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1.
Medicine (Baltimore) ; 98(32): e16782, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393404

RESUMO

INTRODUCTION: Over the past 10 years, epilepsy genetics has made dramatic progress. This study aimed to analyze the knowledge structure and the advancement of epilepsy genetics over the past decade based on co-word analysis of medical subject headings (MeSH) terms. METHODS: Scientific publications focusing on epilepsy genetics from the PubMed database (January 2009-December 2018) were retrieved. Bibliometric information was analyzed quantitatively using Bibliographic Item Co-Occurrence Matrix Builder (BICOMB) software. A knowledge social network analysis and publication trend based on the high-frequency MeSH terms was built using VOSviewer. RESULTS: According to the search strategy, a total of 5185 papers were included. Among all the extracted MeSH terms, 86 high-frequency MeSH terms were identified. Hot spots were clustered into 5 categories including: "ion channel diseases," "beyond ion channel diseases," "experimental research & epigenetics," "single nucleotide polymorphism & pharmacogenetics," and "genetic techniques". "Epilepsy," "mutation," and "seizures," were located at the center of the knowledge network. "Ion channel diseases" are typically in the most prominent position of epilepsy genetics research. "Beyond ion channel diseases" and "genetic techniques," however, have gradually grown into research cores and trends, such as "intellectual disability," "infantile spasms," "phenotype," "exome," " deoxyribonucleic acid (DNA) copy number variations," and "application of next-generation sequencing." While ion channel genes such as "SCN1A," "KCNQ2," "SCN2A," "SCN8A" accounted for nearly half of epilepsy genes in MeSH terms, a number of additional beyond ion channel genes like "CDKL5," "STXBP1," "PCDH19," "PRRT2," "LGI1," "ALDH7A1," "MECP2," "EPM2A," "ARX," "SLC2A1," and more were becoming increasingly popular. In contrast, gene therapies, treatment outcome, and genotype-phenotype correlations were still in their early stages of research. CONCLUSION: This co-word analysis provides an overview of epilepsy genetics research over the past decade. The 5 research categories display publication hot spots and trends in epilepsy genetics research which could consequently supply some direction for geneticists and epileptologists when launching new projects.


Assuntos
Bibliometria , Epilepsia/genética , Medical Subject Headings/estatística & dados numéricos , Epigenômica/métodos , Humanos , Canais Iônicos/genética , Mutação , Testes Farmacogenômicos/métodos , Fenótipo , Convulsões/genética
2.
Zhonghua Er Ke Za Zhi ; 57(7): 532-537, 2019 Jul 02.
Artigo em Chinês | MEDLINE | ID: mdl-31269553

RESUMO

Objective: To analyze the clinical phenotypes of epilepsies in children with GABRB2 variants. Methods: Data of 8 epileptic patients with heterozygous GABRB2 variants were retrospectively collected at the Department of Pediatrics, Peking University First Hospital from April 2016 to December 2018. The clinical, electroencephalographic, neuroimaging characteristics, therapeutic and follow-up were analyzed. Results: Eight patients (4 boys, 4 girls) with heterozygous GABRB2 gene pathogenic variants were enrolled. Eight patients had different GABRB2 variants, among whom 2 patients inherited the variants from either parent, and the other 6 patients had de novo variants. Seven variants were novel. Ages at seizure onset ranged from 1 day to 22 months after birth, and the median age was 6 months. The seizure was first observed within one month of age in 2 patients, 1-6 months in 2 patients, 7-12 months in 2 patients, and beyond 1 year of age in 2 patients. Multiple seizure types were observed, including focal seizures in 6 patients, generalized tonic clonic seizures (GTCS) in 4 patients, myoclonic seizures in 3 patients, and epileptic spasm in 2 patients. Developmental delay was present in 6 patients. In 8 patients, Dravet syndrome was diagnosed in 3 patients, febrile seizures plus and West syndrome in 2 patients, respectively, Ohtahara syndrome in 1 patient. Six patients had epilepsy with fever sensitivity, and status epilepticus developed in all these patients. The ages at the last follow-up ranged from 8 months to 11 years, and the follow-up data showed that 5 patients were seizure-free, and 2 patients still had seizures, and 1 patient died of recurrent status epilepticus complicated with fungal infection. Conclusions: Epilepsies associated with GABRB2 variants were characterized by an onset in infancy, and the clinical features were heterogenous in seizure types and severities. Most patients had multiple seizures with fever sensitivity, and status epilepticus was common. Their seizures were easily induced by fever or infection. Additionally, the majority of the patients had varying degrees of developmental delay.


Assuntos
Epilepsias Mioclônicas/genética , Epilepsia/genética , Receptores de GABA-A/genética , Idade de Início , Criança , Pré-Escolar , Eletroencefalografia , Epilepsias Mioclônicas/diagnóstico , Epilepsia/diagnóstico , Feminino , Humanos , Lactente , Masculino , Mutação , Estudos Retrospectivos , Convulsões , Espasmos Infantis/genética
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 704-707, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302916

RESUMO

OBJECTIVE: To explore the genetic basis of a child featuring intellectual disability, developmental delay and epilepsy. METHODS: Cytogenetic and molecular analysis including chromosomal karyotyping analysis, single nucleotide polymorphism array (SNP array) and qPCR were performed. RESULTS: The karyotype of the child was determined as 46, XX; SNP array: arr [19]21q22.12q22.13(36 860 195-38 801 482)×1 dn. A heterozygous 1.9 Mb microdeletion was detected at 21q22.12q22.13. qPCR has confirmed deletion of exon 1 of the DYRK1A gene, which has occurred de novo. CONCLUSION: A 21q22 deletion was diagnosed with multiple genetic methods. Genotype-phenotype correlation suggested DYRK1A to be a candidate for intellectual disability.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Deleção de Sequência , Criança , Estudos de Associação Genética , Humanos , Cariotipagem
4.
Klin Padiatr ; 231(5): 233-239, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31340405

RESUMO

BACKGROUND: Shared decision-making is indispensable when it comes to molecular genetic investigations, but data on the expectations of the parents is scarce. METHODS: Using a step-by-step approach we initially performed free in-depth-interviews with five parents on which base we developed a half standardized questionnaire. This questionnaire was then applied in interviews with 30 parents of children with intellectual disability, autism or epilepsy subject to genetic examination. RESULTS: Pre-diagnostic discussions are challenging for the parents in an intellectual as well as emotional way. The most important general aspects are diagnosis and therapy. Self-assessment of prior knowledge is very variable and many parents expressed problems in understanding. During the conversation parents rate the following specific aspects as "very important" or "important": findings of unclear relevance, incidental findings, psychic consequences, prognostic aspects, possible therapeutic interventions. 10 Parents did not have any school-degree and 20 parents were not native speakers. DISCUSSION: All parents express a high need for information covering almost all aspects of the investigation. Communicational hurdles pose additional challenges leaving a large room for improvement. Trustworthy internet-based information systems in different languages including plain language could be a first step.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Deficiência Intelectual/genética , Pais/psicologia , Criança , Humanos , Inquéritos e Questionários
5.
BMC Neurol ; 19(1): 114, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164100

RESUMO

BACKGROUND: Epigenetics underlying refractory epilepsy is poorly understood. DNA methylation may affect gene expression in epilepsy patients without affecting DNA sequences. Herein, we investigated the association between Carbamazepine-resistant (CBZ-resistant) epilepsy and EPHX1 methylation in a northern Han Chinese population, and conducted an analysis of clinical risk factors for CBZ-resistant epilepsy. METHODS: Seventy-five northern Han Chinese patients participated in this research. 25 cases were CBZ-resistant epilepsy, 25 cases were CBZ-sensitive epilepsy and the remaining 25 cases were controls. Using a CpG searcher was to make a prediction of CpG islands; bisulfite sequencing PCR (BSP) was applied to test the methylation of EPHX1. We then did statistical analysis between clinical parameters and EPHX1 methylation. RESULTS: There was no difference between CBZ-resistant patients, CBZ-sensitive patients and healthy controls in matched age and gender. However, a significant difference of methylation levels located in NC_000001.11 (225,806,929.....225807108) of the EPHX1 promoter was found in CBZ-resistant patients, which was much higher than CBZ-sensitive and controls. Additionally, there was a significant positive correlation between seizure frequency, disease course and EPHX1 methylation in CBZ-resistant group. CONCLUSION: Methylation levels in EPHX1 promoter associated with CBZ-resistant epilepsy significantly. EPHX1 methylation may be the potential marker for CBZ resistance prior to the CBZ therapy and potential target for treatments.


Assuntos
Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Resistência a Medicamentos/genética , Epilepsia Resistente a Medicamentos/genética , Epóxido Hidrolases/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Metilação de DNA , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia/tratamento farmacológico , Epilepsia/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Adulto Jovem
6.
Yakugaku Zasshi ; 139(6): 923-929, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31155537

RESUMO

Brain function is controlled by the balance between the excitatory and inhibitory systems. If this balance is disrupted and the excitatory system dominates, convulsions or epileptic seizures are induced. Neuronal hyperexcitability in the brain leads to marked changes in the function of the neurons, which adversely affect the stability of the neural network. Many of the currently used antiepileptic drugs are symptomatic treatments that suppress the electrical hyperexcitability of the cerebrum. Although patients with epilepsy should continuously take antiepileptic drugs to control their seizures, approximately 20% of patients are drug resistant. The brain has the ability to control neuronal functions within acceptable limits while it maintains the amount of synaptic inputs that form the basis of information accumulation. Neuronal self-regulation is known as homeostatic scaling by which the intensity of all excitatory synapses is suppressed when neuronal excitability is increased. However, the molecular mechanisms of homeostatic scaling and their pathophysiological significance in vivo remain unclear. Repeated treatment with a subconvulsive dosage of pentylenetetrazol (PTZ), a γ-aminobutyric acid (GABA)A receptor antagonist, is known to induce kindling in mice, which is a common animal model used to study epilepsy. We found that PTZ-induced kindling was potentiated in mice deficient in the transcription factor neuronal PAS domain protein 4 (Npas4), the expression of which is immediately induced in response to neuronal activity. At this symposium, we will discuss the possibility of Npas4 as a novel target molecule for epilepsy treatment.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Encéfalo/fisiologia , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Homeostase , Terapia de Alvo Molecular , Neurônios/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Modelos Animais de Doenças , Epilepsia/genética , Humanos , Excitação Neurológica , Camundongos , Sinapses/fisiologia
7.
Gene ; 706: 162-171, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31085274

RESUMO

In clinical genetics, the need to discriminate between benign and pathogenic variants identified in patients with neurodevelopmental disorders is an absolute necessity. Copy number variants (CNVs) of small size can enable the identification of genes that are critical for neurologic development. However, assigning a definite association with a specific disorder is a difficult task. Among 328 trios analyzed over seven years of activity in a single laboratory, we identified 19 unrelated patients (5.8%) who carried a small (<500 kb) de novo CNV. Four patients had an additional independent de novo CNV. Nine had a variant that could be assigned as definitely pathogenic, whereas the remaining CNVs were considered as variants of unknown significance (VUS). We report clinical and molecular findings of patients harboring VUS. We reviewed the medical literature available for genes impacted by CNVs, obtained the probability of truncating loss-of-function intolerance, and compared overlapping CNVs reported in databases. The classification of small non-recurrent CNVs remains difficult but, among our findings, we provide support for a role of SND1 in the susceptibility of autism, describe a new case of the rare 17p13.1 microduplication syndrome, and report an X-linked duplication involving KIF4A and DLG3 as a likely cause of epilepsy.


Assuntos
Variações do Número de Cópias de DNA/genética , Transtornos do Neurodesenvolvimento/genética , Adulto , Transtorno Autístico/genética , Criança , Pré-Escolar , Epilepsia/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Cinesina/genética , Masculino , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Fatores de Transcrição/genética
8.
Nat Commun ; 10(1): 2129, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086189

RESUMO

De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors' proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1Y92C/+ mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1Y92C/+ animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1Y92C/+ mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations.


Assuntos
Malformações do Desenvolvimento Cortical/genética , Microtúbulos/metabolismo , Neurogênese/genética , Neurônios/fisiologia , Tubulina (Proteína)/genética , Animais , Comportamento Animal , Movimento Celular/genética , Centrossomo/metabolismo , Córtex Cerebral/anormalidades , Córtex Cerebral/citologia , Córtex Cerebral/diagnóstico por imagem , Modelos Animais de Doenças , Embrião de Mamíferos , Epilepsia/genética , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Técnicas de Introdução de Genes , Predisposição Genética para Doença , Células HeLa , Humanos , Microscopia Intravital , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Microscopia Eletrônica , Microtúbulos/genética , Mutação de Sentido Incorreto
9.
Chem Biol Interact ; 307: 223-233, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31018114

RESUMO

OBJECTIVE: The aim of this study is to investigate the role of mircoRNA-200c-3p (miR-200c-3p) on hippocampal neuron injury in epileptic rats through the regulation of the AKT signaling pathway by targeting RECK. METHODS: The epilepsy rat model was induced by intraperitoneal injection of lithium chloride-pilocarpine. Successful modeled rats were injected with miR-200c-3p inhibitors, inhibitors NC, siRNA-negative control (NC) and RECK-siRNA. The astrocyte activation, levels of oxidative stress indexes, contents of inflammatory factors and the AKT signaling pathway-related proteins in hippocampus tissues were evaluated. RESULTS: High expression of miR-200c-3p and low expression of RECK were found in the hippocampus tissues of epileptic rats. Downregulation of miR-200c-3p or upregulation of RECK decreased apoptosis of hippocampal neurons, expression of GFAP, content of MDA and increased the activities of GSH-Px and SOD, decreased expression of TNF-α, IL-1ß and IL-6 as well as expression of p-PI3K/t-PI3K and p-Akt/t-Akt in hippocampus tissues of epileptic rats. CONCLUSION: Our study provides evidence that downregulation of miR-200c-3p reduces damage of hippocampal neurons in epileptic rats by upregulating RECK and inactivating the AKT signaling pathway.


Assuntos
Hipocampo/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Apoptose , Modelos Animais de Doenças , Regulação para Baixo , Epilepsia/genética , Epilepsia/patologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Hipocampo/patologia , Hipocampo/ultraestrutura , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética , Regulação para Cima
10.
Int J Mol Sci ; 20(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018519

RESUMO

Epilepsy is a common neurological disorder associated with increased morbidity and mortality. Sudden unexpected death in epilepsy, also known as SUDEP, is the main cause of death in patients with epilepsy. SUDEP has an incidence of 1.2 per 1000 person-years in adults and 0.2 per 1000 person-years in children. SUDEP accounts for 8-17% of deaths in patients with epilepsy. It is commonly associated with a history of generalized tonic-clonic seizures, and its risk may be increased by other factors such as postictal electroencephalographic suppression, prone sleeping position, altered heart rate variability, conduction abnormalities, gender, or antiepileptic medications. Recently, electrocardiograms, electroencephalograms, and imaging markers have helped clinicians stratify SUDEP risk and identify patients in need of close monitoring. However, the pathophysiology of SUDEP is likely multifactorial and still unknown. Improving the knowledge of SUDEP incidence, risk factors, and biomarkers can help design and implement effective prevention strategies.


Assuntos
Morte Súbita/epidemiologia , Epilepsia/genética , Animais , Arritmias Cardíacas/complicações , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Morte Súbita/patologia , Epilepsia/epidemiologia , Epilepsia/patologia , Epilepsia/fisiopatologia , Predisposição Genética para Doença , Humanos , Fatores de Risco
11.
Expert Opin Drug Saf ; 18(4): 273-283, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30943798

RESUMO

INTRODUCTION: Epilepsy is a serious chronic neurological disorder manifested by an enduring symptomatic predisposition to seizures. Newly diagnosed individuals face increased morbidity, mortality, and socioeconomic costs. Anti-epileptic drug therapy is the treatment usually prescribed, which has efficacy in seizure control and mitigating long-term mortality. AREAS COVERED: Safety of anti-epileptic drug therapy in adults with a focus in newly diagnosed patients. Areas covered include the most commonly experienced adverse drug effects, as well as those with the highest impacts on drug tolerability, quality of life, morbidity and mortality. Evidence was also reviewed to identify clinical strategies to improve the safety of anti-epileptic drug therapy. EXPERT OPINION: Anti-epileptic drugs (AEDs) are mostly effective and well tolerated. However, a lack of standardised reporting of adverse drug effects in trials and in clinical practice provides an obstacle for evaluation of which adverse drug effects need to be prioritised in management. Improvement in the reporting of cognitive and other effects, as well as improved precision medicine and pharmacogenomics to target the incidence of high-mortality idiosyncratic reactions, will help to reduce the harm of AEDs in people newly diagnosed with epilepsy.


Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsia/tratamento farmacológico , Qualidade de Vida , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Anticonvulsivantes/efeitos adversos , Epilepsia/genética , Epilepsia/fisiopatologia , Humanos , Farmacogenética , Medicina de Precisão/métodos
12.
Epilepsy Res ; 153: 49-58, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30986657

RESUMO

The Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are highly expressed in the Central Nervous Systems, where they are responsible for the Ih current. Together with specific accessory proteins, these channels finely regulate neuronal excitability and discharge activity. In the last few years, a substantial body of evidence has been gathered showing that modifications of Ih can play an important role in the pathogenesis of epilepsy. However, the extent to which HCN dysfunction is spread among the epileptic population is still unknown. The aim of this work is to evaluate the impact of genetic mutations potentially affecting the HCN channels' activity, using a NGS approach. We screened a large cohort of patients with epilepsy of unknown etiology for mutations in HCN1, HCN2 and HCN4 and in genes coding for accessory proteins (MiRP1, Filamin A, Caveolin-3, TRIP8b, Tamalin, S-SCAM and Mint2). We confirmed the presence of specific mutations of HCN genes affecting channel function and predisposing to the development of the disease. We also found several previously unreported additional genetic variants, whose contribution to the phenotype remains to be clarified. According to these results and data from literature, alteration of HCN1 channel function seems to play a major role in epilepsy, but also dysfunctional HCN2 and HCN4 channels can predispose to the development of the disease. Our findings suggest that inclusion of the genetic screening of HCN channels in diagnostic procedures of epileptic patients should be recommended. This would help pave the way for a better understanding of the role played by Ih dysfunction in the pathogenesis of epilepsy.


Assuntos
Epilepsia/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Mutação/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Caderinas/genética , Proteínas de Transporte/genética , Caveolina 3/genética , Estudos de Coortes , Eletroencefalografia , Saúde da Família , Feminino , Filaminas/genética , Testes Genéticos , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Receptores Citoplasmáticos e Nucleares/genética
13.
Gene ; 700: 168-175, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30904718

RESUMO

To evaluate the additional diagnostic yield of whole exome sequencing (WES) reanalysis in patients with epilepsy and intellectual disability/mental retardation, we reanalyzed raw WES data and clinical information for 76 patient trios whose initial reports returned negative results. Eight patients (10.5%, 8/76) had positive genetic diagnoses finally, including six novel mutations in five genes. The reasons for the previous false-negative reports were divided into four categories: specific gene-disease associations had not been established at the time of the initial report; the disease database of the genetic test center had not been updated in a timely manner; the patient's clinical phenotype had not been carefully or correctly collected, submitted and reviewed when applicating genetic test and analyzing the variants; and the first round of data analysis missed a synonymous variant that affected splicing. Therefore, physicians should not give up the discovery of disease-causing mutations before re-examining the WES data and clinical phenotype by themselves or by collaborating with bioinformatic experts in the genetic test centers, especially for patients with strongly suspected genetic disease whose initial WES result was "negative". The suitable time points for reanalysis might be the 6-12 months after initial report.


Assuntos
Epilepsia/genética , Testes Genéticos/métodos , Deficiência Intelectual/genética , Sequenciamento Completo do Exoma/métodos , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Mutação , Fenótipo
14.
Seizure ; 67: 86-90, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30922778

RESUMO

PURPOSE: MEF2C-related epilepsy has been poorly described in the literature, despite a consistent MEF2C haploinsufficiency phenotype characterized by severe language impairment and motor delay (MIM# 613443). We aimed to delineate the spectrum of electroclinical manifestations of MEF2C-related epilepsy from an illustrative case and literature review. METHODS: A retrospective chart review of our case was performed followed by a literature review on PubMed and OMIM. Publications including patients with MEF2C pathogenic, likely pathogenic variants, or microdeletions without involvement of other genes were selected. RESULTS: The index case is a 2-year-old male with global developmental delay who presented at 7 months with atypical febrile seizures, generalized myoclonias, and focal impaired awareness seizures. Neuroimaging studies were unremarkable and electroencephalograms showed high voltage 200-400uV, 2-2.5 Hz generalized spike-and-waves and polyspikes with alternating frontal predominance, and multifocal spike-and-slow waves. Whole exome sequencing showed an unreported de novo likely pathogenic variant in the MEF2C gene c.236 G > C (p.Arg79Pro). Data from ten additional publications including 22 patients were gathered. From the 23 patients in total, 19 (82%) had seizures. Febrile seizures were most common, but myoclonic, focal-onset and generalized seizures were also reported. Electroencephalogram findings were described in eleven, and nine (82%) showed epileptiform abnormalities. CONCLUSION: MEF2C-related epilepsy may be described as a spectrum of manifestations including febrile seizures, myoclonia, and focal-onset or generalized seizures. Electroencephalogram is consistently abnormal, showing findings such as background slowing, multifocal and generalized epileptiform discharges and polyspikes. It remains unclear whether most patients are responsive or refractory to treatment with anti-epileptic medications.


Assuntos
Epilepsia/genética , Mutação , Encéfalo/fisiopatologia , Pré-Escolar , Epilepsia/fisiopatologia , Epilepsia/psicologia , Epilepsia/terapia , Humanos , Fatores de Transcrição MEF2/genética , Masculino , Fenótipo
15.
Acta Neurol Scand ; 139(6): 540-545, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30908586

RESUMO

AIMS: The association of single nucleotide polymorphisms (SNPs) of glutamate receptor 2 (GRIK2) gene, as well as gene-gene interaction with the risk of early-onset epilepsy susceptibility, was studied in Chinese children. METHODS: Generalized multi-factor dimension reduction (GMDR) is used to identify the optimal linkage between interaction among four SNPs and early-onset epilepsy susceptibility. Logistic regression was performed to assess association between four SNPs within GRIK2 gene and the risk of epilepsy. RESULTS: The results show that the risk of epilepsy in the rs4840200-T allele carriers was significantly higher than CC (CT/TT vs CC), adjusted OR (95% CI) = 1.74 (1.31-2.20), and the carrier of rs3213607-A allele was also higher than CC (CG/GG vs CC) with adjusted OR (95% CI) = 1.61 (1.23-2.10). We did not detect significant association between rs9390754 and rs2235076 within GRIK2 gene and epilepsy risk. In the GMDR analysis for the gene/gene interaction (2-4 locus models), we found a significant two-locus model (P = 0.001) involving rs4840200 and rs9390754. The cross-validation consistency was 10/10, and the prediction error was 0.632. Participants with rs4840200-CT/TT and rs9390754-GA/AA genotype within GRIK2 gene have the highest epilepsy risk, compared to participants with rs4840200-CC and rs9390754-GG genotype within GRIK2 gene, OR (95% CI) = 2.42 (1.78-3.11), after covariates adjustment for age and gender. CONCLUSIONS: Both rs4840200-T and rs3213607-A, and the interactions between rs4840200 and rs9390754 are related to the increased risk of epilepsy risk.


Assuntos
Epilepsia/genética , Predisposição Genética para Doença/genética , Receptores de Ácido Caínico/genética , Grupo com Ancestrais do Continente Asiático/genética , Criança , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Polimorfismo de Nucleotídeo Único
16.
Epilepsy Res ; 152: 18-30, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30870728

RESUMO

The last decade saw impressive advances not only in the discovery of gene mutations causing epilepsy, but also in unraveling the molecular mechanisms underlying the clinical manifestations of the disease. Increasing evidence is emerging that understanding these mechanisms is relevant for selection of the most appropriate treatment in the affected individual(s). The present article discusses the therapeutic implications of epilepsy-causing variants affecting a broad range of targets, from ion channels to genes controlling cellular metabolism and cell signaling pathways. Identification of a precise genetic etiology can direct physicians to (i) prescribe treatments that correct specific metabolic defects (e.g., the ketogenic diet for GLUT1 deficiency, or pyridoxine for pyridoxine-dependent epilepsies); (ii) avoid antiepileptic drugs (AEDs) that can aggravate the pathogenic defect (e.g., sodium channel blocking drugs in SCN1A-related Dravet syndrome), or (iii) select AEDs that counteract the functional disturbance caused by the gene mutation (e.g., sodium channel blockers for epilepsies due to gain-of-function SCN8A mutations). In some instances, different pathogenic variants of the same gene can have opposite functional effects, which determines whether certain treatments can be beneficial or deleterious (e.g., gain-of-function versus loss-of-function variants in SCN2A determine whether sodium channel blockers improve or worsen seizure control). There are also cases where functional disturbances caused by the gene defect may not be corrected by existing AEDs, but can be countered by medications already available in the market for other indications (e.g., memantine has been used to treat the epileptic encephalopathy caused by a specific gain-of-function GRIN2A mutation), thus making 'drug repurposing' a valuable tool for personalized epilepsy therapies. As our understanding of pathogenic mechanisms improve, opportunities arise for development of treatments targeting the specific gene defect or its consequences. Everolimus, an mTOR inhibitor approved for the treatment of focal seizures associated with tuberous sclerosis complex, is an example of a medication targeting the etiological mechanisms of the disease. Several treatments aimed at correcting specific pathogenic defects responsible for rare genetic epilepsies are currently in development, and range from traditional small molecules to novel approaches involving peptides, antisense oligonucleotides, and gene therapy.


Assuntos
Reposicionamento de Medicamentos , Epilepsia/genética , Epilepsia/terapia , Mutação/genética , Anticonvulsivantes/uso terapêutico , Humanos , Receptores de N-Metil-D-Aspartato/genética , Canais de Sódio Disparados por Voltagem/genética
17.
Brain Dev ; 41(6): 542-545, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30922528

RESUMO

Neuronal ceroid lipofuscinosis (NCL) is a group of progressive neurodegenerative disorders characterized by intracellular accumulation of ceroid lipopigments. Based on gene defect of NCL-associated proteins, 14 types of NCL have been described till date. NCL type 11 was first described in 2014 in two siblings as adult-onset NCL and was found to be due to a homozygous progranulin gene mutation. These siblings had progressive retinopathy, recurrent generalized seizures, moderate ataxia and subtle cognitive dysfunction. Palinopsia was present and MRI showed selective and severe cerebellar atrophy which was progressive with age. There have been no further reports of NCL 11 in literature. We here present a 14-year old girl born to second degree consanguineous couple who presented with gradually increasing frequency of seizures for the past 1 year without any signs of visual abnormalities and dementia. She had an elder sister who had progressive seizures and dementia from 8 years of age and died after few years. Her electroencephalogram showed frequent generalized epileptiform discharges and magnetic resonance imaging (MRI) showed pure cerebellar atrophy mainly affecting the vermis. MRI findings suggested a neurodegenerative disorder like NCL and prompted us to go for whole exome screen which revealed NCL type 11 due to homozygous mutation c.912G>A (p.Trp304Ter) in exon 9 of GRN gene (OMIM#614706). To the best of our knowledge this is the third case of NCL 11 and the first from Asia.


Assuntos
Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Adolescente , Adulto , Ásia , Atrofia/metabolismo , Sequência de Bases , Cerebelo/fisiopatologia , Eletroencefalografia , Epilepsia/genética , Feminino , Homozigoto , Humanos , Índia , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Mutação , Lipofuscinoses Ceroides Neuronais/diagnóstico por imagem , Linhagem , Progranulinas/genética , Convulsões , Sequenciamento Completo do Exoma
18.
Ther Drug Monit ; 41(2): 168-173, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30883510

RESUMO

Epilepsy is characterized by seizures recurring at interindividually differing time intervals. It may be difficult to assess drug response if time intervals between seizures are long. Thus, the existence of surrogate parameters that could be used to reliably identify drug efficacy and tolerability at an early stage and also as prognostic factors would be desirable. Electroencephalography, magnetic resonance imaging, and genetic markers are the domains to be assessed in this respect. The availability of clinically useful pharmacodynamic parameters is, however, currently disappointing.


Assuntos
Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Biomarcadores , Monitoramento de Medicamentos/métodos , Eletroencefalografia , Epilepsia/tratamento farmacológico , Epilepsia/genética , Humanos , Imagem por Ressonância Magnética
19.
Seizure ; 66: 81-85, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30818181

RESUMO

PURPOSE: Mutations in SZT2 have been previously reported in several cases of early onset epilepsy and intellectual disability. In this study we investigate potential causal mutations in two male siblings affected by early onset epilepsy, intellectual disability and macrocephaly. METHODS: We use family-based whole-exome sequencing to identify candidate variants. RESULTS: We report the identification of two potential causal SZT2 mutations in compound heterozygous state. We observe considerable differences in the clinical phenotype severity of the two affected individuals. The cerebral MRI revealed no abnormalities in the older affected brother, while in the youngest one it revealed a right frontal polymicrogiria. Moreover, while good seizure control was achieved in the older affected individual the younger brother is affected by pharmacoresistant epilepsy, progressive spastic paraplegia, cortical myoclonus and a more severe intellectual disability. We also analyzed the relative location of the reported pathogenic mutations in the SZT2 protein. CONCLUSION: Variable phenotypic expressivity is observed for this condition, while the location and type of mutations in SZT2 also has a potential impact on epilepsy severity. These findings extend our knowledge of epileptogenic conditions related to SZT2 and mTOR signaling.


Assuntos
Epilepsia/genética , Saúde da Família , Deficiência Intelectual/genética , Megalencefalia/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Adulto , Análise Mutacional de DNA , Epilepsia/complicações , Epilepsia/diagnóstico por imagem , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico por imagem , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Megalencefalia/complicações , Megalencefalia/diagnóstico por imagem , Sequenciamento Completo do Exoma , Adulto Jovem
20.
Seizure ; 66: 99-103, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30826555

RESUMO

PURPOSE: Aromatic antiepileptic drugs (AEDs) are frequently implicated in cutaneous adverse drug reactions (cADRs), a few of which are associated with certain human leukocyte antigen (HLA) alleles in some populations. We aimed to find HLA-associations with AED-related cADRs among North Indians. METHODS: North Indian subjects with cADR due to an AED, and those who were AED-tolerant were recruited as cases and controls, respectively. Genotyping for HLA-A, B and DRB1 were performed. Statistical analysis to compare carrier-rates and allele-frequencies between cases and controls (and healthy population, where necessary), was done for HLA-alleles occurring more than twice in either group. RESULTS: 120 cases {11 - Lamotrigine (LTG), 14 -Valproic acid (VPA), 8 -Levetiracetam (LEV), 35 -Carbamazepine (CBZ) and 52 - Phenytoin (PHT)}, and 250 controls were recruited. Presence of HLA-A*31:01 and HLA-B*51:01 were found to increase the risk of Maculopapular exanthema (MPE) due to CBZ and PHT (OR = 6.38; 95% CI: 1.46-27.75; OR = 4.60; 95% CI: 1.54-13.72, respectively). Among the severe cADRs, HLA-B*57:01(OR = 11.00 95% CI: 1.41-85.81) and HLA-DRB1*07:01 (OR = 7.25; 95% CI: 1.09-48.18) were noted to be significantly associated with CBZ-induced Stevens Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN); HLA-B *51:01 was associated with drug reaction eosinophilia and systemic symptoms (DRESS) caused by PHT (OR = 6.90; 95% CI: 1.38-34.29). CONCLUSIONS: We found significant associations of some HLA alleles with specific cADRs to CBZ and PHT in North Indians, which may need to be tested before AED-initiation; only screening for HLA-B*15:02 may not help in this population.


Assuntos
Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Epilepsia/genética , Antígenos HLA/genética , Dermatopatias/induzido quimicamente , Adolescente , Adulto , Criança , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA/genética , Adulto Jovem
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