12 resultados para X chromosome inactivation
Resumo:
Rett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene. We investigated the genetic basis of disease in a female patient with a Rett-like clinical. Karyotype analysis revealed a pericentric inversion in the X chromosome -46,X,inv(X)(p22.1q28), with breakpoints in the cytobands where the MECP2 and CDKL5 genes are located. FISH analysis revealed that the MECP2 gene is not dislocated by the inversion. However, and in spite of a balanced pattern of X inactivation, this patient displayed hypomethylation and an overexpression of the MECP2 gene at the mRNA level in the lymphocytes (mean fold change: 2.55±0.38) in comparison to a group of control individuals; the expression of the CDKL5 gene was similar to that of controls (mean fold change: 0.98±0.10). No gains or losses were detected in the breakpoint regions encompassing known or suspected transcription regulatory elements. We propose that the de-regulation of MECP2 expression in this patient may be due to alterations in long-range genomic interactions caused by the inversion and hypothesize that this type of epigenetic de-regulation of the MECP2 may be present in other RTT-like patients.
Resumo:
Introduction. Fabry disease is a rare metabolic disorder caused by the genetic deficiency of the lysosomal hydrolase alpha-galactosidase A, located on chromosome X. Females with the defective gene are more than carriers and can develop a wide range of symptoms. Nevertheless, disease symptoms generally occur later and are less severe in women than in men. The enzyme deficiency manifests as a glycosphingolipidosis with progressive accumulation of glycosphingolipids and deposit of inclusion bodies in lysosomes giving a myelinlike appearance. Patients and Methods. Records of renal biopsies performed on adults from 1st January 2008 to 31st August 2011, were retrospectively examined at the Renal Pathology Laboratory. We retrieved biopsies diagnosed with Fabry disease and reviewed clinical and laboratory data and pathology findings. Results. Four female patients with a mean age of 49.3±4.5 (44-55) years were identified. The mean proteinuria was 0.75±0.3 g/24h (0.4-1.2) and estimated glomerular filtration rate (CKD EPI equation) was 71±15.7 ml/min/1.73m2 (48-83). Three patients experienced extra-renal organ involvement (cerebrovascular, cardiac, dermatologic, ophthalmologic and thyroid) with distinct severity degrees. Leukocyte α-GAL A activity was below normal range in the four cases but plasma and urinary enzymatic activity was normal. Light microscopy showed predominant vacuolisation of the podocyte cytoplasm and darkly staining granular inclusions on paraffin and plastic-embedded semi-thin sections. Electron microscopy showed in three patients the characteristic myelin-like inclusions in the podocyte cytoplasm and also focal podocyte foot process effacement. In one case the inclusions were also present in parietal glomerular cells, endothelial cells of peritubular capillary and arterioles. Conclusion. Clinical signs and symptoms are varied and can be severe among heterozygous females with Fabry disease. Intracellular accumulation of glycosphingolipids is a characteristic histologic finding of Fabry nephropathy. Since this disease is a potentially treatable condition, its early identification is imperative. We should consider it in the differential diagnosis of any patient presenting with proteinuria and/or chronic kidney disease, especially if there is a family history of kidney disease.
Resumo:
O síndroma de Turner (TS) tem sido descrito em associação com diversas anomalias dos cromossomas sexuais. Embora a maioria dos individuos com TS não apresentem evidência citogenética de sequências do cromossoma Y, diferentes autores consideram que algumas doentes com TS podem possuir uma linha celular minoritária contendo material do cromossoma Y, que não é detectada pela análise citogenética convencional. A identificação de moisacismos minoritários ou subrepresentados contendo o cromossoma Y é de importância fundamental em termos clínicos devido ao risco aumentado que estas doentes possuem para desenvolvimento de gonadoblastoma. No presente estudo procedeu-se à análise citogenética convencional de linfócitos de sangue periférico obtidos de 22 doentes com TS. Destas doentes, doze possuíam cariotipo 45,X, em sete foram detectados mosaicos com ou sem anomalias estruturais do cromossoma X e nas restantes três foram identificados os seguintes cariotipos: 46,X,i (X)(q10); 46,X,+mar/47,X,idic(Y),+mar e 45,X/46,X,+r. Os estudos moleculares foram realizados em DNA genómico obtido a partir de linfócitos de sangue periférico e de células de mucosa bucal, dois tecidos que derivam de folhetos embrionários diferentes, respectivamente, mesoderme e ectoderme. A pesquisa de moisacismos minoritários envolvendo o cromossoma Y foi efectuada por PCR simples e PCR nested para os seguintes loci específicos do cromossoma Y: SRY (sex determining region Y), TSPY (testis specific protein Y encoded), DYZ3 (locus centromérico) e DAZ1 (deleted in azoospermia). O uso de STSs localizados nos braços curto e longo do cromossoma Y permitiu a caracterização de um idic (Y)e de um cromossoma em anel, detectados em duas das doentes estudadas. A eleveda sensibilidade da PCR nested (1 célila masculina/125 000 células femininas) permitiu excluir a presença de moisacismos minoritários do Y em 20 das 22 doentes com TS. Na doente com um idic(Y) a análise por PCR simples foi posistiva para todos os loci estudados com excepção da região heterocromática. Este resultado permitiu identificar o ponto de quebra no braço longo entre sY158 e sY159, tendo-se confirmado por hibridação in situ de fluorescência (FISH), a duplicação da eurocromatina do braço longo, centrómero e braço curto do cromossoma Y. A caracterização do cromossoma em anel, detectado num das doentes com TS só foi possível por FISH e por PCR. Neste cromossoma, derivado de Y, foi detectada, no braço curto, a delecção da região pseudoautossómica 1 (PARY1)e, no braço longo, a delecção dos intervalos 6 e 7. Contudo, o referido cromossoma foi positivo para os loci SRY, RPS4Y, AMGY, TSPY localizados no braço curto, DYZ3 (centrómero) e, sY85, DFFRY, GY6, sY87, sY113, sY119, sY122, sY126 e RBMY1 localizados no braço longo do cromossoma Y. Este estudo permitiu, assim, excluir a presença de moisacismos minoritários do cromossoma Y em dois tecidos obtidos de 20 doentes com TS, e caracterizar por FISH e análise molecular, um idic(Y) e um cromossoma em anel, em que a natureza deste último não tinha sido identificada por análise citogenética convencional. O risco elevado de desenvolvimento de gonadoblastoma nos indivíduos com TS que possuem sequências do cromossoma Y justifica a aplicação de FISH e PCR para a caracterização de cromossomas marcadores e a utilização de PCR nested para a detecção de moisacismos minoritários do Y sempre que o material deste cromossoma não seja detectado pela análise citogenética convencional em doentes com cariotipo 45,X e/ou virilização.
Resumo:
Pericardial cysts are rare benign congenital malformations, usually small, asymptomatic and detected incidentally on chest X-ray as a mass located in the right costophrenic angle. Giant pericardial cysts are very uncommon and produce symptoms by compressing adjacent structures. In this report, the authors present a case of a symptomatic giant pericardial cyst incorrectly diagnosed as dextrocardia on chest X-ray.
Resumo:
Introdução:A miopatia miotubular ligada ao cromossoma X e uma miopatia congénita grave neonatal que afecta o sexo masculino, com prognóstico reservado. Relato de Caso: Lactente com hipotonia generalizada grave detectada após o nascimento, atrofia muscular generalizada e abolição dos reflexos osteotendinosos, cujo estudo etiológico específico (biópsia muscular e estudo de genética molecular) revelo tratar-se de miopatia miotubular ligada ao cromossoma X. Internado em Unidade de Cuidados Intensivos até aos oito meses, foi submetido a traqueostomia e gastrotomia, tendo alta para domicílio. Faleceu aos dez meses, subitamente, de causa indeterminada. Discussão: Este caso mostra que, apesar da terapêutica actual ser apenas paliativa, a importância do conhecimento do mecanismo genético é enorme, abrindo novos horizontes para uma terapia génica no futuro.
Resumo:
Acquired factor X deficiency is an extremely rare situation. It has shown to be associated with systemic amyloidosis, respiratory mycoplasma infection, factor X inhibitors, antiphospholipid antibodies, vitamin K defi ciency/liver disease as well as the use of certain medications (meropenem, valproic acid). The pathogenesis and transient nature of this deficit remain poorly understood. The authors describe the case of a teenager hospitalised for extensive burns that developed active bleeding after removal of central venous catheter. He was diagnosed with transient factor X deficiency. Normalisation of coagulation status and factor X levels occurred spontaneously 10 days after the bleeding episode.
Resumo:
Os autores apresentam um caso clínico de encefalite crónica a enterovírus num rapaz de 9 anos com agamaglobulinémia congénita ligada ao cromossoma X (doença de Bruton). Apesar da terapêutica intraventricular com doses elevadas de gamaglobulina, registou-se uma progressão da doença com deterioração neurológica maciça e morte. Discutem-se os aspectos diagnósticos e terapêuticos desta situação.
Resumo:
Adult B-cell acute lymphoblastic leukemia remains a major therapeutic challenge, requiring a better characterization of the molecular determinants underlying disease progression and resistance to treatment. Here, using a phospho-flow cytometry approach we show that adult diagnostic B-cell acute lymphoblastic leukemia specimens display PI3K/Akt pathway hyperactivation, irrespective of their BCR-ABL status and despite paradoxically high basal expression of PTEN, the major negative regulator of the pathway. Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation. In agreement, we found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls. Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells. Our studies indicate that CK2-mediated PTEN posttranslational inactivation, associated with PI3K/Akt pathway hyperactivation, are a common event in adult B-cell acute lymphoblastic leukemia and suggest that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy.