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Pesquisa : D12.776.157.530.400.875.750.100 [Categoria DeCS]
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[PMID]:27777328
[Au] Autor:McDonald CL; Saneto RP; Carmant L; Sotero de Menezes MA
[Ad] Endereço:1 Pediatric Neuroscience Center, Seattle, WA, USA.
[Ti] Título:Focal Seizures in Patients With SCN1A Mutations.
[So] Source:J Child Neurol;32(2):170-176, 2017 02.
[Is] ISSN:1708-8283
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The SCN1A gene has been implicated in the etiology of various forms of epilepsy. New research has linked this gene to specific types of epilepsy, all of which present in infancy or early childhood. This study examines the time course and pathology of pediatric patients who have a mutation in the SCN1A gene in order to open a discussion regarding the key trends of this form of epilepsy as well as important clinical considerations in management for patients who present with symptoms relating to the SCN1A mutations. We retrospectively examined 20 patients who presented to the clinic with focal seizures, as well as were positive for an SCN1A genetic mutation. Despite the small sample size, we were able to find important trends in the time course of the disorder as well as important areas of clinical practice that must be taken into consideration for these patients.
[Mh] Termos MeSH primário: Epilepsia/tratamento farmacológico
Epilepsia/genética
Canal de Sódio Disparado por Voltagem NAV1.1/genética
Convulsões/tratamento farmacológico
Convulsões/genética
[Mh] Termos MeSH secundário: Adolescente
Anticonvulsivantes/uso terapêutico
Encéfalo/fisiopatologia
Criança
Pré-Escolar
Eletroencefalografia
Epilepsia/fisiopatologia
Feminino
Seguimentos
Predisposição Genética para Doença
Seres Humanos
Masculino
Modelos Moleculares
Fenótipo
Estudos Retrospectivos
Convulsões/fisiopatologia
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (SCN1A protein, human)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180112
[Lr] Data última revisão:
180112
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161101
[St] Status:MEDLINE
[do] DOI:10.1177/0883073816672379


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[PMID]:28880996
[Au] Autor:Steel D; Symonds JD; Zuberi SM; Brunklaus A
[Ad] Endereço:The Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom.
[Ti] Título:Dravet syndrome and its mimics: Beyond SCN1A.
[So] Source:Epilepsia;58(11):1807-1816, 2017 Nov.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy, and evolving to drug-resistant epilepsy with accompanying cognitive, behavioral, and motor impairment. Most cases are now known to be caused by pathogenic variants in the sodium channel gene SCN1A, but several other genes have also been implicated. This review examines current understanding of the role of non-SCN1A genes in DS, and what is known about phenotypic similarities and differences. We discuss whether these are best thought of as minority causes of DS, or as similar but distinct conditions. METHODS: Based on a review of literature, a list of genes linked to DS was compiled and PubMed was searched for reports of DS-like phenotypes arising from variants in each. Online Mendelian Inheritance in Man (OMIM) was used to identify further reports relevant to each gene. RESULTS: Genes that have been reported to cause DS-like phenotypes include SCN2A, SCN8A, SCN9A, SCN1B, PCDH19, GABRA1, GABRG2, STXBP1, HCN1, CHD2, and KCNA2. Many of these genes, however, appear to be associated with their own, different, clinical picture. Other candidate genes for DS have been reported, but there is currently an insufficient body of literature to support their causative role. SIGNIFICANCE: Although most cases of DS arise from SCN1A variants, numerous other genes cause encephalopathies that are clinically similar. Increasingly, a tendency is noted to define newly described epileptic disorders primarily in genetic terms, with clinical features being linked to genotypes. As genetic diagnosis becomes more readily available, its potential to guide pathophysiologic understanding and therapeutic strategy cannot be ignored. Clinical assessment remains essential; the challenge now is to develop a gene-based taxonomy that complements traditional syndromic classifications, allowing elements of both to inform new approaches to treatment.
[Mh] Termos MeSH primário: Epilepsias Mioclônicas/diagnóstico
Epilepsias Mioclônicas/genética
Mutação/genética
Canal de Sódio Disparado por Voltagem NAV1.1/genética
[Mh] Termos MeSH secundário: Seres Humanos
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Fenótipo
Receptores de GABA-A/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (GABRA1 protein, human); 0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (Receptors, GABA-A); 0 (SCN1A protein, human); 0 (SCN2A protein, human); 0 (SCN8A protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13889


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[PMID]:28880874
[Au] Autor:Sousa SR; Wingerd JS; Brust A; Bladen C; Ragnarsson L; Herzig V; Deuis JR; Dutertre S; Vetter I; Zamponi GW; King GF; Alewood PF; Lewis RJ
[Ad] Endereço:IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
[Ti] Título:Discovery and mode of action of a novel analgesic ß-toxin from the African spider Ceratogyrus darlingi.
[So] Source:PLoS One;12(9):e0182848, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical potential. We screened a panel of 60 spider venoms to find modulators of ion channels involved in pain transmission. We isolated, synthesized and pharmacologically characterized Cd1a, a novel peptide from the venom of the spider Ceratogyrus darlingi. Cd1a reversibly paralysed sheep blowflies (PD50 of 1318 pmol/g) and inhibited human Cav2.2 (IC50 2.6 µM) but not Cav1.3 or Cav3.1 (IC50 > 30 µM) in fluorimetric assays. In patch-clamp electrophysiological assays Cd1a inhibited rat Cav2.2 with similar potency (IC50 3 µM) without influencing the voltage dependence of Cav2.2 activation gating, suggesting that Cd1a doesn't act on Cav2.2 as a classical gating modifier toxin. The Cd1a binding site on Cav2.2 did not overlap with that of the pore blocker ω-conotoxin GVIA, but its activity at Cav2.2-mutant indicated that Cd1a shares some molecular determinants with GVIA and MVIIA, localized near the pore region. Cd1a also inhibited human Nav1.1-1.2 and Nav1.7-1.8 (IC50 0.1-6.9 µM) but not Nav1.3-1.6 (IC50 > 30 µM) in fluorimetric assays. In patch-clamp assays, Cd1a strongly inhibited human Nav1.7 (IC50 16 nM) and produced a 29 mV depolarising shift in Nav1.7 voltage dependence of activation. Cd1a (400 pmol) fully reversed Nav1.7-evoked pain behaviours in mice without producing side effects. In conclusion, Cd1a inhibited two anti-nociceptive targets, appearing to interfere with Cav2.2 inactivation gating, associated with the Cav2.2 α-subunit pore, while altering the activation gating of Nav1.7. Cd1a was inactive at some of the Nav and Cav channels expressed in skeletal and cardiac muscles and nodes of Ranvier, apparently contributing to the lack of side effects at efficacious doses, and suggesting potential as a lead for development of peripheral pain treatments.
[Mh] Termos MeSH primário: Analgésicos/farmacologia
Venenos de Aranha/química
Aranhas/química
[Mh] Termos MeSH secundário: Analgésicos/química
Animais
Sítios de Ligação/efeitos dos fármacos
Canais de Cálcio Tipo N/metabolismo
Eletrofisiologia
Fluorometria
Seres Humanos
Camundongos
Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo
Peptídeos/química
Peptídeos/farmacologia
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 0 (Cacna1b protein, rat); 0 (Calcium Channels, N-Type); 0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.7 Voltage-Gated Sodium Channel); 0 (Peptides); 0 (Spider Venoms)
[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:170908
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182848


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[PMID]:28794249
[Au] Autor:Sadleir LG; Mountier EI; Gill D; Davis S; Joshi C; DeVile C; Kurian MA; Mandelstam S; Wirrell E; Nickels KC; Murali HR; Carvill G; Myers CT; Mefford HC; Scheffer IE; DDD Study
[Ad] Endereço:From the Department of Paediatrics and Child Health (L.G.S., E.I.M.), University of Otago, Wellington, New Zealand; Department of Neurology (D.G.), University of Sydney, Australia; Department of Neurology (S.D.), Starship Children's Health, Auckland, New Zealand; Department of Neurology (C.J.), Chil
[Ti] Título:Not all epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype.
[So] Source:Neurology;89(10):1035-1042, 2017 Sep 05.
[Is] ISSN:1526-632X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To define a distinct developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder. METHODS: A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and mutation. RESULTS: We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable. CONCLUSIONS: Here, we present a phenotype-genotype correlation for . We describe a distinct phenotype, early infantile encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.
[Mh] Termos MeSH primário: Deficiências do Desenvolvimento/genética
Epilepsia/genética
Hipercinese/genética
Mutação de Sentido Incorreto
Canal de Sódio Disparado por Voltagem NAV1.1/genética
[Mh] Termos MeSH secundário: Idade de Início
Encéfalo/diagnóstico por imagem
Encéfalo/fisiopatologia
Criança
Pré-Escolar
Deficiências do Desenvolvimento/diagnóstico por imagem
Deficiências do Desenvolvimento/fisiopatologia
Epilepsias Mioclônicas/genética
Epilepsias Mioclônicas/fisiopatologia
Epilepsia/diagnóstico por imagem
Epilepsia/fisiopatologia
Feminino
Seres Humanos
Hipercinese/diagnóstico por imagem
Hipercinese/fisiopatologia
Masculino
Fenótipo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (SCN1A protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170811
[St] Status:MEDLINE
[do] DOI:10.1212/WNL.0000000000004331


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[PMID]:28784306
[Au] Autor:Yamagata T; Ogiwara I; Mazaki E; Yanagawa Y; Yamakawa K
[Ad] Endereço:Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
[Ti] Título:Nav1.2 is expressed in caudal ganglionic eminence-derived disinhibitory interneurons: Mutually exclusive distributions of Nav1.1 and Nav1.2.
[So] Source:Biochem Biophys Res Commun;491(4):1070-1076, 2017 Sep 30.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nav1.1 and Nav1.2 are the voltage-gated sodium channel pore-forming alpha I and II subunits, encoded by the genes SCN1A and SCN2A. Although mutations of both genes have similarly been described in patients with epilepsy, autism and/or intellectual disability, their expression sites in brain are largely distinct. Nav1.1 was shown to be expressed dominantly in parvalbumin (PV)-positive or somatostatin (SST)-positive inhibitory neurons and in a sparsely-distributed subpopulation of excitatory neurons. In contrast, Nav1.2 has been reported to be dominantly expressed in excitatory neurons. Here we show that Nav1.2 is also expressed in caudal ganglionic eminence (CGE)-derived inhibitory neurons, and expressions of Nav1.1 and Nav1.2 are mutually-exclusive in many of brain regions including neocortex, hippocampus, cerebellum, striatum and globus pallidus. In neocortex at postnatal day 15, in addition to the expression in excitatory neurons we show that Nav1.2 is expressed in reelin (RLN)-positive/SST-negative inhibitory neurons that are presumably single-bouquet cells because of their cortical layer I-limited distribution, and vasoactive intestinal peptide (VIP)-positive neurons that would be multipolar cell because of their layer I/II margin and layer VI distribution. Although Nav1.2 has previously been reported to be expressed in SST-positive cells, we here show that Nav1.2 is not expressed in either of PV-positive or SST-positive inhibitory neurons. PV-positive and SST-positive inhibitory neurons derive from medial ganglionic eminence (MGE) and innervate excitatory neurons, while VIP-positive and RLN-positive/SST-negative inhibitory neurons derive from CGE, innervate on inhibitory neurons and play disinhibitory roles in the neural network. Our results therefore indicate that, while Nav1.1 is expressed in MEG-derived inhibitory neurons, Nav1.2 is expressed in CGE-derived disinhibitory interneurons in addition to excitatory neurons. These findings should contribute to understanding of the pathology of neurodevelopmental diseases caused by SCN2A mutations.
[Mh] Termos MeSH primário: Interneurônios/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.1/biossíntese
Canal de Sódio Disparado por Voltagem NAV1.2/biossíntese
[Mh] Termos MeSH secundário: Animais
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.2 Voltage-Gated Sodium Channel)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE


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[PMID]:28686619
[Au] Autor:Hammer MF; Ishii A; Johnstone L; Tchourbanov A; Lau B; Sprissler R; Hallmark B; Zhang M; Zhou J; Watkins J; Hirose S
[Ad] Endereço:ARL Division of Biotechnology, University of Arizona, Tucson, AZ, United States of America.
[Ti] Título:Rare variants of small effect size in neuronal excitability genes influence clinical outcome in Japanese cases of SCN1A truncation-positive Dravet syndrome.
[So] Source:PLoS One;12(7):e0180485, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dravet syndrome (DS) is a rare, devastating form of childhood epilepsy that is often associated with mutations in the voltage-gated sodium channel gene, SCN1A. There is considerable variability in expressivity within families, as well as among individuals carrying the same primary mutation, suggesting that clinical outcome is modulated by variants at other genes. To identify modifier gene variants that contribute to clinical outcome, we sequenced the exomes of 22 individuals at both ends of a phenotype distribution (i.e., mild and severe cognitive condition). We controlled for variation associated with different mutation types by limiting inclusion to individuals with a de novo truncation mutation resulting in SCN1A haploinsufficiency. We performed tests aimed at identifying 1) single common variants that are enriched in either phenotypic group, 2) sets of common or rare variants aggregated in and around genes associated with clinical outcome, and 3) rare variants in 237 candidate genes associated with neuronal excitability. While our power to identify enrichment of a common variant in either phenotypic group is limited as a result of the rarity of mild phenotypes in individuals with SCN1A truncation variants, our top candidates did not map to functional regions of genes, or in genes that are known to be associated with neurological pathways. In contrast, we found a statistically-significant excess of rare variants predicted to be damaging and of small effect size in genes associated with neuronal excitability in severely affected individuals. A KCNQ2 variant previously associated with benign neonatal seizures is present in 3 of 12 individuals in the severe category. To compare our results with the healthy population, we performed a similar analysis on whole exome sequencing data from 70 Japanese individuals in the 1000 genomes project. Interestingly, the frequency of rare damaging variants in the same set of neuronal excitability genes in healthy individuals is nearly as high as in severely affected individuals. Rather than a single common gene/variant modifying clinical outcome in SCN1A-related epilepsies, our results point to the cumulative effect of rare variants with little to no measurable phenotypic effect (i.e., typical genetic background) unless present in combination with a disease-causing truncation mutation in SCN1A.
[Mh] Termos MeSH primário: Epilepsias Mioclônicas/genética
Epilepsia/genética
Estudo de Associação Genômica Ampla
Canal de Sódio Disparado por Voltagem NAV1.1/genética
[Mh] Termos MeSH secundário: Alelos
Epilepsias Mioclônicas/fisiopatologia
Epilepsia/fisiopatologia
Exoma/genética
Feminino
Genes Modificadores/genética
Genótipo
Haploinsuficiência/genética
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
Mutação
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (SCN1A protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180485


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[PMID]:28683073
[Au] Autor:Li T; Lu G; Chiang EY; Chernov-Rogan T; Grogan JL; Chen J
[Ad] Endereço:Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, California, United States of America.
[Ti] Título:High-throughput electrophysiological assays for voltage gated ion channels using SyncroPatch 768PE.
[So] Source:PLoS One;12(7):e0180154, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ion channels regulate a variety of physiological processes and represent an important class of drug target. Among the many methods of studying ion channel function, patch clamp electrophysiology is considered the gold standard by providing the ultimate precision and flexibility. However, its utility in ion channel drug discovery is impeded by low throughput. Additionally, characterization of endogenous ion channels in primary cells remains technical challenging. In recent years, many automated patch clamp (APC) platforms have been developed to overcome these challenges, albeit with varying throughput, data quality and success rate. In this study, we utilized SyncroPatch 768PE, one of the latest generation APC platforms which conducts parallel recording from two-384 modules with giga-seal data quality, to push these 2 boundaries. By optimizing various cell patching parameters and a two-step voltage protocol, we developed a high throughput APC assay for the voltage-gated sodium channel Nav1.7. By testing a group of Nav1.7 reference compounds' IC50, this assay was proved to be highly consistent with manual patch clamp (R > 0.9). In a pilot screening of 10,000 compounds, the success rate, defined by > 500 MΩ seal resistance and >500 pA peak current, was 79%. The assay was robust with daily throughput ~ 6,000 data points and Z' factor 0.72. Using the same platform, we also successfully recorded endogenous voltage-gated potassium channel Kv1.3 in primary T cells. Together, our data suggest that SyncroPatch 768PE provides a powerful platform for ion channel research and drug discovery.
[Mh] Termos MeSH primário: Ensaios de Triagem em Larga Escala/métodos
Potenciais da Membrana/fisiologia
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo
Técnicas de Patch-Clamp/métodos
Bloqueadores dos Canais de Potássio/farmacologia
Bloqueadores dos Canais de Sódio/farmacologia
[Mh] Termos MeSH secundário: Animais
Células CHO
Cricetulus
Avaliação Pré-Clínica de Medicamentos
Expressão Gênica
Ensaios de Triagem em Larga Escala/instrumentação
Canal de Potássio Kv1.3/deficiência
Canal de Potássio Kv1.3/genética
Canal de Sódio Disparado por Voltagem NAV1.1/genética
Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.3/genética
Canal de Sódio Disparado por Voltagem NAV1.3/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.4/genética
Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.5/genética
Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.7/genética
Técnicas de Patch-Clamp/instrumentação
Cultura Primária de Células
Ratos
Canais de Sódio/genética
Canais de Sódio/metabolismo
Linfócitos T/citologia
Linfócitos T/efeitos dos fármacos
Linfócitos T/metabolismo
Transgenes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Kv1.3 Potassium Channel); 0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (NAV1.3 Voltage-Gated Sodium Channel); 0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (NAV1.5 Voltage-Gated Sodium Channel); 0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (NAV1.7 Voltage-Gated Sodium Channel); 0 (Potassium Channel Blockers); 0 (SCN1A protein, human); 0 (SCN3A protein, human); 0 (SCN4A protein, human); 0 (SCN5A protein, human); 0 (SCN8A protein, human); 0 (SCN9A protein, human); 0 (Sodium Channel Blockers); 0 (Sodium Channels)
[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:170707
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180154


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[PMID]:28525652
[Au] Autor:Jiménez-Arredondo RE; Brambila-Tapia AJL; Mercado-Silva FM; Magaña-Torres MT; Figuera LE
[Ad] Endereço:Doctorado en Genética Humana, Centro Universitario de Ciencias de la Salud, , , Mexico.
[Ti] Título:Determination of SCN1A genetic variants in Mexican patients with refractory epilepsy and Dravet syndrome.
[So] Source:Genet Mol Res;16(2), 2017 May 18.
[Is] ISSN:1676-5680
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:Mutations in the SCN1A gene can result in syndromes associated with epilepsy, including the Dravet syndrome (DS). However, the prevalence of such mutations in these diseases varies widely between different studies, and has not been examined in Mexican patients with epilepsy. Therefore, the objective of this study was to determine the frequency of SCN1A mutations (in the exon 26) in a cohort of Mexican patients with DS and refractory epilepsy (RE). We recruited 24 Mexican patients (14 males and 10 females), of which 15 were diagnosed with RE and 9 were diagnosed with DS. The SCN1A gene was sequenced to uncover mutations in exon 26. We detected 2 novel genotypes in 2 DS patients. One was a synonymous variant, c.5418 G > A (E1806E), and the other was a missense variant, c. 5324 T > C (L1775P). The missense mutation was predicted to be damaging with a score of 100% by the PolyPhen-2 program. The frequency of pathogenic variants was 4.17% in all the patients and 11.1% in DS patients, which, together with other publications, emphasize that specific and more severe phenotypes are associated with SCN1A mutations.
[Mh] Termos MeSH primário: Epilepsia Resistente a Medicamentos/genética
Epilepsias Mioclônicas/genética
Canal de Sódio Disparado por Voltagem NAV1.1/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Adolescente
Estudos de Casos e Controles
Criança
Pré-Escolar
Feminino
Seres Humanos
Lactente
Masculino
Mutação de Sentido Incorreto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (SCN1A protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE
[do] DOI:10.4238/gmr16029405


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[PMID]:28518218
[Au] Autor:Holland KD; Bouley TM; Horn PS
[Ad] Endereço:Departments of Pediatrics and Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.
[Ti] Título:Comparison and optimization of in silico algorithms for predicting the pathogenicity of sodium channel variants in epilepsy.
[So] Source:Epilepsia;58(7):1190-1198, 2017 Jul.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Variants in neuronal voltage-gated sodium channel α-subunits genes SCN1A, SCN2A, and SCN8A are common in early onset epileptic encephalopathies and other autosomal dominant childhood epilepsy syndromes. However, in clinical practice, missense variants are often classified as variants of uncertain significance when missense variants are identified but heritability cannot be determined. Genetic testing reports often include results of computational tests to estimate pathogenicity and the frequency of that variant in population-based databases. The objective of this work was to enhance clinicians' understanding of results by (1) determining how effectively computational algorithms predict epileptogenicity of sodium channel (SCN) missense variants; (2) optimizing their predictive capabilities; and (3) determining if epilepsy-associated SCN variants are present in population-based databases. This will help clinicians better understand the results of indeterminate SCN test results in people with epilepsy. METHODS: Pathogenic, likely pathogenic, and benign variants in SCNs were identified using databases of sodium channel variants. Benign variants were also identified from population-based databases. Eight algorithms commonly used to predict pathogenicity were compared. In addition, logistic regression was used to determine if a combination of algorithms could better predict pathogenicity. RESULTS: Based on American College of Medical Genetic Criteria, 440 variants were classified as pathogenic or likely pathogenic and 84 were classified as benign or likely benign. Twenty-eight variants previously associated with epilepsy were present in population-based gene databases. The output provided by most computational algorithms had a high sensitivity but low specificity with an accuracy of 0.52-0.77. Accuracy could be improved by adjusting the threshold for pathogenicity. Using this adjustment, the Mendelian Clinically Applicable Pathogenicity (M-CAP) algorithm had an accuracy of 0.90 and a combination of algorithms increased the accuracy to 0.92. SIGNIFICANCE: Potentially pathogenic variants are present in population-based sources. Most computational algorithms overestimate pathogenicity; however, a weighted combination of several algorithms increased classification accuracy to >0.90.
[Mh] Termos MeSH primário: Algoritmos
Simulação por Computador
Epilepsia/genética
Epilepsia/fisiopatologia
Variação Genética/genética
Mutação de Sentido Incorreto/genética
Canal de Sódio Disparado por Voltagem NAV1.1/genética
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Canais de Sódio/genética
[Mh] Termos MeSH secundário: Análise Mutacional de DNA
Bases de Dados Genéticas
Predisposição Genética para Doença/genética
Seres Humanos
Lactente
Fenótipo
Valor Preditivo dos Testes
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (SCN1A protein, human); 0 (SCN2A protein, human); 0 (SCN8A protein, human); 0 (Sodium Channels)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13798


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[PMID]:28441824
[Au] Autor:Tian XJ; Zhang YH; Liu AJ; Yang XL; Zeng Q; Yang ZX; Ye JT; Liu XY; Jiang YW; Wu XR
[Ad] Endereço:Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
[Ti] Título:[Clinical and neuroimaging features of acute encephalopathy after status epilepticus in Dravet syndrome].
[So] Source:Zhonghua Er Ke Za Zhi;55(4):277-282, 2017 Apr 02.
[Is] ISSN:0578-1310
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:To investigate the clinical and neuroimaging characteristics of acute encephalopathy (AE) after status epilepticus (SE) of patients with Dravet syndrome (DS). The clinical data of DS patients who had AE (coma ≥24 h) after SE were retrospectively collected from February 2005 to August 2016 in Peking University First Hospital and SCN1A gene tests were performed.The clinical and neuroimaging features were summarized. Twenty-two patients (9 males and 13 females) with AE were collected among 412 DS patients during follow-up.Of which 18 patients had SCN1A gene mutations while the remaining 4 patients had no SCN1A gene mutations.The onset age of AE was between 6 months and 10 years.The duration of SE varied between 40 minutes and 9 hours.Prior to the onset of SE, twenty-one patients had high fever, and one patient had normal temperature.Coma lasted from 2 days to 20 days.Nine patients died after the AE, and 13 patients survived with massive neurological regression.From AE to the last visit, the median time of follow-up was 2 years and 3 months (from 7 months to 4 years and 4 months). Nine of 13 survivors had varied improvement in motor, language and cognition, while the remaining 4 patients had no significant improvement.After AE, there were 6 patients with seizure-free, 4 patients with reduced seizures, and 3 patients with no change in seizure frequency, moreover, spasm occurred in 2 patients.Six patients had brain magnetic resonance imaging (MRI) in acute phase and showed bilateral (2 patients) or unilateral (4 patients) hemisphere edema, accompanied by subcortical white matter hyperintense signal in T1 and T2 weighted images in two patients.The neuroimaging of 13 survivors demonstrated diverse cortical atrophy during recovery phase, among which 4 patients showed cerebellar atrophy, one patient had right pontine atrophy, 4 patients accompanied by signal abnormalities in subcortical and periventricular white matter, 2 patients showed right hippocampal sclerosis, and one patient showed signal abnormalities in bilateral basal ganglia. SE is more prone to occur in Dravet patients who have high fever.It may result in AE or even death in severe cases.Survivors will leave severe neurological sequelae.The neuroimaging shows brain edema in acute phase.In recovery phase the neuroimaging shows diverse brain atrophy, moreover, a few patients may be associated with cerebellar or pontine atrophy, hippocampal sclerosis or abnormal signals in white matter or basal ganglia.
[Mh] Termos MeSH primário: Epilepsias Mioclônicas
Estado Epiléptico
[Mh] Termos MeSH secundário: Edema Encefálico
Criança
Pré-Escolar
Feminino
Hipocampo
Seres Humanos
Lactente
Imagem por Ressonância Magnética
Masculino
Mutação
Canal de Sódio Disparado por Voltagem NAV1.1/genética
Neuroimagem
Estudos Retrospectivos
Convulsões
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (SCN1A protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.0578-1310.2017.04.009



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