Laura Muiño Mosquera

Gene panel sequencing in heritable thoracic aortic disorders and related entities – results of comprehensive testing in a cohort of 264 patients

BackgroundHeritable Thoracic Aortic Disorders (H-TAD) may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. About one dozen genes are now available for clinical molecular testing. Targeted single gene testing is hampered by significant clinical overlap between syndromic H-TAD entities and the absence of discriminating features in isolated cases. Therefore panel testing of multiple genes has now emerged as the preferred approach. So far, no data on mutation detection rate with this technique have been reported.MethodsWe performed Next Generation Sequencing (NGS) based screening of the seven currently most prevalent H-TAD-associated genes (FBN1, TGFBR1/2, TGFB2, SMAD3, ACTA2 and COL3A1) on 264 samples from unrelated probands referred for H-TAD and related entities. Patients fulfilling the criteria for Marfan syndrome (MFS) were only included if targeted FBN1 sequencing and MLPA analysis were negative.ResultsA mutation was identified in 34 patients (13%): 12 FBN1, one TGFBR1, two TGFBR2, three TGFB2, nine SMAD3, four ACTA2 and three COL3A1 mutations. We found mutations in FBN1 (N = 3), TGFBR2 (N = 1) and COL3A1 (N = 2) in patients without characteristic clinical features of syndromal H-TAD. Six TAD patients harboring a mutation in SMAD3 and one TAD patient with a TGFB2 mutation fulfilled the diagnostic criteria for MFS.ConclusionNGS based H-TAD panel testing efficiently reveals a mutation in 13% of patients. Our observations emphasize the clinical overlap between patients harboring mutations in syndromic and nonsyndromic H-TAD related genes as well as within syndromic H-TAD entities, justifying a widespread application of this technique.

Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans

Background:Mild intrinsic cardiomyopathy in patients with Marfan syndrome (MFS) has consistently been evidenced by independent research groups. So far, little is known about the long-term evolution and pathophysiology of this finding.Methods:To gain more insights into the pathophysiology of MFS-related cardiomyopathy, we performed in-vivo and ex-vivo studies of 11 Fbn1C1039G/+ mice and 9 wild-type (WT) littermates. Serial ultrasound findings obtained in mice were correlated to the human phenotype. We therefore reassessed left ventricular (LV) function parameters over a 6-y follow-up period in 19 previously reported MFS patients, in whom we documented mild LV dysfunction.Results:Fbn1C1039G/+ mice demonstrated LV contractile dysfunction. Subsequent ex-vivo studies of the myocardium of adult mutant mice revealed upregulation of TGFβ-related pathways and consistent abnormalities of the microfibrillar network, implicating a role for microfibrils in the mechanical properties of the myocardium. Echocardiographic parameters did not indicate clinical significant deterioration of LV function during follow-up in our patient cohort.Conclusion:In analogy with what is observed in the majority of MFS patients, the Fbn1C1039G/+ mouse model demonstrates mild intrinsic LV dysfunction. Both extracellular matrix and molecular alterations are implicated in MFS-related cardiomyopathy. This model may now enable us to study therapeutic interventions on the myocardium in MFS.

Marfan Syndrome and Related Heritable Thoracic Aortic Aneurysms and Dissections.

In this overview we aim to address a number of recent insights and developments regarding clinical aspects, etiology, and treatment of Heritable Thoracic Aortic Disease (H-TAD). We will focus on monogenetic disorders related to aortic aneurysms. H-TADs are rare but they provide a unique basis for the study of underlying pathogenetic pathways in the complex disease process of aneurysm formation. The understanding of pathomechanisms may help us to identify medical treatment targets to improve prognosis. Among the monogenetic aneurysm disorders, Marfan syndrome is considered as a paradigm entity and many insights are derived from the study of clinical, genetic and animal models for Marfan syndrome. We will therefore first provide a detailed overview of the various aspects of Marfan syndrome after which we will give an overview of related H-TAD entities.

Managing aortic aneurysms and dissections during pregnancy.

Cardiovascular diseases during pregnancy account for significant morbidity and mortality, with aortic aneurysms, complicated by aortic dissection or rupture, being high on the list of underlying causes in this category. Correct knowledge of the diagnosis, risks and treatment is mandatory to improve the outcome and save lives. In this article, the authors aim to provide an overview of the underlying causes and risk factors for aortic aneurysms and dissections during pregnancy, while presenting the ways of preventing and treating these conditions. Although an important focus lies on the proximal part of the aorta due to it bearing the greatest risk for complications and being more frequently implicated in aortic disease in younger subjects, many aspects on the etiology and underlying diseases also apply to the other parts of the vessel.Cardiovascular diseases during pregnancy account for significant morbidity and mortality, with aortic aneurysms, complicated by aortic dissection or rupture, being high on the list of underlying causes in this category. Correct knowledge of the diagnosis, risks and treatment is mandatory to improve the outcome and save lives. In this article, the authors aim to provide an overview of the underlying causes and risk factors for aortic aneurysms and dissections during pregnancy, while presenting the ways of preventing and treating these conditions. Although an important focus lies on the proximal part of the aorta due to it bearing the greatest risk for complications and being more frequently implicated in aortic disease in younger subjects, many aspects on the etiology and underlying diseases also apply to the other parts of the vessel.

Megaconial muscular dystrophy caused by mitochondrial membrane homeostasis defect, new insights from skeletal and heart muscle analyses.

Megaconial congenital muscular dystrophy is a disease caused by pathogenic mutations in the gene encoding choline kinase beta (CHKB). Microscopically, the disease is hallmarked by the presence of enlarged mitochondria at the periphery of skeletal muscle fibres leaving the centre devoid of mitochondria. Clinical characteristics are delayed motor development, intellectual disability and dilated cardiomyopathy in half of reported cases. This study describes a patient presenting with the cardinal clinical features, in whom a homozygous nonsense mutation (c.248_249insT; p.Arg84Profs*209) was identified in CHKB and who was treated by heart transplantation. Microscopic evaluation of skeletal and heart muscles typically showed enlarged mitochondria. Spectrophotometric evaluation in both tissues revealed a mild decrease of all OXPHOS complexes. Using BN-PAGE analysis followed by activity staining subcomplexes of complex V were detected in both tissues, indicating incomplete complex V assembly. Mitochondrial DNA content was not depleted in analysed tissues. This is the first report describing the microscopic and biochemical abnormalities in the heart from an affected patient. A likely hypothesis is that the biochemical findings are caused by an abnormal lipid profile in the inner mitochondrial membrane resulting from a defective choline kinase B activity.

Mitral valve prolapse syndrome and MASS phenotype: stability of aortic dilatation but progression of mitral valve prolapse

Background Mitral valve prolapse syndrome (MVPS) and MASS phenotype (MASS) are Marfan-like syndromes that exhibit aortic dilatation and mitral valve prolapse. Unlike in Marfan syndrome (MFS), the presence of ectopia lentis and aortic aneurysm preclude diagnosis of MVPS and MASS. However, it is unclear whether aortic dilatation and mitral valve prolapse remain stable in MVPS or MASS or whether they progress like in MFS. Methods This retrospective longitudinal observational study examines clinical characteristics and long-term prognosis of 44 adults with MVPS or MASS (18 men, 26 women aged 38 ± 17 years) as compared with 81 adults with Marfan syndrome (MFS) with similar age and sex distribution. The age at final contact was 42 ± 15 years with mean follow-up of 66 ± 49 months. Results At baseline, ectopia lentis and aortic sinus aneurysm were absent in MVPS and MASS, and systemic scores defined by the revised Ghent nosology were lower than in MFS (all P < .001). Unlike in MFS, no individual with MVPS and MASS developed aortic complications (P < .001). In contrast, the incidence of endocarditis (P = .292), heart failure (P = .644), and mitral valve surgery (P = .140) was similar in all syndromes. Cox regression analysis identified increased LV end-diastolic (P = .013), moderate MVR (P = .019) and flail MV leaflet (P = .017) as independent predictors of mitral valve surgery. Conclusions The study provides evidence that MVPS and MASS are Marfan-like syndromes with stability of aortic dilatation but with progression of mitral valve prolapse. Echocardiographic characteristics of mitral valve disease rather than the type of syndrome, predict clinical progression of mitral valve prolapse.

Looking for the Missing Links: Challenges in the Search for Genotype–Phenotype Correlation in Marfan Syndrome

See Article by Takeda, Inuzuka, and Maemura et al Since the middle of the past century, identification of the causal gene for monogenic disorders has undoubtedly led to improvement in diagnostics and knowledge of the pathophysiological mechanisms underlying these disorders. Yet an explanation for the often extensive variability in the clinical expression of diseases caused by variants in the same gene often remains elusive, and this is no less the case for Marfan syndrome (MFS). MFS is an autosomal dominant inherited connective tissue disorder, caused by pathogenic variants in the fibrillin 1 gene ( FBN1 ). This gene encodes the extracellular matrix protein, fibrillin1, which plays an essential structural role in the assembly of the microfibrils, as well as a functional role in the regulation of growth factors, such as transforming growth factor β and bone morphogenetic protein.1 MFS is a pleiotropic disease affecting predominantly the ocular, skeletal, and cardiovascular systems. Survival of patients with MFS is mainly determined by the degree of cardiovascular involvement. Progressive enlargement of the aortic root at the level of the sinuses of Valsalva in particular accounts for excess mortality because it may lead to life-threatening aortic dissection or rupture. Whereas the prognosis for people with MFS was initially bleak, mainly because of aortic complications, this has improved significantly for the past decades.2 This positive trend is not only because of optimization of medical and surgical treatment but also related to increased awareness and better diagnostics. Other cardiovascular features, present in a variable amount of patients, include mitral valve prolapse and myocardial dysfunction.3,4 To date, treatment of cardiovascular manifestations in patients with MFS is fairly uniform, with guidelines for medical treatment and (prophylactic) surgery based on simple parameters, such as age, body surface, and aortic diameters. Nevertheless, we know that not everyone …

Pregnancy in Women With SMAD3 Mutation

Women with genetic aortic disease, such as Marfan syndrome, are at increased risk of pregnancy complications, in particular those with aortic dissection [(1)][1]. Aneurysms-osteoarthritis syndrome (AOS) is an autosomal-dominant syndrome caused by SMAD3 mutations, and is characterized by arterial