Abstract 11621: Fibrillin-1 Gene Mutations in Left Ventricular Non-Compaction Cardiomyopathy

Introduction: Left ventricular non-compaction cardiomyopathy (LVNC) is a rare and unique cardiomyopathy. Its presentation can range from a benign phenotype to overt heart failure and sudden cardiac death. The genetics of LVNC are not completely understood and current genetic testing has a yield of about 30% in identifying a causative gene mutation. We present a series of patients with LVNC and fibrillin-1 (FBN1) gene mutations. Hypothesis: We hypothesize that FBN1 gene mutations can lead to LVNC by way of its role in the myocardial extracellular matrix during cardiac development. Methods: A retrospective review of all patients with LVNC at our institution was performed for purposes of another investigation. The process unexpectedly identified patients with LVNC and FBN1 gene mutations, as well as LVNC and Marfan syndrome. Results: Approximately 150 patients are followed in our clinic with LVNC. We screened this population and found 51 patients on medical therapy for reduced function. We retrospectively reviewed gene testing in these 51 patients, when available, and identified 5 patients (10%) with an FBN1 gene mutation. All 5 patients had a dilated LVNC phenotype and previous or current evidence of left ventricular dysfunction. Syndrome breakdown as follows: 3 with Marfan, 1 with Shprintzen-Goldberg, and 1 with no identifiable syndrome. Dilated cardiomyopathy/LVNC gene testing was performed in 3 patients; 2 had disease causing myosin heavy chain 7 gene defects and 1 had no defects. Conclusions: The role of FBN1 in the human myocardium is not completely understood but it is expressed in the developing fetal heart and is a component of the myocardial extracellular matrix. Although causation has not been proven by our report, it certainly raises interest in a mechanistic relationship between LVNC and FBN1 given the increased prevalence of Marfan syndrome and probable increased prevalence of FBN1 gene mutations in this cohort of LVNC patients in light of FBN1.

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Overview of Marfan Syndrome: knowns and unknowns

Journal of Controversies in Biomedical Research ◽

10.15586/jcbmr.2015.10 ◽

2015 ◽

Vol 1 (1) ◽

pp. 51-66

Author(s):

Pratiek N Matkar ◽

Hao H Chen ◽

Howard Leong-Poi ◽

Krishna Kumar Singh

Keyword(s):

Marfan Syndrome ◽

Drug Targets ◽

Transforming Growth Factor ◽

Surgical Techniques ◽

Clinical Manifestations ◽

Gene Mutations ◽

Transforming Growth Factor Β ◽

The Body ◽

Fbn1 Gene ◽

Fibrillin 1

Marfan syndrome (MFS) is a relatively rare disease of the connective tissue that affects several organs of the body. Cardiovascular abnormalities such as aortic root dilatation and mitral valve prolapse are the two main life-threatening complications associated with MFS. The complete pathogenesis of MFS is yet unclear. However, fibrillin-1 (FBN1) gene mutations and mutations in the transforming growth factor-β (TGFβ) signaling pathway are the leading causes of this lethal disease. Detailed assessment based on several major and minor clinical manifestations has led to the evolution of different nosologies for MFS diagnoses with reliable accuracies. Nevertheless, heterogeneous disease advancement and overlapping clinical outcomes make MFS diagnosis challenging. Rapid strides in research and surgical avenues over the last two decades have improved the life expectancy and the quality of life of MFS patients remarkably. More specific diagnostic criteria have been established, novel therapeutic targets for pharmacotherapy have been identified and validated, and newer surgical techniques have been tested. Current research efforts are focusing on the identification of prognostic biomarkers, gene modifiers, drug targets, and surgical procedures. This review aims to provide a brief overview of these aspects associated with MFS.

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A Case of Neonatal Marfan Syndrome: A Management Conundrum and the Role of a Multidisciplinary Team

Case Reports in Pediatrics ◽

10.1155/2017/8952428 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Elliott J. Carande ◽

Samuel J. Bilton ◽

Satish Adwani

Keyword(s):

Marfan Syndrome ◽

Surgical Intervention ◽

Rare Condition ◽

Mitral Valve Regurgitation ◽

Left Ventricular ◽

Cardiac Complications ◽

Chromosome 15 ◽

Fibrillin 1 ◽

Neonatal Marfan Syndrome

Neonatal Marfan syndrome (nMFS) is a rare condition with a poor prognosis. It is genotypically and phenotypically distinct from the typical Marfan syndrome and carries a poorer prognosis. This case report describes the progression of a 14-month-old girl diagnosed with nMFS at 5 months of age. Her diagnosis followed the identification of a fibrillin-1 mutation (FBN1gene, exon 26, chromosome 15), which is a common locus of nMFS. This patient developed severe cardiac complications resulting in congestive cardiac failure in early life and required major cardiac surgery. Since surgical intervention, our patient is still reliant on a degree of ventilator support, but the patient has gained weight and echocardiography has demonstrated improved left ventricular function and improved tricuspid and mitral valve regurgitation. Therefore, we argue the importance of a cautious multidisciplinary approach to early surgical intervention in cases of nMFS.

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Genetics of vascular disease: Marfan syndrome and aortic disease

ESC CardioMed ◽

10.1093/med/9780198784906.003.0160 ◽

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.

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Effect of beta-blocker therapy on progression of aortic dilatation in the Marfan syndrome patients with subtypes of fibrillin 1 gene mutation

Archives of Cardiovascular Diseases Supplements ◽

10.1016/j.acvdsp.2018.10.289 ◽

2019 ◽

Vol 11 (1) ◽

pp. 131

Author(s):

N. Kim ◽

J. Plaisancie ◽

T. Edouard ◽

M. Ratsimandresy ◽

P. Acar ◽

...

Keyword(s):

Gene Mutation ◽

Marfan Syndrome ◽

Beta Blocker ◽

Aortic Dilatation ◽

Blocker Therapy ◽

Beta Blocker Therapy ◽

Fibrillin 1

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A bioinformatics framework for genotype–phenotype correlation in humans with Marfan syndrome caused by FBN1 gene mutations

Journal of Biomedical Informatics ◽

10.1016/j.jbi.2005.06.001 ◽

2006 ◽

Vol 39 (2) ◽

pp. 171-183 ◽

Cited By ~ 8

Author(s):

Christian Baumgartner ◽

Gábor Mátyás ◽

Beat Steinmann ◽

Martin Eberle ◽

Jörg I. Stein ◽

...

Keyword(s):

Marfan Syndrome ◽

Gene Mutations ◽

Phenotype Correlation ◽

Fbn1 Gene ◽

Genotype Phenotype Correlation

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Identification of fibrillin-1 gene mutations in Marfan syndrome by high-resolution melting analysis

Analytical Biochemistry ◽

10.1016/j.ab.2009.03.032 ◽

2009 ◽

Vol 389 (2) ◽

pp. 102-106 ◽

Cited By ~ 11

Author(s):

Chia-Cheng Hung ◽

Shin-Yu Lin ◽

Chien-Nan Lee ◽

Hui-Yu Cheng ◽

Chiou-Ya Lin ◽

...

Keyword(s):

High Resolution ◽

Marfan Syndrome ◽

High Resolution Melting ◽

Gene Mutations ◽

High Resolution Melting Analysis ◽

Fibrillin 1 ◽

Melting Analysis

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IL‐6 Regulates Extracellular Matrix Remodeling Associated With Aortic Dilation in a Fibrillin‐1 Hypomorphic mgR/mgR Mouse Model of Severe Marfan Syndrome

Journal of the American Heart Association ◽

10.1161/jaha.113.000476 ◽

2014 ◽

Vol 3 (1) ◽

Cited By ~ 42

Author(s):

Xiaoxi Ju ◽

Talha Ijaz ◽

Hong Sun ◽

Wanda LeJeune ◽

Gracie Vargas ◽

...

Keyword(s):

Extracellular Matrix ◽

Mouse Model ◽

Marfan Syndrome ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Aortic Dilation ◽

Fibrillin 1

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Phenotypic Variability in Marfan Syndrome in a Family With a Novel Nonsense FBN1 Gene Mutation

Revista Española de Cardiología (English Edition) ◽

10.1016/j.rec.2011.05.031 ◽

2012 ◽

Vol 65 (4) ◽

pp. 380-381 ◽

Cited By ~ 1

Author(s):

Aránzazu Díaz de Bustamante ◽

Eva Ruiz-Casares ◽

M. Teresa Darnaude ◽

Teresa Perucho ◽

Gabriel Martínez-Quesada

Keyword(s):

Gene Mutation ◽

Marfan Syndrome ◽

Phenotypic Variability ◽

Fbn1 Gene

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Abstract 122: Pharmacological Inhibition Of Macrophage Infiltration Prevents Myxomatous Valve Degeneration In Marfan Syndrome

Circulation Research ◽

10.1161/res.129.suppl_1.122 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Na Xu ◽

Katherine E Yutzey

Keyword(s):

Immune Response ◽

Extracellular Matrix ◽

Marfan Syndrome ◽

Macrophage Infiltration ◽

Histological Evaluation ◽

Matrix Remodeling ◽

Ecm Remodeling ◽

Mitral Valves ◽

Fibrillin 1 ◽

Underlying Mechanisms

Introduction: Myxomatous valve degeneration (MVD) is the most common cause of mitral regurgitation, characterized by valve leaflet thickening and progressive valve degeneration, leading to impaired cardiac function and heart failure. Currently, there is no medical therapy for the treatment of MVD. MVD in a mouse model of Marfan syndrome (MFS) is characterized leaflet thickening and increased macrophage infiltration, which are reduced with loss of C-C chemokine receptor type 2 (CCR2). However, the specific contributions of macrophages to pathological extracellular matrix (ECM) remodeling and underlying mechanisms are unknown. Hypothesis: Inhibition of macrophage infiltration by a CCR2 inhibitor blocks ECM abnormalities and MVD progression in mitral valves of MFS mice by suppressing the response to cytokine/chemokines. Methods: Mice with the mutation of Fibrillin 1 (Fbn1 C1039G/+ ) recapitulate histopathological features of MFS. Here, we tested the efficacy of a selective CCR2 antagonist RS504393 in the valves of MFS mice in the initiation (1-month-old) and the progression (2-month-old) of MVD, respectively. MFS mice were intraperitoneally injected with RS504393 at 2 mg/kg/d for 30 days. Histological evaluation and immunofluorescence for macrophages and ECM were performed. RNAseq was performed in mitral valves from 2-month old Fbn1 C1039G/+ mice with CCR2 knockout (CCR2 RFP/RFP ). Results: MFS valves revealed ECM abnormalities characterized by collagen fragmentation and proteoglycan accumulation. RS504393 treatment reduced infiltrating macrophages (MHCII+, CCR2+) in myxomatous valves. Remarkably, RS504393 was protective against both the initiation and the progression of MVD, detected by decreased mitral valve thickness and prevention of pathological ECM remodeling in MFS mice. RNAseq data confirmed increased leukocyte activation involved in immune response and abnormal extracellular matrix remodeling in MFS valves. CCR2 deficiency blocked macrophage infiltration and inhibited the response to cytokines in Fbn1 C1039G/+ valves. Conclusions: Our results show that macrophage infiltration is critical for progressive MVD. Moreover, CCR2 inhibition ameliorates MVD progression by preventing immune response. Thus, the CCR2 inhibitor RS504393 is a potential pharmacological candidate to treat MVD in MFS.

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