empleó el programa Molsoft ICM; se utilizaron las estructuras cristalinas de la proteína integrina αVβ3 y los fragmentos de la proteína fibrilina-1; además se generó una sucesión de mutaciones en la fibrilina-1, las cuales son características de pacientes con síndrome de Marfan, y posteriormente se realizó el acoplamiento molecular. Adicionalmente se determinó los aminoácidos que con mayor frecuencia estaban presentes en el sitio de interacción y su hidrofobicidad. Resultados: Se cuantificó la cantidad de aminoácidos hidrófobos presentes en las zonas de interacción producidas por los acoplamientos, teniendo en cuenta la energía del sistema; esta ponderación estuvo entre el 40 y 50 % de los aminoácidos de la zona de interacción, con un porcentaje mayor con respecto a aminoácidos neutros o cargados. En los resultados obtenidos utilizando las mutaciones realizadas sobre los fragmentos cbEGF22-TB4-cbEGF23 y cbEGF9-hyb2-cbEGF10 de la fibrilina-1 se encontró que no se ubicaron en zonas cercanas al sitio de interacción en la mayoría de los casos. Conclusiones: Las interacciones entre los fragmentos de fibrilina-1, y estos con respecto a la integrina, mostraron en sus zonas de interacción la presencia mayoritariamente de aminoácidos hidrofóbicos, que es lo esperado normalmente.

Abstract Objective: To assess protein-protein interactions between fragments of fibrillin-1 protein, whose mutations cause Marfan syndrome (MS). Materials and Methods: We performed a series of protein-protein docking calculations between the macromolecules of interest for this purpose was used Molsoft ICM program. We used the crystal structures of αVβ3 Integrin protein and fragments of fibrillin-1 protein also were generated mutations in the fibrillin-1, which are characteristic in patients with Marfan syndrome and subsequently to the molecular docking. We determined the amino acids most often present at the site of interaction and its hydrophobicity. Results: The amount of hydrophobic amino acids present in the areas of interaction given by the couplings was quantified. Given the energy of the system, was between 40 and 50% of the amino acids of the interaction zone, with a higher proportion relative to charged or neutral amino acids. In the results obtained using the mutations performed on fragments cbEGF23 cbEGF22-TB4-and-cbEGF10 cbEGF9-HYB2 of fibrillin-1, was found they were not placed in areas near the site of interaction in most cases. Conclusion: The interaction between fragments of fibrillin-1, and those with respect to their integrin showed the presence interaction zones mostly hydrophobic amino acids, which are normally expected.

Revisión Bibliográfica y Presentación de un Caso: Síndrome de Marfán / Bibliographic Review and Presentation of a Case: Marfán Syndrome

El síndrome de Marfán es una patología poco común, causada por una mutación genética de fibrilina 1, imprescindible para la síntesis de fibras elásticas del tejido conectivo. Se caracteriza por una alta penetrancia y mar-cada heterogeneidad fenotípica. Entre las diferentes manifestaciones clínicas, la afectación cardiovascular merece una consideración especial, debido a su impacto en el pronóstico. El diagnóstico requiere una evaluación clínica completa de múltiples órganos y sistemas; por su ampliada sintomatología, la toma de decisiones es compleja, por tanto, cuando se sospeche síndrome de Marfán debe apli-carse la revisión de los criterios de Ghent. Si el diagnóstico es confirmado, debe iniciarse tempranamente su manejo multidisciplinario con un seguimiento minucioso, ya que se dis-pone de tratamientos farmacológicos y qui-rúrgicos que mejoran la esperanza de vida.Se reporta un caso clínico, con la revisión de las manifestaciones clínicas, criterios diagnósticos y manejo.

Marfan syndrome is a rare disease, caused by a genetic mutation of fibrillin-1, essential for the synthesis of connective tissue elastic fibers. It is characterized by a high penetran-ce and a marked phenotypic heterogeneity. Among the different clinical manifestations, cardiovascular involvement deserves a spe-cial consideration because of their impact on prognosis.The diagnosis requires a complete medical evaluation of multiple organs and systems; with expanded symptoms where the decision making is complex, so when Marfan syndro-me is suspected should be applied the revi-sed criteria of Ghent. If the diagnosis is confir-med, it must start early with its multidisciplinary approach carefully monitored because there are pharmacological and surgical treatments that improve life expectancy.Finally a case is reported, with the review of clinical manifestations, diagnostic criteria and management.

Processamento intracelular da fibrilina-1 mutada na síndrome de Marfan: escape do controle de qualidade pela dissulfeto isomerase proteica / Mutated fibrillin-1 intracellular processing in Marfan syndrome: bypass of a protein disulfide isomerase-mediated quality control

A Síndrome de Marfan (SMF) é a enfermidade hereditária mais comum dentre as que afetam o sistema conjuntivo, causada por mutações da glicoproteína fibrilina-1, o principal componente estrutural das microfibrilas elásticas da matriz extracelular. As manifestações fenotípicas da SMF são sistêmicas e acometem tipicamente os sistemas ocular, esquelético e cardiovascular, este uma importante causa de morbi-mortalidade. Entretanto, não está claro como a mutação induz a doença. Estudos anteriores sugerem anomalias morfológicas do retículo endoplasmático (RE) ou retenção intracelular da fibrilina-1 nos estágios avançados da SMF. Entretanto, a contribuição do enovelamento da fibrilina-1 mutada e do estresse do RE na fisiopatologia celular da SMF não é conhecida. Proteínas mal-enoveladas podem levar à retenção intracelular e/ou aumento da degradação através da via de degradação associada ao RE (ERAD), além da indução da resposta a proteínas mal-enoveladas (UPR), ambas com potencial contribuição à fisiopatologia de doenças, incluindo a SMF. Assim, estudamos em fibroblastos embrionários isolados de camundongos (MEFs) com SMF se a fibrilina-1 mutada é reconhecida pelo controle de qualidade do RE pelo seu mal- enovelamento e induz estresse do RE por sua retenção intracelular. Demonstramos que a mutação na fibrilina-1 per se não promoveu chaperonas marcadoras de UPR ou geração de oxidantes. Além disso, não levou a uma maior sensibilização das células à indução exógena de estresse do RE, nem promoveu maior morte celular após inibição do proteassoma. Além disso, não foi observada retenção intracelular da fibrilina-1 nas células SMF, e mesmo após inibição da via secretora ou indução de estresse do RE, a inibição da secreção da fibrilina-1 foi similar nos MEFs SMF e wild-type (WT). A dissulfeto isomerase proteica (PDI), uma importante chaperona redox do RE, interage com fibrilina-1, e seu silenciamento levou a um aumento na secreção da fibrilina-1 pelos MEFs WT...

Marfan syndrome (MFS) is the most common connective tissue hereditary disease, caused by mutations in the glycoprotein fibrillin-1, the main structural component of extracellular matrix elastic microfibrils. MFS phenotypic manifestations are systemic and typically involve the ocular, skeletal and cardiovascular systems, the latter a major cause of morbidity/mortality. However, how gene mutation induxes disease is yet unclear. Previous studies suggest endoplasmic reticulum (ER) morphological abnormalities or fibrillin-1 intracellular retention in advanced MFS stages. However, the contribution of mutated fibrillin-1 folding and ER stress to MFS cellular pathophysiology is unknown. Un/misfolded proteins may associate with their intracellular retention and/or increased degradation through ER-associated degradation (ERAD), in addition to inducing the unfolded protein response (UPR), both sharing potential contributions to disease pathophysiology, including MFS. Thus, we studied in embryonic fibroblasts (MEFs) isolated from WT and MFS mice, if mutated fibrillin-1 can be recognized by ER quality control as a misfolded protein, able to induce ER stress due to its intracellular retention. We showed that fibrillin-1 mutation by itself did not promote UPR chaperone markers or oxidant generation. Moreover, it did not sensitize cells to exogenous ER stress nor affected cell survival curves after proteasome inhibition. Furthermore, no intracellular retention of fibrillin-1 was observed in MFS cells, and even after secretory pathway inhibition or ER stress induction, fibrillin-1 secretion inhibition was similar in MFS and wild-type (WT) MEFs. Protein disulfide isomerase (PDI), an important ER redox chaperone, interacts with fibrillin-1 and its silencing induced an increased fibrillin-1 secretion in WT...

Candidate gene linkage analysis indicates genetic heterogeneity in Marfan syndrome

Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue that affects the ocular, skeletal and cardiovascular systems, with a wide clinical variability. Although mutations in the FBN1 gene have been recognized as the cause of the disease, more recently other loci have been associated with MFS, indicating the genetic heterogeneity of this disease. We addressed the issue of genetic heterogeneity in MFS by performing linkage analysis of the FBN1 and TGFBR2 genes in 34 families (345 subjects) who met the clinical diagnostic criteria for the disease according to Ghent. Using a total of six microsatellite markers, we found that linkage with the FBN1 gene was observed or not excluded in 70.6 percent (24/34) of the families, and in 1 family the MFS phenotype segregated with the TGFBR2 gene. Moreover, in 4 families linkage with the FBN1 and TGFBR2 genes was excluded, and no mutations were identified in the coding region of TGFBR1, indicating the existence of other genes involved in MFS. Our results suggest that the genetic heterogeneity of MFS may be greater that previously reported.

Identification of Molecular Defects in Korean Patients with Marfan Syndrome

BACKGROUND AND OBJECTIVES: Marfan syndrome is an autosomal dominant heritable disease of connective tissue which is characterized by cardinal features mainly in the cardiovascular, ocular and skeletal systems. Aneurysms or dissections of the aorta are the major cardiovascular complications of the disorder causing early mortality. Mutations in the fibrillin-1 (FBN1) gene on chromosome 15q21.1 have been found to be major causes of Marfan syndrome. The purpose of this study was to characterize the molecular defect in Korean Marfan patients, thus contributing to the effort of correlating the genotype with the phenotype. SUBJECTS AND METHODS: We screened all 65 exons of the FBN1 gene in 14 subjects diagnosed as Marfan syndrome by the method of single strand conformation polymorphism-heteroduplex analysis. RESULTS: We found mutations in only 10 among 14 patients. This study identified 8 novel mutations and 2 previously reported mutations in 14 Korean Marfan patients. Two cases were nonsense mutations and 8 were missense mutations, including 3 frameshift. Seven cases of the mutations occurred in one of the 43 calcium binding epidermal growth factor-like domains within an FBN1 gene. Mutations in Marfan patients occurred variably over the whole field of this FBN1 gene. CONCLUSION: Our results will contribute to the establishment of a database of Korean Marfan patients. Extending this study and using the database will help early detection of the disease and prevention of complications.