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1.
Nat Genet ; 38(8): 910-6, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16845400

RESUMO

Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.


Assuntos
Transtornos Heredodegenerativos do Sistema Nervoso/enzimologia , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Ribonuclease H/genética , Sequência de Aminoácidos , Sequência de Bases , DNA/genética , Encefalite Viral/congênito , Feminino , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Estrutura Quaternária de Proteína , Subunidades Proteicas , Ribonuclease H/química , Ribonuclease H/metabolismo , Síndrome
2.
Eur J Hum Genet ; 15(4): 463-72, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17264864

RESUMO

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12-p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD = 3.54, alpha = 0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum non-parametric linkage score was 2.87 (P < 0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP-based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear pedigrees. Evidence for transmission disequilibrium (P < or = 0.01) was found for SNPs within a approximately 35 kb region of high LD encompassing the 5'UTR, exon 1 and part of intron 1 of CACNG3. Re-sequencing of this interval was undertaken in 24 affected individuals. Seventy-two variants were identified: 45 upstream; two 5'UTR; and 25 intronic SNPs. No coding sequence variants were identified, although four variants are predicted to affect exonic splicing. This evidence supports CACNG3 as a susceptibility locus in a subset of CAE patients.


Assuntos
Canais de Cálcio Tipo T/genética , Canais de Cálcio/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 16/genética , Epilepsia Tipo Ausência/genética , Predisposição Genética para Doença , Desequilíbrio de Ligação/genética , Feminino , Marcadores Genéticos/genética , Humanos , Masculino , Repetições de Microssatélites/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Convulsões
3.
Epilepsy Res ; 75(2-3): 145-53, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17580110

RESUMO

In order to assess the chloride channel gene CLCN2 as a candidate susceptibility gene for childhood absence epilepsy, parametric and non-parametric linkage analysis was performed in 65 nuclear pedigrees. This provided suggestive evidence for linkage with heterogeneity: NPL score=2.3, p<0.009; HLOD=1.5, alpha=0.44. Mutational analysis of the entire genomic sequence of CLCN2 was performed in 24 unrelated patients from pedigrees consistent with linkage, identifying 45 sequence variants including the known non-synonymous polymorphism rs2228292 (G2154C, Glu718Asp) and a novel variant IVS4+12G>A. Intra-familial association analysis using the pedigrees and a further 308 parent-child trios showed suggestive evidence for transmission disequilibrium of the G2154C minor allele: AVE-PDT chi(1)2 = 5.17, p<0.03. Case-control analysis provided evidence for a protective effect of the IVS4+12G>A minor allele: chi(1)2 = 7.27, p<0.008. The 65 nuclear pedigrees were screened for three previously identified mutations shown to segregate with a variety of idiopathic generalised epilepsy phenotypes (597insG, IVS2-14del11 and G2144A) but none were found. We conclude that CLCN2 may be a susceptibility locus in a subset of cases of childhood absence epilepsy.


Assuntos
Canais de Cloreto/genética , Epilepsia Tipo Ausência/genética , Alelos , Canais de Cloro CLC-2 , Criança , DNA/genética , Análise Mutacional de DNA , Eletroencefalografia , Frequência do Gene , Ligação Genética/genética , Humanos , Imunoglobulina E/genética , Imunoglobulina E/fisiologia , Repetições de Microssatélites , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Polimorfismo Genético/genética
4.
Brain Dev ; 27(3): 164-71, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15737696

RESUMO

Aicardi syndrome (AS) is characterized by a triad of callosal agenesis, infantile spasms and chorioretinal 'lacunae'. It occurs only in individuals with two X chromosomes and is not familial. The outcome of AS is severe, with a high early mortality, considerable morbidity and a generally poor developmental outcome. However, the spectrum of AS seems broader than previously defined with a small proportion of the affected girls only moderately or mildly retarded. Several novel and important features should be added to the classic triad. The brain malformation is complex with cortical migration abnormalities, often cystic formations and sometimes choroid plexus papillomas; the eye anomalies, often feature a coloboma in addition to the lacunae, and focal seizures rather than spasms, are common. AS has been reported in 2 boys, both with an XXY complement, supporting the hypothesis of an X-linked gene lethal early in pregnancy for male conceptuses. A locus at Xp22.3 has been suggested but has not been confirmed. Treatment is only symptomatic.


Assuntos
Doenças da Coroide , Corpo Caloso , Doenças Retinianas , Espasmos Infantis , Agenesia do Corpo Caloso , Doenças da Coroide/congênito , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Doenças Retinianas/congênito , Espasmos Infantis/congênito
5.
Epileptic Disord ; 7(3): 253-96, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16162436

RESUMO

In April 2004, a group of physicians with an interest in nonconvulsive status epilepticus representing a spectrum of opinion met in Oxford, sponsored by the Epilepsy Research Foundation (a charitable organization), to discuss and debate the definition, diagnosis and treatment of nonconvulsive status epilepticus. We felt that such a meeting would be useful, as nonconvulsive status epilepticus is a subject that provokes strong reactions, perhaps largely due to the relative lack of evidence and the surfeit of opinion. The meeting was arranged such that there were formal talks followed by a discussion led by one of the attendees. We present here the extended abstracts of the main talks with the points raised by the discussants. Despite disagreements on certain issues there was much in the way of consensus. First, it was agreed that nonconvulsive status epilepticus is a term that covers a range of disparate conditions with varying prognoses and treatments. The agreed definition was thus suitably vague, A<>. Secondly, it was agreed that even within a specific condition (e.g. complex partial status epilepticus), the prognosis and treatment depends upon the context in which the condition occurs (e.g. in the critically ill, in coma, in the A<> and in people with prior epilepsy). Perhaps, most importantly it was agreed that we lacked good clinical data, and the challenge was to design good studies for a condition that is underrecognised and often difficult to diagnose.


Assuntos
Epilepsias Parciais , Estado Epiléptico , Dano Encefálico Crônico/etiologia , Dano Encefálico Crônico/patologia , Criança , Coma/patologia , Eletroencefalografia , Epilepsias Parciais/complicações , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/genética , Epilepsia Tipo Ausência/patologia , Epilepsia Parcial Complexa/patologia , Humanos , Estado Epiléptico/complicações , Estado Epiléptico/diagnóstico , Estado Epiléptico/genética
6.
J Clin Neurophysiol ; 20(6): 449-61, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14734934

RESUMO

Myoclonic attacks are not characteristic of a specific syndrome. In infancy and early childhood, they are often observed in the context of syndromes that are associated with other types of seizures and with cognitive impairment but no obvious brain lesion. Characterization of the associated seizures and age of expression allows inclusion of a number of cases in two main subgroups: severe myoclonic epilepsy (SME, or Dravet syndrome) and myoclonic-astatic epilepsy (MAE). Severe myoclonic epilepsy is an epileptic encephalopathy with invariably poor outcome in which myoclonic seizures, though frequently observed, may be absent altogether in some children. Prolonged and repeated febrile and afebrile convulsive seizures starting in infancy are the main feature and are probably causally related to cognitive decline. One third of children harbor mutation of the SCN1A gene, but the genetics of SME is probably more complex than expected with simple monogenic disorders. Treatment is usually disappointing. Myoclonic-astatic epilepsy is perhaps more a conceptual category of idiopathic myoclonic epilepsy than a discrete syndrome. Childhood-onset myoclonic-astatic attacks are the characteristic seizures associated in most with episodes of nonconvulsive status and generalized tonic-clonic seizures. Outcome is unpredictable. Either remission within a few years with normal cognition or long-lasting intractability with cognitive impairment is possible. Likewise, the effectiveness of antiepileptic drugs is variable. A number of cases of myoclonic epilepsies in infancy and early childhood, however, remain unclassified, and intermediate forms between the different syndromes exist. They must be distinguished from other syndromes with frequent brief attacks and repeated falls, especially the Lennox-Gastaut syndrome. This differentiation is often difficult and may require extensive neurophysiologic studies.


Assuntos
Eletroencefalografia , Epilepsias Mioclônicas , Fatores Etários , Criança , Pré-Escolar , Epilepsias Mioclônicas/epidemiologia , Epilepsias Mioclônicas/etiologia , Epilepsias Mioclônicas/fisiopatologia , Epilepsias Mioclônicas/terapia , Epilepsia , Potenciais Evocados/fisiologia , Humanos , Lactente , Recém-Nascido , Convulsões/etiologia , Convulsões/fisiopatologia , Convulsões/terapia , Síndrome , Resultado do Tratamento
7.
Epilepsy Res ; 48(3): 169-79, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11904235

RESUMO

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy (IGE) characterised by onset of typical absence seizures in otherwise normal children of school age. A genetic component to aetiology is well established but the mechanism of inheritance and the genes involved are unknown. Available evidence suggests that mutations in genes encoding GABA receptors or brain expressed voltage-dependent calcium channels (VDCCs) may underlie CAE. The aim of this work was to test this hypothesis by linkage analysis using microsatellite loci spanning theses genes in 33 nuclear families each with two or more individuals with CAE. Seventeen VDCC subunit genes, ten GABA(A)R subunit genes, two GABA(B) receptor genes and the ECA1 locus on 8q24 were investigated using 35 microsatellite loci. Assuming locus homogeneity, all loci gave statistically significant negative LOD scores, excluding these genes as major loci in the majority of these families. Positive HLOD scores assuming locus heterogeneity were observed for CACNG3 on chromosome 16p12-p13.1 and the GABRA5, GABRB3, GABRG3 cluster on chromosome 15q11-q13. Association studies are required to determine whether these loci are the site of susceptibility alleles in a subset of patients with CAE.


Assuntos
Canais de Cálcio/genética , Cromossomos Humanos Par 8/genética , Epilepsia Tipo Ausência/genética , Ligação Genética/genética , Receptores de GABA-A/genética , Receptores de GABA-B/genética , Feminino , Marcadores Genéticos/genética , Humanos , Escore Lod , Masculino , Repetições de Microssatélites/genética , Linhagem
8.
Epileptic Disord ; 5(1): 57-9, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12773298

RESUMO

We report the electro-clinical characteristics of a case with Gastaut type idiopathic occipital epilepsy. The visual seizures, a cardinal feature of the syndrome, are described and illustrated by video sequences. A number of stereotyped seizures are shown where the child, an 11-year-old boy, clearly describes the visual phenomena experienced. Prognosis of this common form of partial idiopathic epilepsy is relatively good but, as in our case, seizures may be very frequent during a long period of time. In such cases the term 'benign' is probably not the most appropriate.


Assuntos
Epilepsia/fisiopatologia , Lobo Occipital , Criança , Eletroencefalografia , Epilepsia/complicações , Humanos , Masculino , Exame Neurológico , Convulsões/fisiopatologia , Comportamento Estereotipado , Gravação de Videoteipe , Vômito/etiologia
9.
Epileptic Disord ; 5(4): 187-99, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14975787

RESUMO

The progresses of neuroimaging have allowed an earlier detection of hypothalamic hamartoma in children presenting with gelastic or dacrystic seizures. Associated symptoms can include other types of seizures, precocious puberty, and behavioral or cognitive deterioration. Combination of all these features is not constant and, when present, their evolution may be variable. When epilepsy proves intractable, surgery may be a solution but is not without risks. Therefore, it can only be justified on the basis of a considerable degree of certainty on the progressive character of the disorder, both in terms of epilepsy and global development. Even though epilepsy is a major and usually the most important problem, it is not always possible to predict its course and to be able to evaluate its potential effects on development. Available data suggests that deterioration is partly related to the epileptogenic activity. We reviewed data from 16 personal cases and discussed the possible evolutions of the epilepsy syndrome on the basis of 6 illustrative cases and a review of the literature. We point out that seizures may start early in life and evolve either towards a catastrophic encephalopathy or may be transiently severe and will progressively settle down. Intermediate situations also exist as well as cases presenting with a mild epilepsy. In almost all cases cognitive difficulties are present and may be associated with behavioral disturbances. They are of variable severity, usually in relation to the severity of the epilepsy and the evolution of the EEG abnormalities. Some of our cases also illustrate that, in young children whose seizures are limited to "a sensation of a pleasant feeling", "a pressure to laugh" or "smiling", early detection of the hamartoma may still be difficult and the epilepsy pattern may be misdiagnosed as an epilepsy temporal or frontal origin. Detailed analysis of the electro-clinical evolution of representative cases highlights the variable expression of the epilepsy syndrome and renders difficult any dogmatic position on early surgery. However, recent data suggests that a surgical solution must be sought early. Prospective studies are needed to evaluate, not only outcome in terms of control the seizures without unacceptable side effects but also on the evolution of the cognitive and behavioral profile of children with HH and epilepsy are needed.


Assuntos
Epilepsias Parciais/congênito , Hamartoma/congênito , Doenças Hipotalâmicas/congênito , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Dano Encefálico Crônico/congênito , Dano Encefálico Crônico/diagnóstico , Dano Encefálico Crônico/cirurgia , Criança , Pré-Escolar , Terapia Combinada , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/etiologia , Diagnóstico Diferencial , Eletroencefalografia , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/cirurgia , Epilepsia Generalizada/congênito , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/cirurgia , Feminino , Seguimentos , Hamartoma/diagnóstico , Hamartoma/cirurgia , Humanos , Doenças Hipotalâmicas/diagnóstico , Doenças Hipotalâmicas/cirurgia , Processamento de Imagem Assistida por Computador , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Radiocirurgia , Síndrome , Tomografia Computadorizada de Emissão de Fóton Único
10.
Clin Dysmorphol ; 13(4): 257-260, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15365465

RESUMO

We report a 6-year-old girl with corpus callosum agenesis and other cerebral malformations, scoliosis and hypopigmented chorioretinal lacunae in both fundi typical of Aicardi syndrome. She has never had epilepsy and the EEG has always been normal, observations not reported previously in Aicardi syndrome. She was mildly mentally retarded with a full scale IQ of 61. The patient exhibited an unusually mild Aicardi syndrome phenotype.


Assuntos
Agenesia do Corpo Caloso , Deficiências do Desenvolvimento/fisiopatologia , Retina/anormalidades , Escoliose/fisiopatologia , Criança , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Eletroencefalografia , Epilepsia , Feminino , Humanos , Lactente , Radiografia
12.
Epilepsy Res ; 87(2-3): 247-55, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19837565

RESUMO

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy (IGE) characterised by typical absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to the aetiology is well recognised but the mechanism of inheritance and the genes involved are yet to be fully established. A genome wide single nucleotide polymorphism (SNP)-based high density linkage scan was carried out using 41 nuclear pedigrees with at least two affected members. Multipoint parametric and non-parametric linkage analyses were performed using MERLIN 1.1.1 and a susceptibility locus was identified on chromosome 3p23-p14 (Z(mean)=3.9, p<0.0001; HLOD=3.3, alpha=0.7). The linked region harbours the functional candidate genes TRAK1 and CACNA2D2. Fine-mapping using a tagSNP approach demonstrated disease association with variants in TRAK1.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 3/genética , Epilepsia Tipo Ausência/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Idade de Início , Feminino , Ligação Genética , Genoma Humano , Humanos , Masculino , Seleção de Pacientes , Linhagem
14.
Am J Hum Genet ; 81(4): 713-25, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17846997

RESUMO

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.


Assuntos
Doenças dos Gânglios da Base/genética , Adolescente , Adulto , Doenças dos Gânglios da Base/líquido cefalorraquidiano , Doenças dos Gânglios da Base/patologia , Encéfalo/patologia , Calcinose/genética , Calcinose/patologia , Pérnio/genética , Pérnio/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Exodesoxirribonucleases/genética , Feminino , Humanos , Lactente , Recém-Nascido , Linfocitose/líquido cefalorraquidiano , Linfocitose/genética , Masculino , Dados de Sequência Molecular , Mutação , Fenótipo , Fosfoproteínas/genética , Ribonuclease H/genética , Síndrome
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