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1.
Medicina (B Aires) ; 79 Suppl 3: 42-47, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31603843

RESUMO

Epileptic encephalopathies is a group of epileptic syndromes characterized by progressive cognitive impairment beyond the expected for the epilepsy activity. They are characterized by severe pharmaco-resistant epilepsy, severely abnormal electroencephalograms, early-age onset, neurocognitve impairment, variable phenotype and usually normal brain MRI. These syndromes are usually genetically determined. A correct and timely diagnosis could help and guide the medical counselling and the correct therapeutic approach improving the short, medium and long term outcomes. In this article we review the electroencephalographic and genetic findings along with the most recommended therapeutic options facilitating the clinical management. We include the following epileptic encephalopathy syndromes: Ohtahara, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West, Dravet, non-progressive myoclonic status, Doose, Lennox-Gastaut, Landau-Kleffner and continuous spike-wave during sleep epilepsy.


Assuntos
Encefalopatias/genética , Epilepsias Mioclônicas/genética , Espasmos Infantis , Anticonvulsivantes/classificação , Anticonvulsivantes/uso terapêutico , Encefalopatias/classificação , Encefalopatias/diagnóstico , Encefalopatias/tratamento farmacológico , Eletroencefalografia , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/tratamento farmacológico , Humanos , Síndrome
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.
Nat Commun ; 10(1): 2620, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197165

RESUMO

Conventional drug screens and treatments often ignore the underlying complexity of brain network dysfunctions, resulting in suboptimal outcomes. Here we ask whether we can correct abnormal functional connectivity of the entire brain by identifying and combining multiple neuromodulators that perturb connectivity in complementary ways. Our approach avoids the combinatorial complexity of screening all drug combinations. We develop a high-speed platform capable of imaging more than 15000 neurons in 50ms to map the entire brain functional connectivity in large numbers of vertebrates under many conditions. Screening a panel of drugs in a zebrafish model of human Dravet syndrome, we show that even drugs with related mechanisms of action can modulate functional connectivity in significantly different ways. By clustering connectivity fingerprints, we algorithmically select small subsets of complementary drugs and rapidly identify combinations that are significantly more effective at correcting abnormal networks and reducing spontaneous seizures than monotherapies, while minimizing behavioral side effects. Even at low concentrations, our polytherapy performs superior to individual drugs even at highest tolerated concentrations.


Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Modelos Biológicos , Rede Nervosa/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Neurotransmissores/farmacologia , Algoritmos , Animais , Animais Geneticamente Modificados , Comportamento Animal/efeitos dos fármacos , Encéfalo/citologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/patologia , Ensaios de Triagem em Larga Escala/métodos , Humanos , Microscopia Confocal/métodos , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neurotransmissores/uso terapêutico , Peixe-Zebra
4.
Nat Commun ; 10(1): 2506, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175295

RESUMO

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10-6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.


Assuntos
Variação Genética , Espasmos Infantis/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , DNA (Citosina-5-)-Metiltransferases/genética , Epilepsias Mioclônicas/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Lactente , Japão , Síndrome de Lennox Gastaut/genética , Modelos Logísticos , Mutação , Neurofibromina 1/genética , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Canais de Cátion TRPM/genética , Sequenciamento Completo do Exoma
5.
Medicine (Baltimore) ; 98(18): e15428, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045803

RESUMO

RATIONALE: The SLC2A1 gene encodes glucose transporter 1 on blood-brain barrier, which plays an important role in the energy supply for neurons. Mutations in SLC2A1 gene can cause many clinical syndromes, including glucose transporter type 1 deficiency syndrome and many types of epilepsy syndromes such as childhood absence epilepsy and myoclonic-atonic epilepsy, etc. Ketogenic diet has been proved to be very effective on those cases. Clinically, SLC2A1 gene mutations are quite rare. PATIENT CONCERNS: Repeated unconsciousness and bilateral limb weakness lasted for 3 years. DIAGNOSES: Myoclonic-atonic epilepsy. LESSONS: After taking whole exome sequencing, we found out that there is a de novo insertion mutation in the patient's SLC2A1 gene, leading to frameshift. As a result, ketogenic diet (2:1, 4 times a day) was used as the treatment. As for the patient, total calories intake per day was controlled at 1190 kcal. The calories per kg per day were 66.11 kcal/kg. The amount of ketone bodies was controlled at 2 to 3 mmol/L and the concentration of plasma glucose was controlled at 4 to 5 mmol/L. OUTCOMES: After the launch of ketogenic diet, the patient has been seizure free for nearly a year and stopped all his antiepileptic drugs. CONCLUSION: Our case suggests that gene examination is very important part of the diagnosis of epilepsy etiology and epilepsy syndromes. Ketogenic diet should be considered as the first line therapy with SLC2A1 gene mutations.


Assuntos
Dieta Cetogênica/métodos , Epilepsias Mioclônicas/dietoterapia , Epilepsias Mioclônicas/genética , Transportador de Glucose Tipo 1/genética , Pré-Escolar , Humanos , Masculino , Mutação
6.
Seizure ; 67: 73-77, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30928698

RESUMO

Familial adult myoclonic epilepsy (FAME), also described with different acronyms (ADCME, BAFME, FEME, FCTE and others), is a high-penetrant autosomal dominant condition featuring cortical hand tremors, myoclonic jerks, and occasional/rare convulsive seizures. Prevalence is unknown since this condition is often under-recognized, but it is estimated to be less than 1/35,000. The disease usually starts in the second decade of life and has been genetically associated with at least 4 different loci (8q24, 2p11.1-q12.2, 5p15.31-p15 and 3q26.32-3q28). Recently, the expansion of non coding TTTTA and TTTCA repeats has been identified as the causative mutation in Japanese families linked to the 8q24. The diagnosis is supported by clinical features and electrophysiological investigations as jerk-locked back averaging, C-reflex, and somatosensory-evoked potential. Photic stimulation, emotional stress, and sleep deprivation may trigger both tonic-clonic and myoclonic seizures. FAME has a slow but progressive clinical course occurring with intellectual disability and worsening of both tremor and myoclonus although with a less severe decline compared to other progressive myoclonic epilepsies. Valproate, levetiracetam, and benzodiazepines are considered the first-line treatments.


Assuntos
Expansão das Repetições de DNA , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Humanos
7.
Epilepsy Res ; 152: 11-17, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30870727

RESUMO

PURPOSE: This study aimed to investigate cardiac electrical and autonomic function, the longitudinal changes, and the associated risk factors in children with Dravet syndrome (DS). METHODS: Twenty-four children with DS (11 boys, 13 girls; mean age, 7.2 ± 2.9 years) and 21 control subjects (9 boys, 12 girls; mean age, 8.2 ± 3.0 years) were enrolled in this study. P dispersion, QTc and QTc dispersion, and heart rate variability (HRV) were evaluated using standard electrocardiography and 24-hr Holter monitoring at the initial and follow-up study of the 6-12 months intervals. RESULTS: The DS group had significantly higher P dispersion (p = 0.017), QT and QTc dispersion values (p < 0.001 for two parameters) than the control group. Most HRV parameters, such as SDNN (p < 0.001), SDANN5 (p < 0.001), SDANN-index (p = 0.001), and RMSSD (p = 0.006) were all significantly lower in the DS group than in the control group. The mean values of initial QTc, QTc dispersion, and HRV parameters showed significantly increase (QTc and QTc dispersion) and decrease (HRV) in the follow-up study (mean duration: 1.2 ± 0.5 years) in 13 DS children. ± On multivariate regression analysis, epilepsy duration had an independently significant effect for the longitudinal change of QTc, QTc dispersion, and HRV. CONCLUSIONS: DS children had significant different values of cardiac electrical and autonomic function compared with control group. Particularly, longer duration of epilepsy was significantly negative effect on the longitudinal change of cardiac autonomic function.


Assuntos
Epilepsias Mioclônicas/complicações , Frequência Cardíaca/fisiologia , Criança , Pré-Escolar , Eletrocardiografia , Epilepsias Mioclônicas/genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Fatores de Risco
8.
Medicine (Baltimore) ; 98(13): e14974, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30921204

RESUMO

Previous research identified SCN1B variants in some cases of Dravet syndrome (DS). We investigated whether SCN1B and SCN2B variants are commonly happened in DS patients without SCN1A variants. A total of 22 DS patients without SCN1A variants and 100 healthy controls were enrolled in this genetic study. DNA from DS patients was sequenced by Sanger method in whole exons of SCN1B and SCN2B genes. We identified two exon variants (c.351C>T, p.G117G and c.467C>T, p.T156M), which were present both in 1000 egenomes database and in healthy controls with a frequency of 0.54% and 4%, 0.06% and 0%, respectively. Additionally, eight intron or 3 prime UTR variants showing benign clinical significance have also been identified. Our results suggest that variants of SCN1B and SCN2B may not be common causes of DS according to our data. Further large sample-size cohort studies are needed to confirm our conclusion.


Assuntos
Epilepsias Mioclônicas/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética , Subunidade beta-2 do Canal de Sódio Disparado por Voltagem/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Mutação , Adulto Jovem
9.
Genome Biol ; 20(1): 58, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890163

RESUMO

Tandemly repeated DNA is highly mutable and causes at least 31 diseases, but it is hard to detect pathogenic repeat expansions genome-wide. Here, we report robust detection of human repeat expansions from careful alignments of long but error-prone (PacBio and nanopore) reads to a reference genome. Our method is robust to systematic sequencing errors, inexact repeats with fuzzy boundaries, and low sequencing coverage. By comparing to healthy controls, we prioritize pathogenic expansions within the top 10 out of 700,000 tandem repeats in whole genome sequencing data. This may help to elucidate the many genetic diseases whose causes remain unknown.


Assuntos
Epilepsias Mioclônicas/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Software , Sequências de Repetição em Tandem , Sequenciamento Completo do Genoma/métodos , Adulto , Algoritmos , Biologia Computacional/métodos , Predisposição Genética para Doença , Humanos
10.
Seizure ; 66: 26-30, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30776697

RESUMO

PURPOSE: This study aimed to investigate the genetic etiology of epilepsy in a cohort of Chinese children. METHODS: Targeted next-generation sequencing (NGS) was performed for 120 patients with unexplained epilepsy, including 71 patients with early-onset epileptic encephalopathies, and 16 patients with Dravet syndrome (including three patients with a Dravet-like phenotype) but without SCN1A pathogenic variants. RESULTS: Pathogenic variants of 14 genes were discovered in 22 patients (18%). A de novo KCND3 pathogenic variant (c.1174G > A, p.Val392Ile) was identified in a boy with refractory epilepsy, psychomotor regression, attention deficit, and visual decline. Pathogenic variants in other coding genes were excluded via whole exome sequencing. This KCND3 variant was previously confirmed to be pathogenic by Giudicessi, et al. However, the clinical profile was different: sudden death at 20 years old without any medical history of neurological disorders, nor with any diseases typically caused by KCND3 pathogenic variants such as Brugada syndrome, spinocerebellar ataxia type 19/22 or ataxia accompanied by epilepsy. This indicates that we have identified a new KCND3 phenotype. In addition, we also uncovered a GRIN1 pathogenic variant and a novel HCN1 pathogenic variant in the Dravet cohort. CONCLUSION: Our study highlights the significant utility of NGS panels in the genetic diagnosis of pediatric epilepsy. Our findings indicate that KCND3 pathogenic variants may be responsible for a wider phenotypic spectrum than previously thought, by including childhood epileptic encephalopathy. Furthermore, this study provides evidence that GRIN1 and HCN1 are candidate genes for Dravet and Dravet-like phenotypes.


Assuntos
Epilepsias Mioclônicas/genética , Mutação/genética , Canais de Potássio Shal/genética , Análise de Variância , Pré-Escolar , China , Estudos de Coortes , Análise Mutacional de DNA , Epilepsias Mioclônicas/diagnóstico por imagem , Feminino , Frequência do Gene , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Lactente , Imagem por Ressonância Magnética , Masculino , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Receptores de N-Metil-D-Aspartato/genética
11.
Exp Neurol ; 311: 247-256, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30347190

RESUMO

Dravet syndrome is a severe, early-onset epileptic encephalopathy frequently resulting from de novo mutations of SCN1A. Mice with heterozygous deletion of Scn1a (Scn1a+/-) model many features of Dravet syndrome, including spontaneous seizures and premature lethality. Scn1a+/- mice exhibit variable phenotype penetrance and expressivity dependent upon the strain background. On the 129S6/SvEvTac (129) strain, Scn1a+/- mice do not display an overt phenotype. However Scn1a+/- mice on the [129S6xB6]F1 strain (F1.Scn1a+/-) exhibit juvenile-onset spontaneous seizures and premature lethality. QTL mapping identified several modifier loci responsible for strain-dependent differences in survival of Scn1a+/- mice, but these loci do not account for all the observed phenotypic variance. Global RNA-seq analysis was performed to identify additional genes and pathways that may contribute to variable phenotypes. Hippocampal gene expression was analyzed in wild-type (WT) and Scn1a+/- mice on both F1 and 129 strains, at two time points during disease development. There were few gene expression differences between 129.WT and 129.Scn1a+/- mice and approximately 100 genes with small expression differences (6-36%) between F1.WT and F1.Scn1a+/- mice. Strain-specific gene expression differences were more pronounced, with dozens of genes with >1.5-fold expression differences between 129 and F1 strains. Age-specific and seizure-related gene expression differences were most prominent, with hundreds of genes with >2-fold differences in expression identified between groups with and without seizures, suggesting potential differences in developmental trajectory and/or homeostatic plasticity during disease onset. Global expression differences in the context of Scn1a deletion may account for strain-dependent variation in seizure susceptibility and survival observed in Scn1a+/- mice.


Assuntos
Modelos Animais de Doenças , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/metabolismo , Perfilação da Expressão Gênica/métodos , Canal de Sódio Disparado por Voltagem NAV1.1/biossíntese , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Animais , Camundongos , Camundongos da Linhagem 129 , Camundongos Transgênicos , Especificidade da Espécie
12.
J Hum Genet ; 64(3): 191-197, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30559482

RESUMO

Long-read sequencing technology is now capable of reading single-molecule DNA with an average read length of more than 10 kb, fully enabling the coverage of large structural variations (SVs). This advantage may pave the way for the detection of unprecedented SVs as well as repeat expansions. Pathogenic SVs of only known genes used to be selectively analyzed based on prior knowledge of target DNA sequence. The unbiased application of long-read whole-genome sequencing (WGS) for the detection of pathogenic SVs has just begun. Here, we apply PacBio SMRT sequencing in a Japanese family with benign adult familial myoclonus epilepsy (BAFME). Our SV selection of low-coverage WGS data (7×) narrowed down the candidates to only six SVs in a 7.16-Mb region of the BAFME1 locus and correctly determined an approximately 4.6-kb SAMD12 intronic repeat insertion, which is causal of BAFME1. These results indicate that long-read WGS is potentially useful for evaluating all of the known SVs in a genome and identifying new disease-causing SVs in combination with other genetic methods to resolve the genetic causes of currently unexplained diseases.


Assuntos
Epilepsias Mioclônicas/genética , Genoma Humano , Íntrons , Mutagênese Insercional , Proteínas Repressoras/genética , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma/métodos , Adolescente , Feminino , Humanos , Masculino , Linhagem , Prognóstico
13.
Epilepsy Behav ; 90: 252-259, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30527252

RESUMO

PURPOSE: Differentiating between Dravet syndrome and non-Dravet SCN1A-related phenotypes is important for prognosis regarding epilepsy severity, cognitive development, and comorbidities. When a child is diagnosed with genetic epilepsy with febrile seizures plus (GEFS+) or febrile seizures (FS), accurate prognostic information is essential as well, but detailed information on seizure course, seizure freedom, medication use, and comorbidities is lacking for this milder patient group. In this cross-sectional study, we explore disease characteristics in milder SCN1A-related phenotypes and the nature, occurrence, and relationships of SCN1A-related comorbidities in both patients with Dravet and non-Dravet syndromes. METHODS: A cohort of 164 Dutch participants with SCN1A-related seizures was evaluated, consisting of 116 patients with Dravet syndrome and 48 patients with either GEFS+, febrile seizures plus (FS+), or FS. Clinical data were collected from medical records, semi-structured telephone interviews, and three questionnaires: the Functional Mobility Scale (FMS), the Pediatric Quality of Life Inventory (PedsQL) Measurement Model, and the Child or Adult Behavior Checklists (CBCL/ABCL). RESULTS: Walking disabilities and severe behavioral problems affect 71% and 43% of patients with Dravet syndrome respectively and are almost never present in patients with non-Dravet syndromes. These comorbidities are strongly correlated to lower quality-of-life (QoL) scores. Less severe comorbidities occur in patients with non-Dravet syndromes: learning problems and psychological/behavioral problems are reported for 27% and 38% respectively. The average QoL score of the non-Dravet group was comparable with that of the general population. The majority of patients with non-Dravet syndromes becomes seizure-free after 10 years of age (85%). CONCLUSIONS: Severe behavioral problems and walking disabilities are common in patients with Dravet syndrome and should receive specific attention during clinical management. Although the epilepsy course of patients with non-Dravet syndromes is much more favorable, milder comorbidities frequently occur in this group as well. Our results may be of great value for clinical care and informing newly diagnosed patients and their parents about prognosis.


Assuntos
Epilepsias Mioclônicas/epidemiologia , Epilepsias Mioclônicas/genética , Epilepsia/epidemiologia , Epilepsia/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Estudos Transversais , Epilepsias Mioclônicas/diagnóstico , Epilepsia/diagnóstico , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/epidemiologia , Síndromes Epilépticas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos , Convulsões Febris/diagnóstico , Convulsões Febris/epidemiologia , Convulsões Febris/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/epidemiologia , Espasmos Infantis/genética , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
14.
Epilepsy Behav ; 90: 217-227, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578097

RESUMO

OBJECTIVE: Behavior problems in Dravet syndrome (DS) are common and can impact the lives of patients tremendously. The current study aimed to give more insight into (1) the prevalence of a wide range of specific behavior difficulties and aspects of health-related quality of life (HRQoL) in patients with DS compared with the general population (gp) and patients with epilepsy without DS, (2) the relations between these behavior problems and different aspects of HRQoL, and (3) the associations between seizure frequency, cognitive impairment (CI), behavior problems, and HRQoL, based on a conceptual model. METHODS: One hundred and sixteen patients (aged between 2 and 67 years), affected by SCN1A-related seizures, were included in the study. Eighty-five were patients with DS, 31 were patients with epilepsy without DS. Behavior problems were measured using the Child/Adult Behavior Checklist (C/ABCL), HRQoL was measured using the Pediatric Quality of Life Inventory (PedsQL) Measurement Model. Other characteristics were obtained by clinical assessments, medical records, and semi-structured telephone interviews with parents. Comparisons between patients with DS, patients without DS, and the gp were calculated by the exact goodness of fit χ2 analyses, relations between subscales were analyzed using Pearson's correlations, and the conceptual model was tested in a path analysis. RESULTS: (1) Patients with DS show significantly more behavior problems compared with the gp and patients with epilepsy without DS. A total of 56.5% of patients with DS scored in the borderline and clinical ranges for total behavior problems. Problems with attention were most prevalent; 62.3% of patients with DS scored in the borderline and clinical ranges. Health-related quality of life was significantly lower for patients with DS compared with the gp and patients without DS. Physical and social functioning scores were especially low and decreased even more in the older age categories. (2) Problems with attention, aggression, and withdrawn behavior were most related to social functioning. Somatic problems and anxiety/depression were most related to emotional functioning. (3) Cognitive impairment and behavior problems were both independent predictors of poorer HRQoL in patients with DS, with behavior problems being the strongest predictor. Seizure frequency was only indirectly related to HRQoL, mediated by cognitive impairment. IMPLICATIONS: The high prevalence of behavior problems in DS and the significant impact on quality of life (QoL), independent of epilepsy-related factors, emphasize the need for active management and treatment of these problems and should be considered as part of the management plan.


Assuntos
Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/psicologia , Comportamento Problema/psicologia , Qualidade de Vida/psicologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Depressão/diagnóstico , Depressão/genética , Depressão/psicologia , Epilepsias Mioclônicas/diagnóstico , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/psicologia , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/genética , Síndromes Epilépticas/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Síndrome de Rett/psicologia , Convulsões/diagnóstico , Convulsões/genética , Convulsões/psicologia , Ajustamento Social , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Espasmos Infantis/psicologia , Inquéritos e Questionários , Adulto Jovem
15.
Neuroscience ; 398: 1-11, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30529264

RESUMO

Dravet syndrome (DS) is a disease that is primarily caused by the inactivation of the SCN1A-encoded voltage-gated sodium channel alpha subunit (Nav1.1). In this study, we constructed an SCN1A gene knockout model using CRISPR/Cas9 genome editing technology to deprive the Nav1.1 function in vitro. With mRNA-seq analysis we found abundant gene changes after SCN1A knockout, which associated with various signaling pathways, such as cancer pathways, the PI3K-AKT signaling pathway, the MAPK signaling pathway, and pathways involved in HTLV-I infection. We also noticed changes in the spliceosome, decreased glycolytic capacity, disturbances in calcium signaling pathways, and changes in the potassium, sodium, chloride, and calcium plasma channels after SCN1A knockout. In this study, we have been the first time to discover these changes and summarize them here and hope it would provide some clue for the study of Nav1.1 in the nervous system.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Técnicas de Inativação de Genes , Canal de Sódio Disparado por Voltagem NAV1.1/deficiência , Animais , Linhagem Celular , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/metabolismo , Expressão Gênica , Técnicas de Inativação de Genes/métodos , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Transdução de Sinais
16.
Medicine (Baltimore) ; 97(50): e13565, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30558019

RESUMO

Dravet syndrome is considered to be one of the most severe types of genetic epilepsy. Mutations in SCN1A gene have been found to be responsible for at least 80% of patients with Dravet syndrome, and 90% of these mutations arise de novo. The variable clinical phenotype is commonly observed among these patients with SCN1A mutations, suggesting that genetic modifiers may influence the phenotypic expression of Dravet syndrome. In the present study, we described the clinical, pathological, and molecular characteristics of 13 Han Chinese pedigrees clinically diagnosed with Dravet syndrome. By targeted-exome sequencing, bioinformatics analysis and Sanger sequencing verification, 11 variants were identified in SCN1A gene among 11 pedigrees including 7 missense mutations, 2 splice site mutations, and 2 frameshift mutations (9 novel variants and 2 reported mutations). Particularly, 2 of these Dravet syndrome patients with SCN1A variants also harbored SCN9A, KCNQ2, or SLC6A8 variants. In addition, 2 subjects were failed to detect any pathogenic mutations in SCN1A and other epilepsy-related genes. These data suggested that SCN1A variants account for about 84.6% of Dravet syndrome in our cohort. This study expanded the mutational spectrum for the SCN1A gene, and also provided clinical and genetic evidence for the hypothesis that genetic modifiers may contribute to the variable manifestation of Dravet syndrome patients with SCN1A mutations. Thus, targeted-exome sequencing will make it possible to detect the interactions of epilepsy-related genes and reveal their modification on the severity of SCN1A mutation-related Dravet syndrome.


Assuntos
Epilepsias Mioclônicas/genética , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Linhagem , Análise de Sequência/métodos , Grupo com Ancestrais do Continente Asiático/genética , Pré-Escolar , China , Feminino , Mutação da Fase de Leitura/genética , Humanos , Lactente , Canal de Potássio KCNQ2/genética , Masculino , Mutação de Sentido Incorreto/genética , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Isoformas de Proteínas/genética
17.
Am J Hum Genet ; 103(6): 1022-1029, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30526861

RESUMO

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs.1-3 This suggests that unknown genetic etiologies exist, potentially in the ∼98% of human genomes not covered by exome sequencing (ES). Here we describe seven likely pathogenic variants in regions outside of the annotated coding exons of the most frequently implicated epilepsy gene, SCN1A, encoding the alpha-1 sodium channel subunit. We provide evidence that five of these variants promote inclusion of a "poison" exon that leads to reduced amounts of full-length SCN1A protein. This mechanism is likely to be broadly relevant to human disease; transcriptome studies have revealed hundreds of poison exons,4,5 including some present within genes encoding other sodium channels and in genes involved in neurodevelopment more broadly.6 Future research on the mechanisms that govern neuronal-specific splicing behavior might allow researchers to co-opt this system for RNA therapeutics.


Assuntos
Epilepsias Mioclônicas/genética , Epilepsia/genética , Éxons/genética , Variação Genética/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/genética , Canais de Sódio/genética , Transcriptoma/genética
18.
Epileptic Disord ; 20(4): 279-282, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30078784

RESUMO

Hyperekplexia is a rare neurogenetic disorder characterized by startle. Accurate diagnosis of this notorious mimicker of epilepsy is important to prevent life-threatening apnoea. We report a novel case of concomitant GLRA1-related hyperkeplexia and myoclonic epilepsy. A toddler with daily paroxysms of head drops and falls presented with epileptic myoclonus on EEG, however, whole-exome sequencing revealed hyperekplexia-related GLRA1 mutation. The boy eventually developed spells induced by noise and surprise. All his spells remitted upon treatment with clonazepam. Paediatricians and paediatric neurologists should be aware of this possible mixed presentation in order to appropriately tailor medication regimens and treatment goals. [Published with video sequence on www.epilepticdisorders.com].


Assuntos
Epilepsias Mioclônicas/diagnóstico , Hiperecplexia/diagnóstico , Receptores da Glicina/genética , Epilepsias Mioclônicas/genética , Humanos , Hiperecplexia/genética , Lactente , Masculino
19.
Proc Natl Acad Sci U S A ; 115(34): E8077-E8085, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30076230

RESUMO

Dravet syndrome is a catastrophic, pharmacoresistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of SCN1A, which encodes the voltage-gated sodium channel NaV1.1. Brain NaV1.1 is primarily localized to fast-spiking inhibitory interneurons; thus the mechanism of epileptogenesis in Dravet syndrome is hypothesized to be reduced inhibitory neurotransmission leading to brain hyperexcitability. We show that selective activation of NaV1.1 by venom peptide Hm1a restores the function of inhibitory interneurons from Dravet syndrome mice without affecting the firing of excitatory neurons. Intracerebroventricular infusion of Hm1a rescues Dravet syndrome mice from seizures and premature death. This precision medicine approach, which specifically targets the molecular deficit in Dravet syndrome, presents an opportunity for treatment of this intractable epilepsy.


Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Interneurônios/metabolismo , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Venenos de Aranha/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Células CHO , Cricetulus , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/metabolismo , Epilepsias Mioclônicas/patologia , Células HEK293 , Humanos , Interneurônios/patologia , Camundongos , Camundongos Mutantes , Canal de Sódio Disparado por Voltagem NAV1.1/genética
20.
Seizure ; 60: 68-70, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29929108

RESUMO

Dravet syndrome is a terrible disease generally caused by mutations of the SCN1A gene. Recently others genes such as STXBP1 have been involved in the pathogenesis of the disease. The STXBP1 mutation in patients with Dravet Syndrome may additionally causes several parkinsonian features usually attributed to carriers of the SCN1A mutation. Management continues to be difficult that is why Cannabidiol emerged as valid option for treatment of this condition.


Assuntos
Anticonvulsivantes/uso terapêutico , Canabidiol/uso terapêutico , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/genética , Proteínas Munc18/genética , Mutação , Encéfalo/fisiopatologia , Quimioterapia Combinada , Epilepsias Mioclônicas/fisiopatologia , Feminino , Humanos , Fenótipo , Adulto Jovem
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