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1.
Epileptic Disord ; 21(2): 185-191, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30977726

RESUMO

Epilepsy with auditory features (EAF) is a focal epilepsy syndrome characterized by prominent auditory ictal manifestations. Two main genes, LGI1 and RELN, have been implicated in EAF, but the genetic aetiology remains unknown in half of families and most sporadic cases. We previously described a pathogenic SCN1A missense variant (p.Thr956Met) segregating in a large family in which the proband and her affected daughter had EAF, thus satisfying the minimum requirement for diagnosis of autosomal dominant EAF (ADEAF). However, the remaining eight affected family members had clinical manifestations typically found in families with genetic epilepsy with febrile seizures plus (GEFS+). We aimed to investigate the role/impact of SCN1A mutations in EAF. We detailed the phenotype of this family and report on SCN1A screening in a cohort of 29 familial and 52 sporadic LGI1 variant-negative EAF patients. We identified two possibly pathogenic missense variants (p.Tyr790Phe and p.Thr140Ile) in sporadic patients (3.8%) showing typical EAF and no antecedent febrile seizures. Both p.Thr956Met and p.Tyr790Phe were previously described in unrelated patients with epilepsies within the GEFS+ spectrum. SCN1A mutations may be involved in EAF within the GEFS+ spectrum, however, the role of SCN1A in EAF without features that lead to a suspicion of underlying GEFS+ remains unclear and should be elucidated in future studies.


Assuntos
Transtornos da Percepção Auditiva , Epilepsias Parciais , Epilepsia Generalizada , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões Febris , Adulto , Idoso , Transtornos da Percepção Auditiva/etiologia , Transtornos da Percepção Auditiva/genética , Transtornos da Percepção Auditiva/fisiopatologia , Epilepsias Parciais/complicações , Epilepsias Parciais/genética , Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/complicações , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Convulsões Febris/complicações , Convulsões Febris/genética , Convulsões Febris/fisiopatologia
2.
Seizure ; 67: 11-14, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30849713

RESUMO

PURPOSE: Ryanodine receptor 2 (RYR2) mutation is well-established in the aetiology of an inherited cardiac disorder known as catecholaminergic polymorphic ventricular tachycardia (CPVT). The RYR2 receptor is expressed in cardiomyocytes, and also in the hippocampus. The RYR2 mutation has not been reported as a potential cause of adult-onset genetic generalised epilepsy (GGE). METHOD: Case report. RESULTS: A 32-year-old right-handed female presented with three unprovoked generalised seizures over twelve years. Electroencephalogram showed epileptiform activity which coincided with normal electrocardiogram recording. Her brother survived a cardiac arrest in his 20's and was diagnosed with CPVT and found to be heterozygous for a novel mutation in the RYR2 gene at chromosome 1q43, c.229 G > A p.(Ala77Thr). The patient inherited the same missense variant, predicted to be damaging by numerous in silico analytic tools. This mutation affects the N-terminal domain of the RYR2 receptor which plays a role in channel activation. However, the patient had repeatedly normal cardiac investigations including normal exercise stress tests. CONCLUSION: We propose that the RYR2 mutation is a potentially novel neurocardiac calcium channelopathy that may manifest with either CPVT or GGE depending on selective involvement of RYR2 receptors expressed in the heart or in the brain. RYR2 mutant mice have demonstrated spontaneous EEG-positive seizures independent of cardiac arrhythmia. Whole exome sequencing analyses have identified RYR2 as a candidate gene in GGE. This case is a reminder for careful assessment of episodes of transient loss of consciousness in an individual with CPVT, so as to not mistake possible neurogenic seizure for cardiogenic syncope, carrying obvious implications for treatment.


Assuntos
Canalopatias/diagnóstico , Canalopatias/genética , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adulto , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Diagnóstico Diferencial , Feminino , Humanos
3.
Zhonghua Er Ke Za Zhi ; 57(3): 206-210, 2019 Mar 02.
Artigo em Chinês | MEDLINE | ID: mdl-30818898

RESUMO

Objective: To explore the clinical characteristics and treatment of a family with inherited generalized epilepsy with febrile seizures plus (GEFS+) caused by STX1B gene mutation and to review the literature. Methods: Clinical data of a child with GEFS+ and his family members who visited Guangzhou Women and Children Medical Center in August 2017 were collected. DNA samples of the proband and his parents, his grandparents were analyzed by the next-generation sequencing and confirmed by Sanger sequencing. A literature search with "STX1B" as the key word was conducted at PubMed, China National Knowledge Infrastructure and Wanfang databases to include recently published studies (up to May 2018). Results: The proband was a 2-year-old boy who was admitted to our hospital because of frequent epileptic seizures in a month, with focal seizures evolving into the generalized bilateral tonic-clonic epileptic attacks after febrile seizure. His seizures were well controlled by levetiracetam. His father presented febrile seizure in early childhood stage and epilepsy in adult stage, which were under control with lamotrigine. The proband's grandmother had a history of febrile seizure. Other family members had no history of convulsion. Ictal electroencephalogram showed low voltage fast activities (8-10 Hz) originating from the central region of the brain. Heterozygous mutation of STX1B gene (c.705C>G, p. Asn235Lys) was detected in the proband, his father and grandmother. The mutation has not been reported previously. Furthermore, no other family members carried the mutation at c. 705 locus of STX1B gene. No article in Chinese was found, and 4 articles in a language other than Chinese provided the complete case data of 9 mutation loci in 33 patients (4 families and 4 sporadic cases). With this research data (3 cases in 1 family) included, there were 36 cases and 10 mutation sites in STX1B gene. Of these mutations, there were 5 missense mutations, 3 nonsense mutations, 1 insert mutation and 1 deletion mutation; and according to the mutation distribution, there were 4 mutation sites in exon 3, 2 in exon 8, 2 in exon 9, and 1 in exon 1.There was incomplete penetrance in the family, so different types of epileptic attacks occurred among different family members. Conclusions: In this study, a de novo mutation of STX1B gene in a family with GEFS+ was defined, which would expand the gene mutation spectrum and provide basis for family genetic counseling. Clinical heterogeneity was found in this family. Seizures caused by STX1B gene mutation were sensitive to antiepileptic drugs.


Assuntos
Epilepsia Generalizada/genética , Mutação Puntual/genética , Convulsões Febris/genética , Sintaxina 1/genética , Criança , Pré-Escolar , China , Epilepsia Generalizada/diagnóstico , Feminino , Humanos , Masculino , Mutação , Convulsões Febris/diagnóstico
4.
PLoS One ; 14(2): e0211917, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30735541

RESUMO

Genetic generalized epilepsies (GGE) are genetically determined, as their name implies and they are clinically characterized by generalized seizures involving both sides of the brain in the absence of detectable brain lesions or other known causes. GGEs are yet complex and are influenced by many different genetic and environmental factors. Methylation specific epigenetic marks are one of the players of the complex epileptogenesis scenario leading to GGE. In this study, we have set out to perform genome-wide methylation profiling to analyze GGE trios each consisting of an affected parent-offspring couple along with an unaffected parent. We have developed a novel scoring scheme within trios to categorize each locus analyzed as hypo or hypermethylated. This stringent approach classified differentially methylated genes in each trio and helped us to produce trio specific and pooled gene lists with inherited and aberrant methylation levels. In order to analyze the methylation differences from a boarder perspective, we performed enrichment analysis with these lists using the PANOGA software. This collective effort has led us to detect pathways associated with the GGE phenotype, including the neurotrophin signaling pathway. We have demonstrated a trio based approach to genome-wide DNA methylation analysis that identified individual and possibly minor changes in methylation marks that could be involved in epileptogenesis leading to GGE.


Assuntos
Metilação de DNA , Epigênese Genética , Epilepsia Generalizada/genética , Predisposição Genética para Doença , Genoma Humano , Fatores de Crescimento Neural/genética , Adulto , Criança , Eletroencefalografia , Epilepsia Generalizada/diagnóstico por imagem , Epilepsia Generalizada/metabolismo , Epilepsia Generalizada/fisiopatologia , Feminino , Perfilação da Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Padrões de Herança , Masculino , Redes e Vias Metabólicas/genética , Fatores de Crescimento Neural/metabolismo , Núcleo Familiar , Fenótipo
5.
BMC Med Genet ; 20(1): 16, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642272

RESUMO

BACKGROUND: KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. CASE PRESENTATION: Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. CONCLUSIONS: This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Epilepsia Generalizada/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Convulsões Febris/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Alelos , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/etiologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Brasil , Eletroencefalografia , Epilepsia Generalizada/fisiopatologia , Facies , Feminino , Loci Gênicos , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/etiologia , Deficiência Intelectual/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Linhagem , Convulsões Febris/fisiopatologia , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/etiologia , Anormalidades Dentárias/fisiopatologia , Sequenciamento Completo do Exoma
6.
Behav Brain Res ; 361: 54-64, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30550952

RESUMO

Abnormalities in social behavior are a co-morbid symptom of idiopathic generalized epilepsies such as childhood absence epilepsy. The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model is a spontaneously occurring absence epilepsy phenotype closely correlated to that of human absence epilepsies. Similar to the human conditions, GAERS display social abnormalities. Previous studies have only demonstrated social abnormalities in female GAERS, whereas social problems are observed in male and female patients. Seizures in GAERS result in part due to a gain-of-function missense mutation in the Cav3.2 T-type calcium channel gene. This study examined the effects of the pan-T-type calcium channel antagonist, Z944, on social interaction behaviors in male and female GAERS using an open field social interaction test. A second objective of this study was to examine the effects of Z944 on anxiety-like behavior in an open field locomotion test and elevated plus maze. Results showed a decrease in social activity in GAERS relative to non-epileptic control (NEC) rats. Acute, systemic Z944 (5 mg/kg; i.p.) consistently reduced introductory and aggressive behaviors in both GAERS and NECs whereas strain effects were observed for over-and-under crawl behaviors. In the open field locomotion test and elevated plus maze, Z944 increased anxiety-like behaviors in GAERS, whereas, Z944 produced inconsistent effects on anxiety-like behaviors in NECs. The results of this study suggest that the regulation of T-type calcium channel activity may be a useful strategy for the development of new therapeutic approaches for the treatment of social and affective abnormalities observed in absence epilepsy disorders.


Assuntos
Comportamento Animal/efeitos dos fármacos , Epilepsia Tipo Ausência/genética , Piperidinas/farmacologia , Animais , Ansiedade/genética , Encéfalo/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/efeitos dos fármacos , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia Generalizada/genética , Feminino , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Convulsões/tratamento farmacológico , Comportamento Social
7.
Seizure ; 60: 39-43, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29894917

RESUMO

PURPOSE: Previous studies have suggested that GABARG2 (Gamma-Aminobutyric acid type A Receptor Gamma 2 subunit) could be a gene of interest in genetic epilepsy; through possible associations with increased epilepsy susceptibility or resistance to antiepileptic drugs. The present study was designed to explore whether the GABARG2 C588 T (rs211037) genetic variant predicts susceptibility to epilepsy and pharmacoresistance among Egyptian children with Idiopathic Generalized Epilepsy (IGE). METHODS: A cohort of 210 Egyptian children was divided into two groups for this case-control study: group (I) included 100 children with IGE, group (II) comprised of 110 paediatric healthy controls. PCR-RFLP was used to amplify the C588 T polymorphism of the GABARG2 gene, which was digested with APOI restriction enzymes. RESULTS: There was a higher frequency of the TT genotype (P = 0.004) and T allele (P = 0.002) of the C588 T polymorphism of the GABARG2 gene in patients than controls. Besides, there was a substantial increase of the T allele among drug-resistant patients compared with those responding to antiepileptic drugs (P = 0.00015). Children with the C allele were four times more likely to be responsive to antiepileptic drugs than non-C-allele-carriers. CONCLUSION: The C588 T polymorphism of GABARG2 is associated with an increased risk of developing childhood IGE and may modulate patients' response to antiepileptic drugs.


Assuntos
Epilepsia Resistente a Medicamentos/genética , Epilepsia Generalizada/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptores de GABA-A/genética , Adolescente , Anticonvulsivantes/uso terapêutico , Estudos de Casos e Controles , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Egito , Epilepsia Generalizada/tratamento farmacológico , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Testes Farmacogenômicos
8.
Seizure ; 59: 38-40, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29734022

RESUMO

Terminal deletions of long arm of chromosome 13 are rare and poorly characterized by cytogenetic studies, making for difficult genotype-phenotype correlations. We report two siblings presenting generalized epilepsy, intellectual disability, and genitourinary tract defects. Array CGH detected a 1.3 Mb deletion at 13q34; it contains two protein-coding genes, SOX1 and ARHGEF7, whose haploinsufficiency can contribute to the epileptic phenotype.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 13 , Epilepsia Generalizada/genética , Deficiência Intelectual/genética , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Criança , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/patologia , Epilepsia Generalizada/fisiopatologia , Face/anormalidades , Humanos , Lactente , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Masculino , Fenótipo , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Fatores de Transcrição SOXB1/genética , Irmãos
9.
Pediatr Ann ; 47(3): e130-e134, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29538787

RESUMO

A 7-year-old girl with 20q13.33 deletion and a history of generalized convulsive epilepsy presented to the Developmental and Behavioral Pediatrics Clinic due to concerns about her behavioral outbursts in the context of overall delayed development. Evaluation by the Developmental and Behavioral and Gastroenterology teams revealed failure to thrive (FTT) as the primary cause of the behavioral outbursts and developed a high-calorie, high-fat, high-protein nutritional counseling plan. Children who have FTT and a genetic disorder are often thought to not thrive because of their underlying genetic disorder; however, feeding skills and nutritional intake need to be thoroughly investigated before determining an etiology for FTT. Motoric, communicative, and developmental skills in children with genetic disorders may impede appropriate feeding mechanisms, inducing or exaggerating FTT in these children with developmental disabilities due to genetic etiologies. [Pediatr Ann. 2018;47(3):e130-e134.].


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/complicações , Cromossomos Humanos Par 20 , Deficiências do Desenvolvimento/complicações , Epilepsia Generalizada/complicações , Insuficiência de Crescimento/diagnóstico , Comportamento Problema , Criança , Transtornos Cromossômicos/genética , Deficiências do Desenvolvimento/genética , Epilepsia Generalizada/genética , Insuficiência de Crescimento/etiologia , Insuficiência de Crescimento/psicologia , Feminino , Humanos , Desnutrição/diagnóstico , Desnutrição/etiologia , Desnutrição/psicologia , Síndrome
10.
Zhongguo Dang Dai Er Ke Za Zhi ; 20(2): 130-133, 2018 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-29429462

RESUMO

OBJECTIVE: To investigate the association between SCN1A rs3812718 polymorphism and generalized epilepsy with febrile seizures plus (GEFS+), and to provide potential molecular targets for the diagnosis and treatment of GEFS+. METHODS: The iPLEX technique in the MassARRAY system was used to determine SCN1A rs3812718 polymorphism, genotype frequency, and allele frequency in 50 patients with GEFS+ and 50 healthy controls. RESULTS: As for the frequencies of CC, CT, and TT genotypes in SCN1A rs3812718, there was a significant difference in the frequency of TT genotype between the GEFS+ group and the control group (P<0.05). There was also a significant difference in the frequency of T allele between the two groups (P<0.05). Compared with those carrying CC genotype or C allele, the individuals with CT genotype , TT genotype or T allele had a higher risk of developing GEFS+ (CT/CC: OR=4.05, 95%CI: 1.04-15.69; TT/CC: OR=30.60, 95%CI: 6.46-144.85; T/C: OR=4.64, 95%CI: 2.54-8.48). CONCLUSIONS: SCN1A rs3812718 polymorphism is a risk factor for GEFS+, and the population carrying T allele may have an increased risk of GEFS.


Assuntos
Epilepsia Generalizada/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Polimorfismo de Nucleotídeo Único , Convulsões Febris/genética , Adolescente , Criança , Pré-Escolar , Epilepsia Generalizada/etiologia , Feminino , Genótipo , Humanos , Masculino , Convulsões Febris/etiologia
11.
Eur J Paediatr Neurol ; 22(3): 516-524, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29422393

RESUMO

BACKGROUND: Early-onset epileptic encephalopathy (EOEE) is a severe convulsive disorder with a poor developmental prognosis. Although it has been associated with mutations in a number of genes, the fact that there is a large proportion of patients who remain undiagnosed suggests that there are many more still-unknown genetic causes of EOEE. Achieving a genetic diagnosis is important for understanding the biological basis of the disease, with its implications for treatment and family planning. METHODS: Whole-exome sequencing was performed in a family of Ashkenazi Jewish origin in which a male infant was diagnosed with EOEE. There was no family history of a similar neurologic disease. The patient had extreme hypotonia, neonatal hypothermia, choreiform movements, and vision impairment in addition to the convulsive disorder. RESULTS: A de novo heterozygous missense mutation, c.1003A > C, p.Asn335His, was identified in a conserved domain of GABRA2. GABRA2 encodes the α2 subunit of the GABAA receptor. CONCLUSIONS: In the context of previous reports of an association of de novo mutations in genes encoding different subunits of the GABAA receptor (GABRB1, GABRA1, GABRG2, GABRB3) with autosomal dominant epileptic disorders, we conclude that a de novo mutation in GABRA2 is likely to cause autosomal dominant EOEE accompanied by a movement disorder and vision impairment.


Assuntos
Coreia/genética , Epilepsia Generalizada/genética , Receptores de GABA-A/genética , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto
12.
Epilepsia ; 59(2): 389-402, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29315614

RESUMO

OBJECTIVE: Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients. METHODS: We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects. RESULTS: Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg). SIGNIFICANCE: Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.


Assuntos
Epilepsias Mioclônicas/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Ataxia/complicações , Ataxia/genética , Ataxia/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Epilepsias Parciais/complicações , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/genética , Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/complicações , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/complicações , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Mutação , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Resultado do Tratamento , Ácido Valproico/uso terapêutico , Adulto Jovem
13.
Mol Genet Genomic Med ; 6(2): 186-199, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29314763

RESUMO

BACKGROUND: Epileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost-effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways. METHODS: We conducted a retrospective cost-effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well-phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after "first-tier" testing. Sensitivity analysis was included with a range of commercial exome and multigene panels. RESULTS: The diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost-effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95% confidence intervals $2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost-effective. The clinical utility of all diagnoses was reported. CONCLUSION: Our study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions.


Assuntos
Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Criança , Pré-Escolar , Análise Custo-Benefício/métodos , Exoma , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos/economia , Testes Genéticos/estatística & dados numéricos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Doenças do Sistema Nervoso/genética , Estudos Retrospectivos , Análise de Sequência de DNA/economia , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Exoma/economia , Sequenciamento Completo do Exoma/métodos
14.
Epilepsia ; 59(1): 226-234, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29150855

RESUMO

OBJECTIVE: Patients with genetic generalized epilepsy (GGE) have subtle morphologic abnormalities of the brain revealed with magnetic resonance imaging (MRI), particularly in the thalamus. However, it is unclear whether morphologic abnormalities of the brain in GGE are a consequence of repeated seizures over the duration of the disease, or are a consequence of treatment with antiepileptic drugs (AEDs), or are independent of these factors. Therefore, we measured brain morphometry in a cohort of AED-naive patients with GGE at disease onset. We hypothesize that drug-naive patients at disease onset have gray matter changes compared to age-matched healthy controls. METHODS: We performed quantitative measures of gray matter volume in the thalamus, putamen, caudate, pallidum, hippocampus, precuneus, prefrontal cortex, precentral cortex, and cingulate in 29 AED-naive patients with new-onset GGE and compared them to 32 age-matched healthy controls. We subsequently compared the shape of any brain structures found to differ in gray matter volume between the groups. RESULTS: The thalamus was the only structure to show reduced gray matter volume in AED-naive patients with new-onset GGE compared to healthy controls. Shape analysis revealed that the thalamus showed deflation, which was not uniformly distributed, but particularly affected a circumferential strip involving anterior, superior, posterior, and inferior regions with sparing of medial and lateral regions. SIGNIFICANCE: Structural abnormalities in the thalamus are present at the initial onset of GGE in AED-naive patients, suggesting that thalamic structural abnormality is an intrinsic feature of GGE and not a consequence of AEDs or disease duration.


Assuntos
Epilepsia Generalizada , Tálamo/diagnóstico por imagem , Adolescente , Adulto , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Criança , Epilepsia Generalizada/diagnóstico por imagem , Epilepsia Generalizada/genética , Epilepsia Generalizada/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Adulto Jovem
15.
Seizure ; 54: 41-44, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29223885

RESUMO

PURPOSE: GLUT1-deficiency syndrome (GLUT1-DS) is a metabolic brain disorder with a great clinical heterogeneity underlined by various mutations in the SLC2A1 gene which make the clinical and genetic diagnosis complicated. The purpose of our study is to investigate the genetic defects affecting the SLC2A1 gene in a group of Bulgarian patients with genetic generalized epilepsy (GGE), and to bring new insights into the molecular pathology of GLUT1-DS that would strengthen the genotype-phenotype correlations and improve the diagnostic procedure. METHODS: We have performed sequencing analysis of the SLC2A1 gene in thirty-eight Bulgarian patients with different forms of GGE having emerged in childhood followed by array comparative genome (aCGH) hybridization in patients with severe forms of GLUT1-DS who display extraneurological features. RESULTS: We have detected three novel SLC2A1 gene mutations that are predicted to have different impacts on the GLUT1 protein structure and function - one being to cause the amino acid substitution p.H160Q, another leading to the truncation p.Q360*, and also a 1p34.2 microdeletion. The overall frequency of the SLC2A1 mutations in the studied group is 8.1%. They have been found in clinical cases that differ notably by their severity. CONCLUSION: Our study enriches the mutation spectrum of the SLC2A1 gene by 3 novel cases that reflect the genetic and phenotypic diversity of GLUT1-DS and brings new insights into the molecular pathology of that disorder. The clinical data showed that the SLC2A1 genetic defects should be considered equally in the entire range of the clinical manifestations of GGE paying attention to the extraneurological features. The aCGH analysis should be considered as an ultimate step during the diagnostic procedure of GLUT1-DS in patients with a complex clinical picture of intractable epilepsy involving neuropsychological impairments and accompanied by extraneurological features.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/complicações , Erros Inatos do Metabolismo dos Carboidratos/genética , Epilepsia Generalizada/complicações , Epilepsia Generalizada/genética , Variação Genética/genética , Transportador de Glucose Tipo 1/genética , Proteínas de Transporte de Monossacarídeos/deficiência , Adolescente , Bulgária , Erros Inatos do Metabolismo dos Carboidratos/fisiopatologia , Criança , Hibridização Genômica Comparativa , Saúde da Família , Feminino , Humanos , Masculino , Modelos Moleculares , Proteínas de Transporte de Monossacarídeos/genética , Fenótipo
16.
Eur Neurol ; 80(5-6): 236-244, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30661063

RESUMO

BACKGROUND: We aimed to evaluate the brain morphology of patients with genetic generalized epilepsy (GGE) compared to healthy subjects. In addition, we investigated whether there are differences in brain morphology among different GGE syndromes. METHODS: We enrolled 100 patients with a clinical diagnosis of GGE. The patients were classified into different syndrome groups according to their predominant seizure type, age of seizure onset, and electroencephalography characteristics (12 childhood absence epilepsy [AE], 13 juvenile AE, 56 juvenile myoclonic epilepsy, and 19 epilepsy with generalized tonic-clonic alone). We used surface-based morphometry of brain magnetic resonance imaging to evaluate brain morphology. RESULTS: We found significantly widespread alterations of brain morphology, including cortical thickness and volumes in several regions in the patients with GGE compared to healthy controls. In addition, we observed significant differences in alterations of cortical thickness and volumes among the different GGE syndromes. However, there were no differences in cortical surface areas between the patients with GGE and healthy controls. There was a significantly negative correlation between the duration of epilepsy and most of the each measures of abnormal brain morphology. CONCLUSIONS: The main finding of this study is that brain morphology in patients with GGE is significantly different from that in healthy controls. In addition, we found that the different GGE syndromes show distinct structural brain morphology, especially cortical thickness, which can help us understand the pathogenesis of GGE syndromes.


Assuntos
Encéfalo/patologia , Epilepsia Generalizada/patologia , Adulto , Criança , Epilepsia Generalizada/genética , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino
17.
Zh Nevrol Psikhiatr Im S S Korsakova ; 118(10. Vyp. 2): 56-60, 2018.
Artigo em Russo | MEDLINE | ID: mdl-30698545

RESUMO

The review presents modern data on the genetics of idiopathic generalized epilepsies. Identified genes encode different structures of neurons, including voltage-dependent channels, receptors of neurotransmitters, protein-associated ion channels and synaptic proteins. The authors describe already identified genes, which are a causative factor of idiopathic generalized epilepsies and discuss further prospects of using molecular genetic studies.


Assuntos
Epilepsia Generalizada , Epilepsia Generalizada/genética , Humanos , Canais Iônicos , Mutação
18.
Epilepsia ; 58(12): 2025-2037, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29063584

RESUMO

According to the International League Against Epilepsy (ILAE) definition, no structural abnormalities are present on a standard brain magnetic resonance image in genetic generalized epilepsy (GGE) patients. However, recent studies raise contradictory evidence with increasing use of quantitative magnetic resonance imaging techniques. Following PRISMA guidelines, a systematic, quantitative review was conducted using 28 peer-reviewed, case-control studies published after 1989. Furthermore, a meta-analysis with a random-effect model revealed differences in structural brain abnormalities between GGE patients and controls. Significant structural differences between GGE and healthy controls were observed with volume reductions in whole brain, thalamus, putamen, caudate, pallidum, and supplementary motor area. Furthermore, gray matter volume reduction in the right and left hemispheres, thalamus, and insula, and surface area reduction in the caudal anterior cingulate cortex were revealed, along with gray matter increase in the medial frontal gyrus. Due to methodological differences, findings should be interpreted with caution. Nevertheless, contrary to the ILAE definition, it would appear that structural brain abnormalities may be present in GGE patients. Findings are consistent with a hypothesis regarding the underlying involvement of the thalamocortical networks in the generation of generalized spike-wave discharges, but structural abnormalities appear to extend outside these regions to potentially involve attention and other cognitive domains.


Assuntos
Encéfalo/patologia , Epilepsia Generalizada/genética , Epilepsia Generalizada/patologia , Encéfalo/diagnóstico por imagem , Epilepsia Generalizada/diagnóstico por imagem , Humanos
19.
Epilepsy Res ; 138: 46-52, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29059589

RESUMO

PURPOSE: Since the approval of Vagal Nerve Stimulation (VNS) Therapy for medically refractory focal epilepsies in 1997, it has been also reported to be effective for a wide range of generalized seizures types and epilepsy syndromes. Instead of conventional VNS Therapy delivered at 20-30Hz signal frequencies, this study evaluates efficacy and tolerability of high-frequency burst VNS in a natural animal model for genetic generalized epilepsy (GGE), the epileptic baboon. METHODS: Two female baboons (B1 P.h. Hamadryas and B2 P.h. Anubis x Cynocephalus) were selected because of frequently witnessed generalized tonic-clonic seizures (GTCS) for VNS implantation. High-frequency burst VNS Therapy was initiated after a 4-5 week baseline; different VNS settings (0.25, 2 or 2.5mA, 300Hz, 4 vs 7 pulses, 0.5-2.5s interburst interval, and intermittent stimulation for 1-2 vs for 24h per day) were tested over the subsequent 19 weeks, which included a 4-6 week wash-out period. GTCS frequencies were quantified for each setting, while seizure duration and postictal recovery times were compared to baseline. Scalp EEG studies were performed at almost every setting, including intermittent light stimulation (ILS) to evaluate photosensitivity. Pre-ILS ictal and interictal discharge rates, as well as ILS responses were compared between trials. The Novel Object test was used to assess potential treatment effects on behavior. RESULTS: High-frequency burst VNS Therapy reduced GTCS frequencies at all treatment settings in both baboons, except when output currents were reduced (0.25mA) or intermittent stimulation was restricted (to 1-2h/day). Seizure duration and postictal recovery times were unchanged. Scalp EEG studies did not demonstrate treatment-related decrease of ictal or interictal epileptic discharges or photosensitivity, but continuous treatment for 120-180s during ILS appeared to reduce photoparoxysmal responses. High-frequency burst VNS Therapy was well-tolerated by both baboons, without cardiac or behavioral changes. Repetitive muscle contractions involving the neck and left shoulder girdle were observed intermittently, most commonly at 0.5 interburst intervals, but these were transient, resolving with a few cycles of stimulation and not noted in wakefulness. CONCLUSIONS: This preclinical pilot study demonstrates efficacy and tolerability of high-frequency burst VNS Therapy in the baboon model of GGE. The muscle contractions may be due to aberrant propagation of the stimulus along the vagal nerve or to the ansa cervicalis, but can be reduced by minimal adjustment of current output or stimulus duration.


Assuntos
Epilepsia Generalizada/terapia , Estimulação do Nervo Vago/métodos , Animais , Biofísica , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia Generalizada/genética , Epilepsia Generalizada/patologia , Epilepsia Generalizada/veterinária , Feminino , Papio
20.
Epilepsy Res ; 137: 9-18, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28865303

RESUMO

Seizure disorders are very common and affect 3% of the general population. The recurrent unprovoked seizures that are also called epilepsies are highly diverse as to both underlying genetic basis and clinic presentations. Recent genetic advances and sequencing technologies indicate that many epilepsies previously thought to be without known causes, or idiopathic generalized epilepsies (IGEs), are virtually genetic epilepsy as they are caused by genetic variations. IGEs are estimated to account for ∼15-20% of all epilepsies. Initially IGEs were primarily considered channelopathies, because the first genetic defects identified in IGEs involved ion channel genes. However, new findings indicate that mutations in many non ion channel genes are also involved in addition to those in ion channel genes. Interestingly, mutations in many genes associated with epilepsy affect GABAergic signaling, a major biological pathway in epilepsy. Additionally, many antiepileptic drugs work via enhancing GABAergic signaling. Hence, the review will focus on the mutations that impair GABAergic signaling and selectively discuss the newly identified STXBP1, PRRT2, and DNM1 in addition to those long-established epilepsy ion channel genes that also impair GABAergic signaling like SCN1A and GABAA receptor subunit genes. GABAergic signaling includes the pre- and post- synaptic mechanisms. Some mutations, such as STXBP1, PRRT2, DNM1, and SCN1A, impair GABAergic signaling mainly via pre-synaptic mechanisms while those mutations in GABAA receptor subunit genes impair GABAergic signaling via post-synaptic mechanisms. Nevertheless, these findings suggest impaired GABAergic signaling is a converging pathway of defects for many ion channel or non ion channel mutations associated with genetic epilepsies.


Assuntos
Epilepsia Generalizada/genética , Epilepsia Generalizada/metabolismo , Receptores de GABA/metabolismo , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Neurônios GABAérgicos/metabolismo , Humanos , Receptores de GABA/genética
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