Overview of Marfan Syndrome: knowns and unknowns

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

Circulation ◽

10.1161/circ.130.suppl_2.11621 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

John J Parent ◽

Jeffrey A Towbin ◽

John L Jefferies

Keyword(s):

Extracellular Matrix ◽

Gene Mutation ◽

Marfan Syndrome ◽

Gene Mutations ◽

Left Ventricular ◽

Current Evidence ◽

Causative Gene ◽

Fbn1 Gene ◽

Gene Testing ◽

Fibrillin 1

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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The activity of transforming growth factor-β in young age with marfanoid habitus

Pediatrician (St Petersburg) ◽

10.17816/ped10149-56 ◽

2019 ◽

Vol 10 (1) ◽

pp. 49-56

Author(s):

Eugene V. Timofeev ◽

Eduard G. Malev ◽

Ekaterina B. Luneva ◽

Eduard V. Zemtsovsky

Keyword(s):

Mitral Valve ◽

Marfan Syndrome ◽

Transforming Growth Factor ◽

Clinical Manifestations ◽

Transforming Growth Factor Β ◽

Young Age ◽

Atrial Septal Aneurysm ◽

Ehlers Danlos Syndrome ◽

Danlos Syndrome ◽

Tgf Β1

According to contemporary views, hereditary connective tissue disorders divided classified Marfan syndrome, Loeys-Dietz’s, Ehlers-Danlos syndrome, the primary mitral valve prolapse. It is known that the fibrillinopaty, which include the Marfan syndrome and Loeys-Dietz’s is characterized by activation of TGF-β signaling pathway. With high le vels of TGF-β attributed most of these clinical manifestations these diseases – aneurysm of the aorta, arahnodaktylya, duralectasy. Assessment of the activity of TGF-β in persons with marfanoid habitus has not previously been studied. Materials and methods. As part of this work, surveyed 70 people: 61 patients young age (median age of 20.1 ± 2.1 years), among which 36 boys and 25 girls and 9 men with verified diagnosis Marfan syndrome (median age 27.9 ± 9.3 years). All survey performed Echocardiography with a targeted search of small anomalies of heart. Results. Correlation analysis showed a direct and reliable connection between arahnodaktylya and concentration of TGF-β1 in serum (r = 0.4, p = 0.05). For young people with signs of marfanoid habitus are characterized by reliably a higher concentration in the serum of both isoforms of TGF-β. Excess of threshold levels of TGF-β1 revealed at 20% of the core group and not found at all in the control (p < 0.05). Among persons with exceedances of threshold values for at least one faction of the TGF-β patients with signs of marfanoid habitus met almost three times more often than in the group with normal values of TGF-β (p = 0.01, χ2 = 5.58). In the group of persons with marfanoid habitus and increases TGF-β are detected more frequently such as atrial septal aneurysm, false chord left ventricle papillary muscles, incremental, deflection of shutters of the mitral valve in 1-2 mm, asymmetry tricuspid aortic valve.

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Vitamin B Mitigates Thoracic Aortic Dilation in Marfan Syndrome Mice by Restoring the Canonical TGF-β Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms222111737 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11737

Author(s):

Tzu-Heng Huang ◽

Hsiao-Huang Chang ◽

Yu-Ru Guo ◽

Wei-Chiao Chang ◽

Yi-Fan Chen

Keyword(s):

Marfan Syndrome ◽

Methylenetetrahydrofolate Reductase ◽

Transforming Growth Factor ◽

Clinical Manifestations ◽

Transforming Growth Factor Β ◽

Potential Method ◽

Methionine Synthase ◽

Vitamin B ◽

Methionine Synthase Reductase ◽

Methionine Cycle

Thoracic aortic aneurysm (TAA) formation is a multifactorial process that results in diverse clinical manifestations and drug responses. Identifying the critical factors and their functions in Marfan syndrome (MFS) pathogenesis is important for exploring personalized medicine for MFS. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) polymorphisms have been correlated with TAA severity in MFS patients. However, the detailed relationship between the folate-methionine cycle and MFS pathogenesis remains unclear. Fbn1C1039G/+ mice were reported to be a disease model of MFS. To study the role of the folate-methionine cycle in MFS, Fbn1C1039G/+ mice were treated orally with methionine or vitamin B mixture (VITB), including vitamins B6, B9, and B12, for 20 weeks. VITB reduced the heart rate and circumference of the ascending aorta in Fbn1C1039G/+ mice. Our data showed that the Mtr and Smad4 genes were suppressed in Fbn1C1039G/+ mice, while VITB treatment restored the expression of these genes to normal levels. Additionally, VITB restored canonical transforming-growth factor β (TGF-β) signaling and promoted Loxl1-mediated collagen maturation in aortic media. This study provides a potential method to attenuate the pathogenesis of MFS that may have a synergistic effect with drug treatments for MFS patients.

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The Potential Association between the Risk of Post-Surgical Adhesion and the Activated Local Angiotensin II Type 1 Receptors: Need for Novel Treatment Strategies

Gastrointestinal Tumors ◽

10.1159/000514614 ◽

2021 ◽

pp. 1-8

Author(s):

Mahmood Tavakkoli ◽

Saeed Aali ◽

Borzoo Khaledifar ◽

Gordon A. Ferns ◽

Majid Khazaei ◽

...

Keyword(s):

Angiotensin Ii ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Therapeutic Potential ◽

Angiotensin Receptor Blockers ◽

Surgical Techniques ◽

Treatment Strategies ◽

Transforming Growth Factor Β

Background: Post-surgical adhesion bands (PSABs) are a common complication after abdominal or pelvic surgeries for different reasons like cancer treatment. Despite improvements in surgical techniques and the administration of drugs or the use of physical barriers, there has only been limited improvement in the frequency of postoperative adhesions. Complications of PSAB are pain, infertility, intestinal obstruction, and increased mortality. The most important molecular mechanisms for the development of PSAB are inflammatory response, oxidative stress, and overexpression of pro-fibrotic molecules such as transforming growth factor β. However, questions remain about the pathogenesis of this problem, for example, the causes for individual differences or why certain tissue sites are more prone to post-surgical adhesions. Summary: Addressing the pathological causes of PSAB, the potential role of local angiotensin II/angiotensin II type 1 receptors (AngII/AT1R), may help to prevent this problem. Key Message: The objective of this article was to explore the role of the AngII/AT1R axis potential to induce PSAB and the therapeutic potential of angiotensin receptor blockers in the prevention and treatment of PSAB.

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Contribution of “Omic” Studies to the Understanding of Cadasil. A Systematic Review

International Journal of Molecular Sciences ◽

10.3390/ijms22147357 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7357

Author(s):

Elena Muiño ◽

Israel Fernández-Cadenas ◽

Adrià Arboix

Keyword(s):

Growth Factor ◽

Protein Misfolding ◽

Drug Targets ◽

Transforming Growth Factor ◽

Small Vessel Disease ◽

Transforming Growth Factor Β ◽

Small Vessel ◽

Vessel Disease ◽

Extracellular Matrix Components ◽

Recurrent Strokes

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets.

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Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor β

International Journal of Molecular Sciences ◽

10.3390/ijms19113672 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3672 ◽

Cited By ~ 40

Author(s):

Yutaro Tsubakihara ◽

Aristidis Moustakas

Keyword(s):

Growth Factor ◽

Tumor Cells ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Transforming Growth Factor Β ◽

Basement Membranes ◽

The Body ◽

Common Denominator ◽

Adhesion Forces ◽

Mesenchymal Transition

Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells can achieve solitary or collective motility, which makes the EMT an intuitive mechanism for the initiation of tumor metastasis. EMT initiates after primary oncogenic events lead to secondary secretion of cytokines. The interaction between tumor-secreted cytokines and oncogenic stimuli facilitates EMT progression. A classic case of this mechanism is the cooperation between oncogenic Ras and the transforming growth factor β (TGFβ). The power of TGFβ to mediate EMT during metastasis depends on versatile signaling crosstalk and on the regulation of successive waves of expression of many other cytokines and the progressive remodeling of the extracellular matrix that facilitates motility through basement membranes. Since metastasis involves many organs in the body, whereas EMT affects carcinoma cell differentiation locally, it has frequently been debated whether EMT truly contributes to metastasis. Despite controversies, studies of circulating tumor cells, studies of acquired chemoresistance by metastatic cells, and several (but not all) metastatic animal models, support a link between EMT and metastasis, with TGFβ, often being a common denominator in this link. This article aims at discussing mechanistic cases where TGFβ signaling and EMT facilitate tumor cell dissemination.

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Serological level of transforming growth factor-β as a predictive biomarker of aortic enlargement in patients with Marfan syndrome

Pediatrician (St Petersburg) ◽

10.17816/ped8161-66 ◽

2017 ◽

Vol 8 (1) ◽

pp. 61-66

Author(s):

Andrey S Rudoy ◽

Alexey M Uryvaev

Keyword(s):

Risk Factors ◽

Growth Factor ◽

Marfan Syndrome ◽

Aortic Root ◽

Transforming Growth Factor ◽

Aortic Rupture ◽

Imaging Techniques ◽

Elevated Serum ◽

Transforming Growth Factor Β ◽

Absolute Size

Marfan syndrome - an inherited, autosomal dominant disease with an expected rate of 3-5/10 000 or fraction of 20-25% of new mutations, accompanied by violation of the connective tissue that occurs as a result of gene mutations FBN1, coding for the synthesis of fibrillin-1, performing the most important role in the modulation physiological bioavailability TGF-β (transforming growth factor-β). Prediction of aortic rupture is based on the identification of risk factors: family history, the absolute size of the aortic root, the rate of expansion of the aorta, which are based on the results of the history and techniques of imaging ultrasound, CT, MRI. At the same time there is a chance of developing aortic rupture under normal aortic root size and the absence of any risk factors, as well as after the prophylactic prosthetic aortic root. This makes it necessary to search for alternative prognostic markers, threatening bundle and rupture of the aorta. Article verified the predictive role of TGF-β as a serological biomarker for assessing the extension of the aortic root in patients with Marfan syndrome (n = 23, F : M / 7 : 16; 33 ± 9.3 years). The article describes the patterns between TGF-β and the size and the reconstruction of the aneurysm of the thoracic aorta. It was found that elevated levels of serum TGF-β1 (49.1 ng/ml Vs 29.15 ng/ml in the control, p < 0.05) in patients with MS diagnosed with an extension of the aortic root (Z > 1.96) can serve as a serological marker to poor prognosis, accompanied by an increase in the size of the aortic root. In patients with normal-sized aorta, and after aortic reconstruction serum TGFβ1 not elevated. Serum TGFβ may be a promising target for therapeutic, diagnostic and prognostic tactics which are not based on imaging techniques.

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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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