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[PMID]:28457992
[Au] Autor:Capal JK; Bernardino-Cuesta B; Horn PS; Murray D; Byars AW; Bing NM; Kent B; Pearson DA; Sahin M; Krueger DA; TACERN Study Group
[Ad] Endereço:Department of Neurology MLC 2015, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. Electronic address: Jamie.capal@cchmc.org.
[Ti] Título:Influence of seizures on early development in tuberous sclerosis complex.
[So] Source:Epilepsy Behav;70(Pt A):245-252, 2017 May.
[Is] ISSN:1525-5069
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Epilepsy is commonly seen in Tuberous Sclerosis Complex (TSC). The relationship between seizures and developmental outcomes has been reported, but few studies have examined this relationship in a prospective, longitudinal manner. The objective of the study was to evaluate the relationship between seizures and early development in TSC. METHODS: Analysis of 130 patients ages 0-36months with TSC participating in the TSC Autism Center of Excellence Network, a large multicenter, prospective observational study evaluating biomarkers predictive of autism spectrum disorder (ASD), was performed. Infants were evaluated longitudinally with standardized evaluations, including cognitive, adaptive, and autism-specific measures. Seizure history was collected continuously throughout, including seizure type and frequency. RESULTS: Data were analyzed at 6, 12, 18, and 24months of age. Patients without a history of seizures performed better on all developmental assessments at all time points compared to patients with a history of seizures and exhibited normal development at 24months. Patients with a history of seizures not only performed worse, but developmental progress lagged behind the group without seizures. All patients with a history of infantile spasms performed worse on all developmental assessments at 12, 18, and 24months. Higher seizure frequency correlated with poorer outcomes on developmental testing at all time points, but particularly at 12months and beyond. Patients with higher seizure frequency during infancy continued to perform worse developmentally through 24months. A logistic model looking at the individual impact of infantile spasms, seizure frequency, and age of seizure onset as predictors of developmental delay revealed that age of seizure onset was the most important factor in determining developmental outcome. CONCLUSIONS: Results of this study further define the relationship between seizures and developmental outcomes in young children with TSC. Early seizure onset in infants with TSC negatively impacts very early neurodevelopment, which persists through 24months of age.
[Mh] Termos MeSH primário: Deficiências do Desenvolvimento/fisiopatologia
Convulsões/fisiopatologia
Espasmos Infantis/fisiopatologia
Esclerose Tuberosa/fisiopatologia
[Mh] Termos MeSH secundário: Pré-Escolar
Deficiências do Desenvolvimento/epidemiologia
Deficiências do Desenvolvimento/psicologia
Feminino
Seres Humanos
Lactente
Estudos Longitudinais
Masculino
Estudos Prospectivos
Convulsões/epidemiologia
Convulsões/psicologia
Espasmos Infantis/epidemiologia
Espasmos Infantis/psicologia
Esclerose Tuberosa/epidemiologia
Esclerose Tuberosa/psicologia
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:28462982
[Au] Autor:Perez D; Hsieh DT; Rohena L
[Ad] Endereço:Department of Pediatrics, San Antonio Military Medical Center, San Antonio, Texas.
[Ti] Título:Somatic Mosaicism of PCDH19 in a male with early infantile epileptic encephalopathy and review of the literature.
[So] Source:Am J Med Genet A;173(6):1625-1630, 2017 Jun.
[Is] ISSN:1552-4833
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Early infantile epileptic encephalopathy-9 (EIEE9) linked to mutations of the PCDH19 gene on the X chromosome was once thought to only affect females. Clinical features of the mutation include early onset of variable types and frequency of recurrent cluster of seizures, mild to profound intellectual disability, autistic traits, psychiatric features, and behavioral disturbances. PCDH19 pathogenic variants usually occur via an unusual X-linked pattern where heterozygous females are affected, but hemizygous males are asymptomatic. Somatic mosaic males for PCDH19 mutations are affected with EIEE9; since this discovery, four somatic mosaic males have been reported. We report the fifth confirmed male with somatic mosaicism of a novel pathogenic variant c.2147+2 T>C located in the splice site of Intron 1 of the PCDH19 gene, which continues to support that cellular interference is responsible for the pathogenic mechanism. The importance of our report is to provide significant knowledge about this rare cause of epilepsy in males, guide subsequent functional studies on males portraying an EIEE9 phenotype that have been potentially misdiagnosed, targeted therapeutic approaches, and further elucidation of this complex and interesting genetic disorder.
[Mh] Termos MeSH primário: Caderinas/genética
Deficiência Intelectual/genética
Mosaicismo
Espasmos Infantis/genética
[Mh] Termos MeSH secundário: Genes Ligados ao Cromossomo X
Seres Humanos
Deficiência Intelectual/fisiopatologia
Masculino
Mutação
Fenótipo
Sítios de Splice de RNA/genética
Espasmos Infantis/fisiopatologia
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cadherins); 0 (PCDH19 protein, human); 0 (RNA Splice Sites)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171201
[Lr] Data última revisão:
171201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1002/ajmg.a.38233


  3 / 3028 MEDLINE  
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[PMID]:28965491
[Au] Autor:Arnadottir GA; Jensson BO; Marelsson SE; Sulem G; Oddsson A; Kristjansson RP; Benonisdottir S; Gudjonsson SA; Masson G; Thorisson GA; Saemundsdottir J; Magnusson OT; Jonasdottir A; Jonasdottir A; Sigurdsson A; Gudbjartsson DF; Thorsteinsdottir U; Arngrimsson R; Sulem P; Stefansson K
[Ad] Endereço:deCODE Genetics/Amgen, Inc., Sturlugata 8, 101, Reykjavik, Iceland.
[Ti] Título:Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters.
[So] Source:BMC Med Genet;18(1):103, 2017 Oct 02.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Epileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease. CASE PRESENTATION: We sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease. CONCLUSIONS: We describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease.
[Mh] Termos MeSH primário: Epilepsia/genética
Mutação de Sentido Incorreto
Espasmos Infantis/genética
Enzimas Ativadoras de Ubiquitina/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idade de Início
Substituição de Aminoácidos
Criança
Pré-Escolar
Epilepsia/complicações
Feminino
Heterozigoto
Seres Humanos
Lactente
Linhagem
Irmãos
Espasmos Infantis/complicações
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 6.2.1.45 (Ubiquitin-Activating Enzymes); EC 6.3.2.19 (UBA5 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0466-8


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[PMID]:28942967
[Au] Autor:Myers CT; Stong N; Mountier EI; Helbig KL; Freytag S; Sullivan JE; Ben Zeev B; Nissenkorn A; Tzadok M; Heimer G; Shinde DN; Rezazadeh A; Regan BM; Oliver KL; Ernst ME; Lippa NC; Mulhern MS; Ren Z; Poduri A; Andrade DM; Bird LM; Bahlo M; Berkovic SF; Lowenstein DH; Scheffer IE; Sadleir LG; Goldstein DB; Mefford HC; Heinzen EL
[Ad] Endereço:Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
[Ti] Título:De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures.
[So] Source:Am J Hum Genet;101(4):516-524, 2017 Oct 05.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10 ) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory epilepsy and further support the emerging role for synaptic dysregulation in epilepsy.
[Mh] Termos MeSH primário: Calcineurina/genética
Epilepsia/genética
Mutação
Transtornos do Neurodesenvolvimento/genética
Transmissão Sináptica/fisiologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Calcineurina/metabolismo
Criança
Pré-Escolar
Estudos de Coortes
Epilepsia/patologia
Exoma/genética
Feminino
Seres Humanos
Lactente
Recém-Nascido
Síndrome de Lennox Gastaut/patologia
Masculino
Transtornos do Neurodesenvolvimento/patologia
Análise de Sequência de DNA
Índice de Gravidade de Doença
Espasmos Infantis/genética
Espasmos Infantis/patologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.3.16 (Calcineurin); EC 3.1.3.16 (PPP3CA protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE


  5 / 3028 MEDLINE  
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[PMID]:28923014
[Au] Autor:Wang J; Gao H; Bao X; Zhang Q; Li J; Wei L; Wu X; Chen Y; Yu S
[Ad] Endereço:Department of Pediatrics, Peking University First Hospital, Beijing, 100034, China.
[Ti] Título:SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures.
[So] Source:BMC Med Genet;18(1):104, 2017 Sep 18.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. This study aimed to broaden the phenotypic-spectrum of disease related with SCN8A mutations. METHODS: To identify the pathogenic gene of a Chinese family, in which six members suffered from epilepsy, whole-exome sequencing was performed. In addition, target next-generation sequencing (NGS) was performed on 178 sporadic patients, who had epilepsy of unknown etiology within 6 months after birth. A detailed clinical history was obtained. RESULTS: A heterozygous missense mutation of SCN8A was identified in the Chinese family. Six de novo mutations of SCN8A were detected in 6 sporadic patients with epilepsy. In the family, six members developed seizures within a few years after birth. Five of them had milder clinical performance, that they had normal cognition and developmental milestones, and seizure-free was achieved by mono-therapy. The other one affected member presented with refractory epilepsy and developmental regression. She died from sudden unexpected death in epilepsy (SUDEP) at 17-year-old. Clinical features of six sporadic patients with SCN8A mutations were diverse, ranging from severe epileptic encephalopathy to benign epilepsy with normal cognition. Seizures started at the mean age of 3.9 months (from 2 months to 6 months). Seizure-free was achieved in four of them by mono- or multi-antiepileptic drugs. Five of them demonstrated mild or severe psychomotor retardation, whereas the other one was normal in development and intelligence. CONCLUSIONS: Our findings extend the spectrum of SCN8A mutations and the clinical features of patients with SCN8A mutations. The majority of SCN8A mutations were de novo, inherited mutations from the heterozygous parents can also occur. The phenotypic spectrum of SCN8A mutation varied largely. Most affected patients manifested as refractory epilepsy and severe intellectual disability, only a small number of patients presented with milder clinical patterns. Additionally, our study confirmed that the same mutation can lead to different phenotypes.
[Mh] Termos MeSH primário: Grupo com Ancestrais do Continente Asiático/genética
Mutação de Sentido Incorreto
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Convulsões/genética
Espasmos Infantis/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Sequência de Aminoácidos
Criança
Pré-Escolar
Morte Súbita
Feminino
Heterozigoto
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Lactente
Meia-Idade
Linhagem
Análise de Sequência de DNA
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (SCN8A protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0460-1


  6 / 3028 MEDLINE  
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[PMID]:28864462
[Au] Autor:Farnaes L; Nahas SA; Chowdhury S; Nelson J; Batalov S; Dimmock DM; Kingsmore SF; RCIGM Investigators
[Ad] Endereço:Rady Children's Institute of Genomic Medicine (RCIGM), San Diego, California 92123, USA.
[Ti] Título:Rapid whole-genome sequencing identifies a novel variant associated with West syndrome.
[So] Source:Cold Spring Harb Mol Case Stud;3(5), 2017 Sep.
[Is] ISSN:2373-2873
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A 9-mo-old infant was admitted with infantile spasms that improved on administration of topiramate and steroids. He also had developmental delay, esotropia, and hypsarrhythmia on interictal electroencephalogram (EEG), and normal brain magnetic resonance imaging (MRI). West syndrome is the triad of infantile spasms, interictal hypsarrhythmia, and mental retardation. Rapid trio whole-genome sequencing (WGS) revealed a novel, likely pathogenic, de novo variant in the gene encoding γ-aminobutyric acid (GABA) type A receptor, α1 polypeptide ( c.789G>A, p.Met263Ile) in the proband. mutations have been associated with early infantile epileptic encephalopathy type 19 (EIEE19). We suggest that p.Met263Ile is associated with a distinct West syndrome phenotype.
[Mh] Termos MeSH primário: Receptores de GABA-A/genética
Espasmos Infantis/genética
[Mh] Termos MeSH secundário: Encéfalo/citologia
Encéfalo/metabolismo
Deficiências do Desenvolvimento/complicações
Deficiências do Desenvolvimento/genética
Eletroencefalografia
Genoma/genética
Sequenciamento de Nucleotídeos em Larga Escala/métodos
Seres Humanos
Lactente
Deficiência Intelectual/complicações
Deficiência Intelectual/genética
Imagem por Ressonância Magnética
Masculino
Mutação
Receptores de GABA-A/metabolismo
Espasmos Infantis/complicações
Espasmos Infantis/metabolismo
Ácido gama-Aminobutírico/genética
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GABRA1 protein, human); 0 (Receptors, GABA-A); 56-12-2 (gamma-Aminobutyric Acid)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170903
[St] Status:MEDLINE


  7 / 3028 MEDLINE  
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[PMID]:28856709
[Au] Autor:Yoo Y; Jung J; Lee YN; Lee Y; Cho H; Na E; Hong J; Kim E; Lee JS; Lee JS; Hong C; Park SY; Wie J; Miller K; Shur N; Clow C; Ebel RS; DeBrosse SD; Henderson LB; Willaert R; Castaldi C; Tikhonova I; Bilgüvar K; Mane S; Kim KJ; Hwang YS; Lee SG; So I; Lim BC; Choi HJ; Seong JY; Shin YB; Jung H; Chae JH; Choi M
[Ad] Endereço:Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
[Ti] Título:GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy.
[So] Source:Ann Neurol;82(3):466-478, 2017 Sep.
[Is] ISSN:1531-8249
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions. METHODS: We screened novel genetic factors from 34 RTT-like patients without MECP2 mutations, which account for ∼90% of RTT cases, by whole-exome sequencing. The biological function of the discovered variants was assessed in cell culture and Xenopus tropicalis models. RESULTS: We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model. INTERPRETATION: GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466-478.
[Mh] Termos MeSH primário: Mutação
Receptores de GABA-B/genética
Síndrome de Rett/genética
Espasmos Infantis/genética
[Mh] Termos MeSH secundário: Exoma
Genótipo
Células HEK293
Seres Humanos
Proteína 2 de Ligação a Metil-CpG/genética
Fenótipo
Transdução de Sinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GABBR2 protein, human); 0 (MECP2 protein, human); 0 (Methyl-CpG-Binding Protein 2); 0 (Receptors, GABA-B)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1002/ana.25032


  8 / 3028 MEDLINE  
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[PMID]:28777935
[Au] Autor:Guella I; McKenzie MB; Evans DM; Buerki SE; Toyota EB; Van Allen MI; Suri M; Elmslie F; Simon MEH; van Gassen KLI; Héron D; Keren B; Nava C; Connolly MB; Demos M; Farrer MJ; Epilepsy Genomics Study; Deciphering Developmental Disorders Study
[Ad] Endereço:Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC V5R 6H8, Canada.
[Ti] Título:De Novo Mutations in YWHAG Cause Early-Onset Epilepsy.
[So] Source:Am J Hum Genet;101(2):300-310, 2017 Aug 03.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A [p.Gly82Arg]) and YWHAG (aka 14-3-3γ) (c.394C>T [p.Arg132Cys]), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n = 1) and YWHAG (n = 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder's etiology and genotype-phenotype correlations.
[Mh] Termos MeSH primário: Proteínas 14-3-3/genética
Predisposição Genética para Doença
Proteínas de Transporte de Glutamato da Membrana Plasmática/genética
Espasmos Infantis/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Sequência de Aminoácidos
Criança
Exoma/genética
Feminino
Genótipo
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Lactente
Masculino
Fenótipo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (14-3-3 Proteins); 0 (Glutamate Plasma Membrane Transport Proteins); 0 (SLC1A2 protein, human); 0 (YWHAG protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170805
[St] Status:MEDLINE


  9 / 3028 MEDLINE  
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[PMID]:28675559
[Au] Autor:Barker-Haliski ML; Löscher W; White HS; Galanopoulou AS
[Ad] Endereço:Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington, U.S.A.
[Ti] Título:Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy.
[So] Source:Epilepsia;58 Suppl 3:39-47, 2017 Jul.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Animal models have provided a wealth of information on mechanisms of epileptogenesis and comorbidogenesis, and have significantly advanced our ability to investigate the potential of new therapies. Processes implicating brain inflammation have been increasingly observed in epilepsy research. Herein we discuss the progress on animal models of epilepsy and comorbidities that inform us on the potential role of inflammation in epileptogenesis and comorbidity pathogenesis in rodent models of West syndrome and the Theiler's murine encephalomyelitis virus (TMEV) mouse model of viral encephalitis-induced epilepsy. Rat models of infantile spasms were generated in rat pups after right intracerebral injections of proinflammatory compounds (lipopolysaccharides with or without doxorubicin, or cytokines) and were longitudinally monitored for epileptic spasms and neurodevelopmental and cognitive deficits. Anti-inflammatory treatments were tested after the onset of spasms. The TMEV mouse model was induced with intracerebral administration of TMEV and prospective monitoring for handling-induced seizures or seizure susceptibility, as well as long-term evaluations of behavioral comorbidities of epilepsy. Inflammatory processes are evident in both models and are implicated in the pathogenesis of the observed seizures and comorbidities. A common feature of these models, based on the data so far available, is their pharmacoresistant profile. The presented data support the role of inflammatory pathways in epileptogenesis and comorbidities in two distinct epilepsy models. Pharmacoresistance is a common feature of both inflammation-based models. Utilization of these models may facilitate the identification of age-specific, syndrome- or etiology-specific therapies for the epilepsies and attendant comorbidities, including the drug-resistant forms.
[Mh] Termos MeSH primário: Infecções por Cardiovirus/imunologia
Modelos Animais de Doenças
Epilepsia/imunologia
Inflamação Neurogênica/tratamento farmacológico
Espasmos Infantis/tratamento farmacológico
Espasmos Infantis/imunologia
Theilovirus
Pesquisa Médica Translacional
[Mh] Termos MeSH secundário: Animais
Anticonvulsivantes/uso terapêutico
Descoberta de Drogas
Epilepsia Resistente a Medicamentos/tratamento farmacológico
Epilepsia Resistente a Medicamentos/imunologia
Epilepsia/tratamento farmacológico
Seres Humanos
Lactente
Mediadores da Inflamação/fisiologia
Camundongos
Inflamação Neurogênica/imunologia
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (Inflammation Mediators)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170705
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13785


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[PMID]:28605011
[Au] Autor:Lim Z; Wong K; Olson HE; Bergin AM; Downs J; Leonard H
[Ad] Endereço:Telethon Kids Institute, University of Western Australia, West Perth, Western Australia, Australia.
[Ti] Título:Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients.
[So] Source:Epilepsia;58(8):1415-1422, 2017 Aug.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Pathogenic variants involving the CDKL5 gene result in a severe epileptic encephalopathy, often later presenting with features similar to Rett syndrome. Cardinal features of epilepsy in the CDKL5 disorder include early onset at a median age of 6 weeks and poor response to antiepileptic drugs. The ketogenic diet (KD) was first introduced in the 1920s as a treatment option for refractory epilepsy in children. This study investigated use of the KD in the CDKL5 disorder and its influences on seizures. METHODS: The International CDKL5 Disorder Database, established in 2012, collects information on individuals with the CDKL5 disorder. Families have provided information regarding seizure characteristics, use, and side effects of the KD treatment. Descriptive statistics and time to event analyses were performed. Clinical vignettes were also provided on patients attending Boston Children's Hospital. RESULTS: Data regarding KD use were available for 204 individuals with a pathogenic CDKL5 variant. Median age of inclusion in the database was 4.8 years (range = 0.3-33.9 years), with median age of 6 weeks (range = 1 day-65 weeks) at seizure onset. History of KD use was reported for 51% (104 of 204) of individuals, with a median duration of use of 17 months (95% confidence interval = 9-24). Changes in seizure activity after commencing KD were reported for two-thirds (69 of 104), with improvements in 88% (61 of 69). Nearly one-third (31.7%) experienced side effects during the diet. At ascertainment, only one-third (32%) remained on the diet, with lack of long-term efficacy as the main reason for diet cessation (51%, 36 of 70). SIGNIFICANCE: Benefits of KD in the CDKL5 disorder are in keeping with previous trials on refractory epilepsies. However, poor long-term efficacy remains as a significant barrier. In view of its side effect profile, KD administration should be supervised by a pediatric neurologist and specialist dietician.
[Mh] Termos MeSH primário: Dieta Cetogênica/métodos
Epilepsia Resistente a Medicamentos/dietoterapia
Epilepsia Resistente a Medicamentos/etiologia
Síndrome de Rett/complicações
Espasmos Infantis/complicações
[Mh] Termos MeSH secundário: Adolescente
Adulto
Criança
Pré-Escolar
Feminino
Seguimentos
Seres Humanos
Lactente
Masculino
Curva ROC
Estudos Retrospectivos
Síndrome de Rett/dietoterapia
Síndrome de Rett/genética
Espasmos Infantis/dietoterapia
Espasmos Infantis/genética
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13813



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