RESUMO
OBJECTIVE: The epilepsy-aphasia spectrum (EAS) is a heterogeneous group of age-dependent childhood disorders characterized by sleep-activated discharges associated with infrequent seizures and language, cognitive, and behavioral deficits. Defects in the GRIN2A gene, encoding a subunit of glutamate-gated N-methyl-d-aspartate (NMDA) receptors, represent the most important cause of EAS identified so far. Neocortical or thalamic lesions were detected in a subset of severe EAS disorders, and more subtle anomalies were reported in patients with so-called "benign" phenotypes. However, whether brain structural alterations exist in the context of GRIN2A defects is unknown. METHODS: Magnetic resonance diffusion tensor imaging (MR-DTI) was used to perform longitudinal analysis of the brain at 3 developmental timepoints in living mice genetically knocked out (KO) for Grin2a. In addition, electroencephalography (EEG) was recorded using multisite extracellular electrodes to characterize the neocortical activity in vivo. RESULTS: Microstructural alterations were detected in the neocortex, the corpus callosum, the hippocampus, and the thalamus of Grin2a KO mice. Most MR-DTI alterations were detected at a specific developmental stage when mice were aged 30 days, but not at earlier (15 days) or later (2 months) ages. EEG analysis detected epileptiform discharges in Grin2a KO mice in the third postnatal week. SIGNIFICANCE: Grin2a KO mice replicated several anomalies found in patients with EAS disorders. Transient structural alterations detected by MR-DTI recalled the age-dependent course of EAS disorders, which in humans start during childhood and show variable outcome at the onset of adolescence. Together with the epileptiform discharges detected in young Grin2a KO mice, our data suggested the existence of early anomalies in the maturation of the neocortical and thalamocortical systems. Whereas the possible relationship of those anomalies with sleep warrants further investigations, our data suggest that Grin2a KO mice may serve as an animal model to study the neuronal mechanisms of EAS disorders and to design new therapeutic strategies.
Assuntos
Encéfalo/patologia , Síndrome de Landau-Kleffner/genética , Síndrome de Landau-Kleffner/patologia , Mutação/genética , Receptores de N-Metil-D-Aspartato/genética , Fatores Etários , Animais , Animais Recém-Nascidos , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Ondas Encefálicas/genética , Eletroencefalografia , Genótipo , Processamento de Imagem Assistida por Computador , Síndrome de Landau-Kleffner/diagnóstico por imagem , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/diagnóstico por imagem , Transtornos do Neurodesenvolvimento , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
OBJECTIVE: To detect potential mutations of the glutamate receptor subunit (GRIN2A) gene and delineate the clinical-genetic characteristics of patients with epilepsy-aphasia spectrum (EAS) disorders. METHODS: One hundred twenty two patients with Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS), benign childhood epilepsy with centrotemporal spikes (BECT) and BECT variants were recruited. Potential mutations of the GRIN2A gene were screened with Sanger sequencing. And clinical-genetic characteristics for all patients were analyzed. RESULTS: The patients have included 9 LKS, 26 CSWS, 42 BECT variants and 45 BECT. The mean age of onset of seizure or aphasia was 5 years old (10 months to 11 years). Mutation screening has detected 4 possible pathogenic missense mutations including c.2278G>A (p.G760S), c.4153G>T (p.D1385Y), c.1364G>A (p.C455Y) and c.691T>C (p.C231R) in four unrelated probands, which comprised one case with LKS and three with BECT variants. The mutation rate was 11.1% (1/9) for LKS and 7.2% (3/42) for BECT variants. No GRIN2A mutation was found in the 26 patients with CSWS and 45 patients with BECT. Among the 122 probands, 25 (20.5%) patients without a GRIN2A mutation had a positive family history of febrile seizures or epilepsy. CONCLUSION: GRIN2A mutation do exist in EAS patients, but with a relatively low rate. A proportion of EAS patients without a GRIN2A mutation have a positive family history, which suggested a complex mechanism for EAS.
Assuntos
Síndrome de Landau-Kleffner/genética , Mutação , Receptores de N-Metil-D-Aspartato/genética , Povo Asiático/genética , Criança , Pré-Escolar , China , Feminino , Humanos , Masculino , Mutação de Sentido Incorreto , LinhagemRESUMO
OBJECTIVE: To test whether mutations in γ-aminobutyric acid type A receptor (GABAA -R) subunit genes contribute to the etiology of rolandic epilepsy (RE) or its atypical variants (ARE). METHODS: We performed exome sequencing to compare the frequency of variants in 18 GABAA -R genes in 204 European patients with RE/ARE versus 728 platform-matched controls. Identified GABRG2 variants were functionally assessed for protein stability, trafficking, postsynaptic clustering, and receptor function. RESULTS: Of 18 screened GABAA -R genes, we detected an enrichment of rare variants in the GABRG2 gene in RE/ARE patients (5 of 204, 2.45%) in comparison to controls (1 of 723, 0.14%; odds ratio = 18.07, 95% confidence interval = 2.01-855.07, p = 0.0024, pcorr = 0.043). We identified a GABRG2 splice variant (c.549-3T>G) in 2 unrelated patients as well as 3 nonsynonymous variations in this gene (p.G257R, p.R323Q, p.I389V). Functional assessment showed reduced surface expression of p.G257R and decreased GABA-evoked currents for p.R323Q. The p.G257R mutation displayed diminished levels of palmitoylation, a post-translational modification crucial for trafficking of proteins to the cell membrane. Enzymatically raised palmitoylation levels restored the surface expression of the p.G257R variant γ2 subunit. INTERPRETATION: The statistical association and the functional evidence suggest that mutations of the GABRG2 gene may increase the risk of RE/ARE. Restoring the impaired membrane trafficking of some GABRG2 mutations by enhancing palmitoylation might be an interesting therapeutic approach to reverse the pathogenic effect of such mutants.
Assuntos
Epilepsia Rolândica/genética , Lipoilação/genética , Mutação/genética , Receptores de GABA-A/genética , Exoma , Feminino , Células HEK293 , Humanos , Síndrome de Landau-Kleffner/genética , Masculino , Linhagem , Síndrome , População Branca/genéticaRESUMO
Autism and epilepsy are two associated disorders that are highly prevalent, share common developmental origins, and demonstrate substantial heritability. In this review, cross-disciplinary data in a rapidly evolving field that bridges neurology and psychiatry are synthesized to identify shared biologic mechanisms. The relationship between these debilitating, lifelong conditions is examined at the clinical, genetic, and neurophysiologic levels in humans and in animal models. Scopus and PubMed searches were used to identify relevant literature. Clinical observations have prompted speculation about the interdependence of autism and epilepsy, but causal relationships have proved difficult to determine. Despite their heritability, the genetic basis of autism spectrum disorder (ASD) and epilepsy has remained largely elusive until the advent of next-generation sequencing. This approach has revealed that mutations that are either causal or confer an increased disease risk are found in numerous different genes, any one of which accounts for only a small percentage of cases. Conversely, even cases with identical clinical phenotypes can be genetically heterogeneous. Candidate gene identification has facilitated the development of mouse genetic models, which in parallel with human studies have implicated shared brain regions and circuits that mediate disease expression. Diverse genetic causes of ASD and epilepsy converge on cortical interneuron circuits as one important mediator of both disorders. Cortical interneurons are among the most diverse cell types in the brain and their unique chemical and electrical coupling exert a powerful inhibitory influence on excitatory neurons via the release of the neurotransmitter, γ-aminobutyric acid (GABA). These multifaceted approaches have validated theories derived from the field of developmental neurobiology, which propose that the neurologic and neuropsychiatric manifestations are caused by an altered ratio of excitation to inhibition in the cortex.
Assuntos
Transtorno do Espectro Autista/fisiopatologia , Córtex Cerebral/fisiopatologia , Epilepsia/fisiopatologia , Interneurônios/metabolismo , Síndrome de Aicardi/complicações , Síndrome de Aicardi/genética , Síndrome de Aicardi/fisiopatologia , Síndrome de Aicardi/psicologia , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/psicologia , Córtex Cerebral/metabolismo , Criança , Pré-Escolar , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Epilepsias Mioclônicas/psicologia , Epilepsia/complicações , Epilepsia/genética , Epilepsia/psicologia , Humanos , Lactente , Síndrome de Landau-Kleffner/complicações , Síndrome de Landau-Kleffner/genética , Síndrome de Landau-Kleffner/fisiopatologia , Síndrome de Landau-Kleffner/psicologia , Síndrome de Lennox-Gastaut/complicações , Síndrome de Lennox-Gastaut/genética , Síndrome de Lennox-Gastaut/fisiopatologia , Síndrome de Lennox-Gastaut/psicologia , Inibição Neural , Neurônios/metabolismo , Espasmos Infantis/complicações , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Espasmos Infantis/psicologia , Ácido gama-Aminobutírico/metabolismoRESUMO
OBJECTIVE: To establish the genetic basis of Landau-Kleffner syndrome (LKS) in a cohort of two discordant monozygotic (MZ) twin pairs and 11 isolated cases. METHODS: We used a multifaceted approach to identify genetic risk factors for LKS. Array comparative genomic hybridization (CGH) was performed using the Agilent 180K array. Whole genome methylation profiling was undertaken in the two discordant twin pairs, three isolated LKS cases, and 12 control samples using the Illumina 27K array. Exome sequencing was undertaken in 13 patients with LKS including two sets of discordant MZ twins. Data were analyzed with respect to novel and rare variants, overlapping genes, variants in reported epilepsy genes, and pathway enrichment. RESULTS: A variant (cG1553A) was found in a single patient in the GRIN2A gene, causing an arginine to histidine change at site 518, a predicted glutamate binding site. Following copy number variation (CNV), methylation, and exome sequencing analysis, no single candidate gene was identified to cause LKS in the remaining cohort. However, a number of interesting additional candidate variants were identified including variants in RELN, BSN, EPHB2, and NID2. SIGNIFICANCE: A single mutation was identified in the GRIN2A gene. This study has identified a number of additional candidate genes including RELN, BSN, EPHB2, and NID2. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Assuntos
Síndrome de Landau-Kleffner/genética , Adolescente , Adulto , Proteínas de Ligação ao Cálcio , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular Neuronais/genética , Criança , Hibridização Genômica Comparativa , Proteínas da Matriz Extracelular/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Receptor EphB2/genética , Receptores de N-Metil-D-Aspartato/genética , Proteína Reelina , Serina Endopeptidases/genética , Gêmeos Monozigóticos/genética , Adulto JovemRESUMO
PURPOSE: To characterize the frequency and nature of the family history of seizures in probands with epilepsy falling within the epilepsy-aphasia spectrum (EAS) in order to understand the genetic architecture of this group of disorders. METHODS: Patients with epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), Landau-Kleffner syndrome (LKS), atypical benign partial epilepsy (ABPE), and intermediate epilepsy-aphasia disorders (IEAD) were recruited. All affected and available unaffected relatives up to three degrees of relatedness underwent phenotyping using a validated seizure questionnaire. Pedigrees were constructed for all families. The proportion of affected relatives according to each degree of relatedness was calculated. The epilepsy phenotypes in close relatives were analyzed. The data were compared to the families of probands with benign childhood epilepsy with centrotemporal spikes (BECTS) using the same methodology. KEY FINDINGS: Thirty-one probands, including five ECSWS, three LKS, one ABPE, and 22 IEAD were recruited. The mean age of seizure onset was 3.9 (range 0.5-7) years. A male predominance was seen (68%, 21/31) . Sixteen (51.6%) of 31 had a positive family history of seizures. Among 1,254 relatives, 30 (2.4%) had a history of seizures: 13 (10.2%) of 128 first-degree relatives, 5 (1.7%) of 291 second-degree relatives, and 12 (1.4%) of 835 third-degree relatives. Thirteen had febrile seizures, including two who had both febrile seizures and epilepsy. Of the 19 relatives with epilepsy, 4 had BECTS, 4 epilepsies with focal seizures of unknown cause, 3 IEAD, and 7 unclassified. One had genetic generalized epilepsy. In the families of the BECTS probands, 9.8% of first-degree, 3% of second-degree, and 1.5% of third-degree relatives had seizures, which was not significantly different from the EAS cohort families. SIGNIFICANCE: The frequencies of seizures in relatives of probands with EAS suggest that the underlying genetic influence of EAS is consistent with complex inheritance and similar to BECTS. The phenotypic pattern observed in the affected relatives comprised predominantly febrile seizures and focal seizures. These findings suggest that a shared genetic predisposition to focal epilepsies underpins the epilepsy-aphasia spectrum.
Assuntos
Afasia/genética , Epilepsia/genética , Adolescente , Adulto , Idade de Início , Idoso , Austrália , Encéfalo/patologia , Criança , Pré-Escolar , Transtornos Cognitivos/genética , Transtornos Cognitivos/psicologia , Interpretação Estatística de Dados , Epilepsias Parciais/genética , Epilepsias Parciais/psicologia , Epilepsia/psicologia , Epilepsia Rolândica/genética , Epilepsia Rolândica/psicologia , Família , Feminino , Humanos , Lactente , Síndrome de Landau-Kleffner/genética , Síndrome de Landau-Kleffner/psicologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Linhagem , Convulsões Febris/complicações , Adulto JovemRESUMO
Language dysfunction is a common and serious comorbidity of epilepsy, especially in individuals with epilepsy aphasia spectrum syndromes. Childhood epilepsy with centrotemporal spikes is on the mild end of the spectrum, while epileptic encephalopathy with continuous spike-and-wave during sleep syndrome is on the severe end. Traditional antiseizure medicines and immunotherapy are currently used to treat severely affected patients, but the results are usually disappointing. The discovery that GRIN2A is the primary monogenic etiology of these diseases has opened the door to precision treatments. The GRIN2A gene encodes GluN2A protein, which constitutes a subunit of the NMDA receptor (NMDAR). The GRIN2A pathogenic variants cause gain or loss of function of NMDAR; the former can be treated with uncompetitive NMDAR antagonists, such as memantine, while the latter with NMDAR co-agonist serine. Hyper-precision therapies with various other effective agents are likely to be developed shortly to target the diverse functional effects of different variants. Precision treatments for GRIN2A-related disorders will benefit those who suffer from the condition and pave the way for new therapeutic approaches to a variety of other NMDAR-linked neurodegenerative and psychiatric diseases (schizophrenia, Parkinson's disease, Alzheimer's disease, and so on). Furthermore, more research into GRIN2A-related disorders will help us better understand the neuroinflammatory and neuroimmunological basis of epilepsy, as well as the pathological and physiological network activation mechanisms that cause sleep activation of central-temporal spikes and language impairment.
Assuntos
Afasia , Epilepsia , Síndromes Epilépticas , Síndrome de Landau-Kleffner , Humanos , Epilepsia/tratamento farmacológico , Epilepsia/genética , Síndrome de Landau-Kleffner/genética , Mutação , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Distúrbios da FalaRESUMO
PURPOSE: The continuous spike and waves during slow-wave sleep syndrome (CSWSS) and the Landau-Kleffner (LKS) syndrome are two rare epileptic encephalopathies sharing common clinical features including seizures and regression. Both CSWSS and LKS can be associated with the electroencephalography pattern of electrical status epilepticus during slow-wave sleep and are part of a clinical continuum that at its benign end also includes rolandic epilepsy (RE) with centrotemporal spikes. The CSWSS and LKS patients can also have behavioral manifestations that overlap the spectrum of autism disorders (ASD). An impairment of brain development and/or maturation with complex interplay between genetic predisposition and nongenetic factors has been suspected. A role for autoimmunity has been proposed but the pathophysiology of CSWSS and of LKS remains uncharacterized. METHODS: In recent years, the participation of rare genomic alterations in the susceptibility to epileptic and autistic disorders has been demonstrated. The involvement of copy number variations (CNVs) in 61 CSWSS and LKS patients was questioned using comparative genomic hybridization assays coupled with validation by quantitative polymerase chain reaction (PCR). KEY FINDINGS: Whereas the patients showed highly heterogeneous in genomic architecture, several potentially pathogenic alterations were detected. A large number of these corresponded to genomic regions or genes (ATP13A4, CDH9, CDH13, CNTNAP2, CTNNA3, DIAPH3, GRIN2A, MDGA2, SHANK3) that have been either associated with ASD for most of them, or involved in speech or language impairment, or in RE. Particularly, CNVs encoding cell adhesion proteins (cadherins, protocadherins, contactins, catenins) were detected with high frequency (≈20% of the patients) and significant enrichment (cell adhesion: p = 0.027; cell adhesion molecule binding: p = 9.27 × 10(-7)). SIGNIFICANCE: Overall our data bring the first insights into the possible molecular pathophysiology of CSWSS and LKS. The overrepresentation of cell adhesion genes and the strong overlap with the genetic, genomic and molecular ASD networks, provide an exciting and unifying view on the clinical links among CSWSS, LKS, and ASD.
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Potenciais de Ação/fisiologia , Transtorno Autístico/genética , Ligação Genética/fisiologia , Genômica , Síndrome de Landau-Kleffner/genética , Sono/fisiologia , Adolescente , Transtorno Autístico/diagnóstico , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Genômica/métodos , Humanos , Lactente , Síndrome de Landau-Kleffner/diagnóstico , Síndrome de Landau-Kleffner/fisiopatologia , MasculinoRESUMO
GRIN2A encodes for the 2A subunit of N-methyl-D-aspartate receptors. Pathogenic variants in GRIN2A have been associated with a wide spectrum of neurodevelopmental disorders ranging from speech disorders and/or self-limiting epilepsy (childhood epilepsy with centrotemporal spikes) to severe and disabling phenotypes (atypical childhood epilepsy with centrotemporal spikes, epileptic encephalopathy with continuous spike-wave during sleep, Landau-Kleffner syndrome and infantile-onset epileptic encephalopathy). Here we describe a family with two affected sisters with atypical childhood epilepsy with centrotemporal spikes and their mildly affected mother carrying a novel N-terminal null variant in GRIN2A gene. These familial cases corroborate previous studies showing that loss-of-function GRIN2A variants are associated with milder phenotypes, possibly due to haploinsufficiency.
Assuntos
Epilepsia , Síndrome de Landau-Kleffner , Criança , Eletroencefalografia , Epilepsia/genética , Humanos , Síndrome de Landau-Kleffner/genética , Mutação , Fenótipo , Receptores de N-Metil-D-Aspartato/genéticaRESUMO
Seizure disorders of the rolandic region comprise a spectrum of different epilepsy syndromes ranging from benign rolandic epilepsy to more severe seizure disorders including atypical benign partial epilepsy/pseudo-Lennox syndrome,electrical status epilepticus during sleep, and Landau-Kleffner syndrome. Centrotemporal spikes are the unifying electroencephalographic hallmark of these benign focal epilepsies, indicating a pathophysiologic relationship between the various epilepsies arising from the rolandic region. The etiology of these epilepsies is elusive, but a genetic component is assumed given the heritability of the characteristic electrographic trait. Herein we report on three patients with intellectual disability, various dysmorphic features, and epilepsies involving the rolandic region, carrying previously undescribed deletions in 16p13. The only gene located in the critical region shared by all three patients is GRIN2A coding for the alpha-2 subunit of the neuronal N-methyl-D-aspartate(NMDA) receptor.
Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 16/genética , Epilepsia Rolândica/genética , Epilepsia/genética , Deficiência Intelectual/genética , Deleção de Sequência/genética , Adulto , Idade de Início , Criança , Eletroencefalografia/estatística & dados numéricos , Epilepsias Parciais/genética , Humanos , Síndrome de Landau-Kleffner/genética , Fenótipo , Receptores de Glutamato/genética , Receptores de N-Metil-D-Aspartato/genética , Estado Epiléptico/genética , SíndromeRESUMO
Epilepsy is a frequent neurologic disease in childhood, characterized by recurrent seizures and sometimes with major effects on social, behavioral, and cognitive development. Childhood focal epilepsies particularly are age-related diseases mainly occurring during developmental critical periods. A complex interplay between brain development and maturation processes and susceptibility genes may contribute to the development of various childhood epileptic syndromes associated with language and cognitive deficits. Indeed, the Landau-Kleffner syndrome (LKS), the continuous spike-and-waves during sleep syndrome (CSWS), and the benign childhood epilepsy with centrotemporal spikes (BCECTS) or benign rolandic epilepsy, are different entities that are considered as part of a single continuous spectrum of disorders. Genetic predisposition with simple to complex modes of inheritance has long been suspected for this wide group of childhood focal epilepsies. Recent reports on the involvement of the SRPX2 and ELP4 genes with possible roles in cell motility, migration, and adhesion have provided first insights into the complex molecular bases of childhood focal epilepsies.
Assuntos
Epilepsias Parciais/genética , Epilepsia Rolândica/genética , Síndrome de Landau-Kleffner/genética , Transtornos Cognitivos/genética , Eletroencefalografia , Humanos , Proteínas de Membrana , Proteínas de Neoplasias , Proteínas do Tecido Nervoso/genética , Prognóstico , Sono/fisiologiaRESUMO
Formerly idiopathic, focal epilepsies (IFE) are self-limiting, "age-related" diseases that mainly occur during critical developmental periods. Childhood epilepsy with centrotemporal spikes, or Rolandic epilepsy (RE), is the most frequent form of IFE. Together with the Landau-Kleffner syndrome and the epileptic Encephalopathy related to Status Epilepticus during slow Sleep syndrome (ESES), RE is part of a single and continuous spectrum of childhood epilepsies and epileptic encephalopathies with acquired cognitive, behavioral and speech and/or language impairment, known as the epilepsy-aphasia spectrum (EAS). The pathophysiology has long been attributed to an elusive and complex interplay between brain development and maturation processes on the one hand, and susceptibility genes on the other hand. Studies based on the variable combination of molecular cytogenetics, Sanger and next-generation sequencing tools, and functional assays have led to the identification and validation of genetic mutations in the GRIN2A gene that can directly cause various types of EAS disorders. The recent identification of GRIN2A defects in EAS represents a first and major break-through in our understanding of the underlying pathophysiological mechanisms. In this review, we describe the current knowledge on the genetic architecture of IFE.
Assuntos
Afasia/genética , Epilepsia Rolândica/genética , Síndrome de Landau-Kleffner/genética , Mutação/genética , Receptores de N-Metil-D-Aspartato/genética , Criança , Eletroencefalografia/métodos , Humanos , Síndrome de Landau-Kleffner/diagnóstico , LinhagemRESUMO
OBJECTIVE: Epilepsy-aphasia spectrum (EAS) are a group of epilepsy syndromes denoting an association between epilepsy, speech disorders and the EEG signature of centrotemporal spikes. Mutations in the GRIN2A gene, encoding the NMDA glutamate receptor α2 subunit were reported in focal epilepsy with speech disorder. We aimed to explore the role of GRIN2A mutations in patients with centrotemporal spikes related epileptic syndromes in a Chinese cohort. METHODS: Patients with Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), atypical benign partial epilepsy (ABPE), and benign epilepsy with centrotemporal spikes (BECTS) were recruited. GRIN2A mutation screening was performed using PCR and Sanger sequencing. RESULTS: 122 patients, including 9 LKS, 26 ECSWS, 42 ABPE and 45 BECTS were enrolled. The mean age of seizure or aphasia onset was 5â¯years, ranging from 10â¯months to 11â¯years. Heterozygous GRIN2A mutations were detected in four patients (G760S, D1385Y, C455Y and C231R) GRIN2A mutation was found in 11.1% (1 out of 9 cases) of LKS, and in 7.1% (3 out of 42 cases) of ABPE, but in none with ECSWS and BECTS. No GRIN2A mutation was found in patients with a family history of febrile seizures or epilepsy. CONCLUSION: GRIN2A mutation is a genetic cause in less than 11% patients with LKS or ABPE. GRIN2A gene is a rare causative gene in Chinese patients with EAS, suggesting the possibility of other gene involved in the pathogenesis.
Assuntos
Saúde da Família , Predisposição Genética para Doença/genética , Síndrome de Landau-Kleffner/genética , Mutação/genética , Receptores de N-Metil-D-Aspartato/genética , Idade de Início , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletroencefalografia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
OBJECTIVE: N-methyl-D-aspartate receptors (NMDAR) subunit GRIN2A/GluN2A mutations have been identified in patients with various neurological diseases, such as epilepsy and intellectual disability / developmental delay (ID/DD). In this study, we investigated the phenotype and underlying molecular mechanism of a GRIN2A missense mutation identified by next generation sequencing on idiopathic focal epilepsy using in vitro electrophysiology. METHODS: Genomic DNA of patients with epilepsy and ID/DD were sequenced by targeted next-generation sequencing within 300 genes related to epilepsy and ID/DD. The effects of one missense GRIN2A mutation on NMDAR function were evaluated by two-electrode voltage clamp current recordings and whole cell voltage clamp current recordings. RESULTS: We identified one de novo missense GRIN2A mutation (Asp731Asn, GluN2A(D731N)) in a child with unexplained epilepsy and DD. The D731N mutation is located in a portion of the agonist-binding domain (ABD) in the GluN2A subunit, which is the binding pocket for agonist glutamate. This residue in the ABD is conserved among vertebrate species and all other NMDAR subunits, suggesting an important role in receptor function. The proband shows developmental delay as well as EEG-confirmed seizure activity. Functional analyses reveal that the GluN2A(D731N) mutation decreases glutamate potency by over 3,000-fold, reduces amplitude of current response, shortens synaptic-like response time course, and decreases channel open probability, while enhancing sensitivity to negative allosteric modulators, including extracellular proton and zinc inhibition. The combined effects reduce NMDAR function. SIGNIFICANCE: We identified a de novo missense mutation in the GRIN2A gene in a patient with childhood focal epilepsy and acquired epileptic aphasia. The mutant decreases NMDAR activation suggesting NMDAR hypofunction may contribute to the epilepsy pathogenesis.
Assuntos
Eletroencefalografia , Epilepsias Parciais , Síndrome de Landau-Kleffner , Potenciais da Membrana/genética , Mutação de Sentido Incorreto , Receptores de N-Metil-D-Aspartato , Substituição de Aminoácidos , Epilepsias Parciais/genética , Epilepsias Parciais/metabolismo , Epilepsias Parciais/fisiopatologia , Feminino , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndrome de Landau-Kleffner/genética , Síndrome de Landau-Kleffner/metabolismo , Síndrome de Landau-Kleffner/fisiopatologia , Masculino , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Epileptic encephalopathies are syndromes in which seizures or interictal epileptiform activity contribute to or exacerbate brain function, beyond that caused by the underlying pathology. These severe epilepsies begin early in life, are associated with poor lifelong outcome, and are resistant to most treatments. Therefore, they represent an immense challenge for families and the medical care system. Furthermore, the pathogenic mechanisms underlying the epileptic encephalopathies are poorly understood, hampering attempts to devise novel treatments. This article reviews animal models of the three classic epileptic encephalopathies-West syndrome (infantile spasms), Lennox-Gastaut syndrome, and continuous spike waves during sleep or Landau-Kleffner syndrome-with discussion of how animal models are revealing underlying pathophysiological mechanisms that might be amenable to targeted therapy.
Assuntos
Modelos Animais de Doenças , Síndrome de Landau-Kleffner , Síndrome de Lennox-Gastaut , Espasmos Infantis , Animais , Humanos , Lactente , Síndrome de Landau-Kleffner/genética , Síndrome de Landau-Kleffner/metabolismo , Síndrome de Landau-Kleffner/fisiopatologia , Síndrome de Lennox-Gastaut/genética , Síndrome de Lennox-Gastaut/metabolismo , Síndrome de Lennox-Gastaut/fisiopatologia , Espasmos Infantis/genética , Espasmos Infantis/metabolismo , Espasmos Infantis/fisiopatologiaRESUMO
Pediatric epileptic encephalopathies represent a clinically challenging and often devastating group of disorders that affect children at different stages of infancy and childhood. With the advances in genetic testing and neuroimaging, the etiologies of these epileptic syndromes are now better defined. The various encephalopathies that are reviewed in this article include the following: early infantile epileptic encephalopathy or Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West syndrome, severe myoclonic epilepsy in infancy (Dravet syndrome), Landau-Kleffner syndrome, Lennox-Gastaut syndrome, and epileptic encephalopathy with continuous spike-and-wave during sleep. Their clinical features, prognosis as well as underlying genetic etiologies are presented and updated.
Assuntos
Epilepsias Mioclônicas , Síndrome de Landau-Kleffner , Síndrome de Lennox-Gastaut , Espasmos Infantis , Epilepsias Mioclônicas/etiologia , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/fisiopatologia , Humanos , Lactente , Síndrome de Landau-Kleffner/etiologia , Síndrome de Landau-Kleffner/genética , Síndrome de Landau-Kleffner/fisiopatologia , Síndrome de Lennox-Gastaut/etiologia , Síndrome de Lennox-Gastaut/genética , Síndrome de Lennox-Gastaut/fisiopatologia , Espasmos Infantis/etiologia , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologiaRESUMO
In this article, we review the treatment options for the pediatric epileptic encephalopathies and provide an update on the new and emerging therapies targeted at the underlying pathophysiology of many of these syndromes. We illustrate how the identification of the specific genetic and autoimmune causes has made possible the evaluation and development of novel, better targeted therapies, as and at times, avoidance of potentially offending agents.
Assuntos
Anticonvulsivantes/farmacologia , Epilepsias Mioclônicas/tratamento farmacológico , Síndrome de Landau-Kleffner/tratamento farmacológico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Espasmos Infantis/tratamento farmacológico , Anticonvulsivantes/administração & dosagem , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/imunologia , Humanos , Lactente , Síndrome de Landau-Kleffner/genética , Síndrome de Landau-Kleffner/imunologia , Síndrome de Lennox-Gastaut/genética , Síndrome de Lennox-Gastaut/imunologia , Espasmos Infantis/genética , Espasmos Infantis/imunologiaRESUMO
Epileptic encephalopathies represent a group of devastating epileptic disorders that occur early in life and are often characterized by pharmaco-resistant epilepsy, persistent severe electroencephalographic abnormalities, and cognitive dysfunction or decline. Next generation sequencing technologies have increased the speed of gene discovery tremendously. Whereas ion channel genes were long considered to be the only significant group of genes implicated in the genetic epilepsies, a growing number of non-ion-channel genes are now being identified. As a subgroup of the genetically mediated epilepsies, epileptic encephalopathies are complex and heterogeneous disorders, making diagnosis and treatment decisions difficult. Recent exome sequencing data suggest that mutations causing epileptic encephalopathies are often sporadic, typically resulting from de novo dominant mutations in a single autosomal gene, although inherited autosomal recessive and X-linked forms also exist. In this review we provide a summary of the key features of several early- and mid-childhood onset epileptic encephalopathies including Ohtahara syndrome, Dravet syndrome, Infantile spasms and Lennox Gastaut syndrome. We review the recent next generation sequencing findings that may impact treatment choices. We also describe the use of conventional and newer anti-epileptic and hormonal medications in the various syndromes based on their genetic profile. At a biological level, developments in cellular reprogramming and genome editing represent a new direction in modeling these pediatric epilepsies and could be used in the development of novel and repurposed therapies.
Assuntos
Encéfalo/fisiopatologia , Epilepsia/genética , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/terapia , Epilepsia/diagnóstico , Epilepsia/terapia , Humanos , Lactente , Recém-Nascido , Síndrome de Landau-Kleffner/diagnóstico , Síndrome de Landau-Kleffner/genética , Síndrome de Landau-Kleffner/terapia , Síndrome de Lennox-Gastaut/diagnóstico , Síndrome de Lennox-Gastaut/genética , Síndrome de Lennox-Gastaut/terapia , Análise de Sequência de DNA , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Espasmos Infantis/terapiaRESUMO
Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes. We identified four probands with GRIN2A variants that segregated with the disorder in their families. Notably, all four families presented with EAS, accounting for 9% of epilepsy-aphasia cases. We did not detect pathogenic variants in GRIN2A in other epileptic encephalopathies (n = 475) nor in probands with benign childhood epilepsy with centrotemporal spikes (n = 81). We report the first monogenic cause, to our knowledge, for EAS. GRIN2A mutations are restricted to this group of cases, which has important ramifications for diagnostic testing and treatment and provides new insights into the pathogenesis of this debilitating group of conditions.