RESUMO
The NOTCH signalling pathway is an essential pathway, involved in many cellular processes, including cell fate decision, cell proliferation, and cell death and important in the development of most organs. Mutations in genes encoding components of the NOTCH signalling pathway lead to a spectrum of congenital disorders. Over the past decades, mutations in human NOTCH signalling genes have been identified in several diseases with cardiovascular involvement. NOTCH1 mutations have been described in bicuspid aortic valve disease, left-sided congenital heart disease, and Adams-Oliver syndrome. NOTCH2 mutations lead to the development of Alagille syndrome, while mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. To date, mutations in NOTCH4 have not been associated with cardiovascular disease. This review focuses on the mutations described in NOTCH1, NOTCH2, and NOTCH3 and their associated cardiovascular phenotypes.
Assuntos
Doenças Cardiovasculares/genética , Receptor Notch1/genética , Receptor Notch2/genética , Receptor Notch3/genética , Síndrome de Alagille/genética , Síndrome de Alagille/patologia , CADASIL/genética , CADASIL/patologia , Doenças Cardiovasculares/patologia , Proliferação de Células/genética , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Humanos , Deformidades Congênitas dos Membros/genética , Deformidades Congênitas dos Membros/patologia , Mutação , Dermatoses do Couro Cabeludo/congênito , Dermatoses do Couro Cabeludo/genética , Dermatoses do Couro Cabeludo/patologiaRESUMO
Sudden cardiac death (SCD) has an enormous impact on those who are left behind, evoking strong feelings of anxiety and incomprehension because such a dramatic event was not anticipated. Moreover, over the last decade a prominent genetic contribution to the pathogenesis of SCD has been unveiled. As many inherited cardiac diseases show an autosomal dominant pattern of inheritance, the risk of carrying the same inherited predisposition is a real concern for the relatives. In this article, we discuss the major causes of primary electrical disorders, cardiomyopathies and thoracic aortic dissection and address issues in genotype-phenotype correlation, personalized management and cardiogenetic counselling.
Assuntos
Aneurisma da Aorta Torácica/genética , Arritmias Cardíacas/genética , Cardiomiopatias/genética , Doença da Artéria Coronariana/genética , Morte Súbita Cardíaca/patologia , Estudos de Associação Genética , Predisposição Genética para Doença , HumanosAssuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Proteínas de Ligação ao Cálcio/genética , Quinase de Cadeia Leve de Miosina/genética , Idoso , Dissecção Aórtica/fisiopatologia , Aneurisma da Aorta Torácica/fisiopatologia , Códon sem Sentido/genética , Feminino , Haploinsuficiência/genética , Humanos , Masculino , Anamnese , Pessoa de Meia-Idade , LinhagemRESUMO
Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with "other type I fibrillinopathy." In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete "clinical" international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort.
Assuntos
Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Adulto , Estudos de Coortes , Ectopia do Cristalino/diagnóstico , Ectopia do Cristalino/genética , Ectopia do Cristalino/patologia , Fibrilina-1 , Fibrilinas , Humanos , Masculino , Síndrome de Marfan/classificação , Síndrome de Marfan/patologia , Mutação , FenótipoRESUMO
BACKGROUND: The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. METHODS: Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the "clinical" international criteria. RESULTS: Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled "clinical criteria" when compared to the Marfan syndrome group (44% vs 73% at 40 years, p<0.001), but the lifelong risk for ascending aortic dissection or surgery was not significantly different in both groups. CONCLUSIONS: Because of its implications for aortic follow-up, FBN1 molecular analysis is recommended in newly suspected MFS when two systems are involved with at least one major system affected. This is of utmost importance in patients without aortic dilatation and in children.
Assuntos
Cooperação Internacional , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Adolescente , Adulto , Idoso , Aorta/patologia , Criança , Feminino , Fibrilina-1 , Fibrilinas , Humanos , Masculino , Mutação/genéticaRESUMO
Arterial tortuosity syndrome (ATS, MIM# 208050) is a rare autosomal recessive connective tissue disease, mainly characterized by widespread arterial involvement with elongation, tortuosity, and aneurysms of the large and middle-sized arteries (Callewaert et al., 2008, Hum Mutat 29:150-158). Recently, mutations were identified in the SLC2A10 gene encoding the facilitative glucose transporter GLUT10 (Coucke et al., 2006, Nat Genet 38:452-457). It was hypothesized that loss-of-function of the transporter results in upregulation of the transforming growth factor beta (TGFbeta) signaling pathway (Coucke et al., 2006, Nat Genet 38:452-457). We anticipated that a mouse model would help to gain more insight in the complex pathophysiological mechanism of human ATS. Here, we report that two mouse models, homozygous respectively for G128E and S150F missense substitutions in glut10 do not present any of the vascular, anatomical, or immunohistological abnormalities as encountered in human ATS patients. We conclude that these mouse strains do not phenocopy human ATS and cannot help the further elucidation of pathogenetic mechanisms underlying this disease.
Assuntos
Artérias/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Mutação de Sentido Incorreto , Animais , Artérias/citologia , Modelos Animais de Doenças , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , CamundongosRESUMO
Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disease, characterized by widespread arterial involvement with elongation, tortuosity, and aneurysms of the large and middle-sized arteries. Recently, SLC2A10 mutations were identified in this condition. This gene encodes the glucose transporter GLUT10 and was previously suggested as a candidate gene for diabetes mellitus type 2. A total of 12 newly identified ATS families with 16 affected individuals were clinically and molecularly characterized. In addition, extensive cardiovascular imaging and glucose tolerance tests were performed in both patients and heterozygous carriers. All 16 patients harbor biallelic SLC2A10 mutations of which nine are novel (six missense, three truncating mutations, including a large deletion). Haplotype analysis suggests founder effects for all five recurrent mutations. Remarkably, patients were significantly older than those previously reported in the literature (P=0.04). Only one affected relative died, most likely of an unrelated cause. Although the natural history of ATS in this series was less severe than previously reported, it does indicate a risk for ischemic events. Two patients initially presented with stroke, respectively at age 8 months and 23 years. Tortuosity of the aorta or large arteries was invariably present. Two adult probands (aged 23 and 35 years) had aortic root dilation, seven patients had localized arterial stenoses, and five had long stenotic stretches of the aorta. Heterozygous carriers did not show any vascular anomalies. Glucose metabolism was normal in six patients and eight heterozygous individuals of five families. As such, overt diabetes is not related to SLC2A10 mutations associated with ATS.
Assuntos
Artérias/anormalidades , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/genética , Proteínas Facilitadoras de Transporte de Glucose/genética , Adulto , Doenças do Tecido Conjuntivo/metabolismo , Família , Glucose/metabolismo , Teste de Tolerância a Glucose , Haplótipos , Humanos , Angiografia por Ressonância Magnética , Modelos Biológicos , Linhagem , Fenótipo , SíndromeRESUMO
The Meier-Gorlin syndrome, first described by Meier and Rothschild [1959: Helv Paediatr Acta 14:213-216] and further delineated by Gorlin et al. [1975: A Selected Miscellany, p 39-50], is characterized by short stature, slender body build, craniofacial anomalies, microtia, delayed skeletal development, hypogonadism, and absence of the patellae. It has also been called the ear-patella-short stature syndrome [Boles et al., 1994: Clin Dysmorphol 3:207-214]. We report on two brothers with Meier-Gorlin syndrome, the younger of whom was more severely affected. Both patients had severe deafness and congenital labyrinthine anomalies, which have not previously been described as features of this syndrome. The neuromotor and mental development of these patients was adversely affected by late diagnosis, deafness, and their sociocultural environment, but their cognitive ability fell within the range observed in other Meier-Gorlin patients. Neuroradiographic imaging and functional inner ear investigations are recommended in the diagnostic workup of this rather specific, probably autosomal recessive mental retardation syndrome with multiple congenital anomalies.
Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Orelha/anormalidades , Transtornos do Crescimento/genética , Patela/anormalidades , Criança , Orelha/diagnóstico por imagem , Genes Recessivos , Humanos , Hipogonadismo/genética , Deficiência Intelectual/genética , Imageamento por Ressonância Magnética , Masculino , Núcleo Familiar , Patela/diagnóstico por imagem , RadiografiaRESUMO
The predisposition for scleroderma, defined as fibrosis and hardening of the skin, is poorly understood. We report that stiff skin syndrome (SSS), an autosomal dominant congenital form of scleroderma, is caused by mutations in the sole Arg-Gly-Asp sequence-encoding domain of fibrillin-1 that mediates integrin binding. Ordered polymers of fibrillin-1 (termed microfibrils) initiate elastic fiber assembly and bind to and regulate the activation of the profibrotic cytokine transforming growth factor-beta (TGFbeta). Altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGFbeta concentration and signaling in the dermis. The observation of similar findings in systemic sclerosis, a more common acquired form of scleroderma, suggests broad pathogenic relevance.
Assuntos
Proteínas dos Microfilamentos/genética , Mutação/genética , Escleroderma Sistêmico/congênito , Escleroderma Sistêmico/genética , Pele/patologia , Biópsia , Adesão Celular , Movimento Celular , Colágeno/metabolismo , Análise Mutacional de DNA , Elastina/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Família , Feminino , Fibrilina-1 , Fibrilinas , Humanos , Imuno-Histoquímica , Masculino , Mesoderma/patologia , Microfibrilas/metabolismo , Microfibrilas/patologia , Proteínas dos Microfilamentos/metabolismo , Linhagem , Fenótipo , Escleroderma Sistêmico/patologia , Transdução de Sinais , Pele/ultraestrutura , Síndrome , Fator de Crescimento Transformador beta/metabolismoRESUMO
BACKGROUND AND PURPOSE: Loeys-Dietz syndrome (LDS) is a recently described entity that has the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Its neuroradiologic manifestations have not been well delineated. We sought to describe the neuroradiologic features of LDS and to assess the manifestations that would warrant follow-up imaging. MATERIALS AND METHODS: Two neuroradiologists retrospectively reviewed CT angiography (CTA), MR imaging, and plain film studies related to the head and neck in 25 patients ranging from 1 to 55 years of age, all of whom had positive genetic testing and clinical characteristics of LDS. Arterial tortuosity was evaluated by subjective assessment of 2D and 3D volumetric CTA and MR angiography data. Craniosynostosis and spinal manifestations were assessed by using plain films and CT images. MR images mostly of the head were reviewed for associated findings such as hydrocephalus, Chiari malformation, etc. Clinical manifestations were collated from the electronic patient record. RESULTS: All patients had extreme arterial tortuosity, which is characteristic of this syndrome. Thirteen patients had scoliosis, 12 had craniosynostosis, 8 had intracranial aneurysms, 6 had spinal instability, 3 had dissections of the carotid and vertebrobasilar arteries, 3 had hydrocephalus, 4 had dural ectasia, 2 had a Chiari malformation, and 1 had intracranial hemorrhage as a complication of vascular dissection. CONCLUSIONS: Significant neuroradiologic manifestations are associated with LDS, predominantly arterial tortuosity. Most of the patients in this series were young and, therefore, may require serial CTA monitoring for development of intra- and extracranial dissections and aneurysms, on the basis of the fact that most of the patients with pseudoaneurysms and dissection were older at the time of imaging. Other findings of LDS such as craniosynostosis, Chiari malformation, and spinal instability may also need to be addressed.
Assuntos
Angiografia Cerebral/métodos , Artérias Cerebrais/diagnóstico por imagem , Artérias Cerebrais/patologia , Síndrome de Loeys-Dietz/diagnóstico , Angiografia por Ressonância Magnética/métodos , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto JovemRESUMO
Mutations in the FBN1 gene cause Marfan syndrome (MFS) and a wide range of overlapping phenotypes. The severe end of the spectrum is represented by neonatal MFS, the vast majority of probands carrying a mutation within exons 24-32. We previously showed that a mutation in exons 24-32 is predictive of a severe cardiovascular phenotype even in non-neonatal cases, and that mutations leading to premature truncation codons are under-represented in this region. To describe patients carrying a mutation in this so-called 'neonatal' region, we studied the clinical and molecular characteristics of 198 probands with a mutation in exons 24-32 from a series of 1013 probands with a FBN1 mutation (20%). When comparing patients with mutations leading to a premature termination codon (PTC) within exons 24-32 to patients with an in-frame mutation within the same region, a significantly higher probability of developing ectopia lentis and mitral insufficiency were found in the second group. Patients with a PTC within exons 24-32 rarely displayed a neonatal or severe MFS presentation. We also found a higher probability of neonatal presentations associated with exon 25 mutations, as well as a higher probability of cardiovascular manifestations. A high phenotypic heterogeneity could be described for recurrent mutations, ranging from neonatal to classical MFS phenotype. In conclusion, even if the exons 24-32 location appears as a major cause of the severity of the phenotype in patients with a mutation in this region, other factors such as the type of mutation or modifier genes might also be relevant.
Assuntos
Éxons/genética , Proteínas dos Microfilamentos/genética , Mutação , Códon sem Sentido , Análise Mutacional de DNA , Ectopia do Cristalino/genética , Fibrilina-1 , Fibrilinas , Humanos , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/metabolismo , FenótipoRESUMO
Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.
Assuntos
Síndrome de Marfan/diagnóstico , Proteínas dos Microfilamentos/genética , Adolescente , Adulto , Fator de Crescimento Epidérmico/genética , Éxons/genética , Feminino , Fibrilina-1 , Fibrilinas , Humanos , Masculino , Mutação , Fenótipo , Prognóstico , Estrutura Terciária de Proteína/genética , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta/genéticaRESUMO
The Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with a prevalence of 2-3 per 10,000 individuals and symptoms ranging from skeletal overgrowth, cutaneous striae to ectopia lentis and aortic dilatation leading to dissection. Mutation in the gene for fibrillin-1 (FBN1) cause MFS and other related disorders of connective tissue, grouped as fibrillinopathies. Fibrillin-1 is the main constituent of extracellular microfibrils. Microfibrils can exist as individual structures or associate with elastin to form elastic fibers. This article provides an overview of the current diagnostic criteria and medical management, estimates the role of fibrillin-1 mutation analysis, sheds new light on genotype-phenotype correlations and summarizes new insights on the pathogenesis of this disorder based on mouse models.
Assuntos
Proteínas da Matriz Extracelular/genética , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Animais , Análise Mutacional de DNA , Diagnóstico Diferencial , Modelos Animais de Doenças , Fibrilina-1 , Fibrilinas , Genótipo , Humanos , Síndrome de Marfan/fisiopatologia , Camundongos , Técnicas de Diagnóstico Molecular , FenótipoRESUMO
UNLABELLED: We report on a patient who presented at 5 years of age with a hemiparesis due to a middle cerebral artery infarction. An embolism had originated from a mycotic aneurysm located in the internal carotid artery. For several months prior to admission he had been suffering from therapeutically resistant candidiasis of the mouth and nails. Family history revealed chronic mycotic infections of the skin, hair, nails and mouth in the father and paternal grandmother suggestive of chronic mucocutaneous candidiasis with autosomal dominant mode of inheritance. Clipping of the aneurysm, after 3 months of anti-mycotic treatment, followed by sustained treatment with itraconazole and fluconazole, led to a favourable outcome. CONCLUSION: Chronic mucocutaneous candidiasis can be associated with an intracranial aneurysm and complicated by cerebral infarction.