• EEG microstates
• IESS etiology
• Infantile epileptic spasm syndrome (IESS)
• Machine learning
• West syndrome

• Humans
• Spasms, Infantile/physiopathology
• Spasms, Infantile/diagnosis
• Male
• Electroencephalography/methods
• Female
• Infant
• Nerve Net/physiopathology
• Brain/physiopathology
• Child, Preschool
• Case-Control Studies

• 2021R1G1A1094236 National Research Foundation of Korea
• RS-2020-KH096139 Ministry of Health and Welfare

• N‐methyl‐D‐aspartate receptors
• child‐hood epilepsy
• electrophysiological studies
• genetics

• Humans
• Receptors, N-Methyl-D-Aspartate/genetics
• Female
• Phenotype
• Male
• Epilepsy/genetics
• Mutation, Missense
• Adult
• Exome Sequencing
• Electroencephalography
• Child
• Adolescent

• 2017YFC0907702, 2021YFC2501401 the National Key Research and Development Program
• 82371461 the National Natural Science Foundation of China

• grin2a mutation
• limbic encephalopathy
• neuropsychiatric disorders
• nmda receptor
• progressive cognitive decline

• CSWS
• ESES
• Landau–Kleffner syndrome
• epilepsy
• epileptic encephalopathies

• GABA receptor
• Glutamate receptor
• Haloperidol
• Pregnant

• centrotemporal spike
• electrical status epilepticus in sleep
• epilepsy progress
• epileptic transformation of system networks
• role of NREM graphoelements
• self-limited epilepsy spectrum

GRIN2A is associated with epilepsy (EP); however, its regulatory mechanism involving upstream miRNA (miR-30b-5p) has been overlooked. In this study, we aimed to identify the regulatory mechanism of the miR-30b-5p/GRIN2A axis in EP. Hippocampal neurons isolated from mice were incubated in magnesium-free medium for 48 h to establish an in vitro EP model. An in vivo model of EP was constructed by the intraperitoneal injection of atropine into mice. Nissl staining and hematoxylin and eosin staining were used to evaluate pathological injuries in the hippocampal CA1 regions of mice. The CCK8 assay confirmed that miR-30b-5p overexpression restored the suppressed proliferative capacity of hippocampal neurons exposed to magnesium-free conditions. Caspase-3 activity assay revealed that miR-30b-5p overexpression abrogated the increased apoptosis of hippocampal neurons under magnesium-free conditions. In an in vivo model of EP, miR-30b-5p overexpression reversed pathological injuries in the hippocampal CA1 regions of mice and abrogated the increased apoptosis in the EP mouse model. Luciferase assays and western blotting confirmed that miR-30b-5p targeted GRIN2A, thereby inhibiting GRIN2A expression. Overall, miR-30b-5p can protect against cell proliferation and attenuate apoptosis in hippocampal neurons under magnesium-free conditions by targeting GRIN2A.

• epilepsy
• mirna
• targeting
• proliferation

Dominant mutations in the human gene GRIN2A, encoding NMDA receptor (NMDAR) subunit GluN2A, make a significant and growing contribution to the catalogue of published single-gene epilepsies. Understanding the disease mechanism in these epilepsy patients is complicated by the surprising diversity of effects that the mutations have on NMDARs. Here we have examined the cell-autonomous effect of five GluN2A mutations, 3 loss-of-function and 2 gain-of-function, on evoked NMDAR-mediated synaptic currents (NMDA-EPSCs) in CA1 pyramidal neurons in cultured hippocampal slices. Despite the mutants differing in their functional incorporation at synapses, prolonged NMDA-EPSC current decays (with only marginal changes in charge transfer) were a common effect for both gain- and loss-of-function mutants. Modelling NMDA-EPSCs with mutant properties in a CA1 neuron revealed that the effect of GRIN2A mutations can lead to abnormal temporal integration and spine calcium dynamics during trains of concerted synaptic activity. Investigations beyond establishing the molecular defects of GluN2A mutants are much needed to understand their impact on synaptic transmission.

The cell-autonomous effect of five severe loss- or gain-of-function GluN2A (NMDA receptor) mutations is assessed on evoked NMDAR-mediated synaptic currents in CA1 pyramidal neurons in cultured mouse hippocampal slices. Data and modelling suggest that mutant-like NMDA-EPSCs can lead to abnormal temporal summation and spine calcium dynamics.

• NMDA
• VUS
• dominant negative

• Autism Spectrum Disorder
• Epilepsy/genetics
• Humans
• N-Methylaspartate/genetics
• Phenotype
• Receptors, N-Methyl-D-Aspartate/genetics

• K01 ES025435 NIEHS NIH HHS

Objective: The objective of this study is to explore the role of GRIN2A gene in idiopathic generalized epilepsies and the potential underlying mechanism for phenotypic variation.

Methods: Whole-exome sequencing was performed in a cohort of 88 patients with idiopathic generalized epilepsies. Electro-physiological alterations of the recombinant N-methyl-D-aspartate receptors (NMDARs) containing GluN2A mutants were examined using two-electrode voltage-clamp recordings. The alterations of protein expression were detected by immunofluorescence staining and biotinylation. Previous studies reported that epilepsy related GRIN2A missense mutations were reviewed. The correlation among phenotypes, functional alterations, and molecular locations was analyzed.

Results: Three novel heterozygous missense GRIN2A mutations (c.1770A > C/p.K590N, c.2636A > G/p.K879R, and c.3199C > T/p.R1067W) were identified in three unrelated cases. Electrophysiological analysis demonstrated R1067W significantly increased the current density of GluN1/GluN2A NMDARs. Immunofluorescence staining indicated GluN2A mutants had abundant distribution in the membrane and cytoplasm. Western blotting showed the ratios of surface and total expression of the three GluN2A-mutants were significantly increased comparing to the wild type. Further analysis on the reported missense mutations demonstrated that mutations with severe gain-of-function were associated with epileptic encephalopathy, while mutations with mild gain of function were associated with mild phenotypes, suggesting a quantitative correlation between gain-of-function and phenotypic severity. The mutations located around transmembrane domains were more frequently associated with severe phenotypes and absence seizure-related mutations were mostly located in carboxyl-terminal domain, suggesting molecular sub-regional effects.

Significance: This study revealed GRIN2A gene was potentially a candidate pathogenic gene of idiopathic generalized epilepsies. The functional quantitative correlation and the molecular sub-regional implication of mutations helped in explaining the relatively mild clinical phenotypes and incomplete penetrance associated with GRIN2A variants.

• GRIN2A gene
• N-methyl-D-aspartate receptors
• gain of function
• idiopathic generalized epilepsy
• sub-regional effect

• Colombia
• Rolandic epilepsy
• clinical features
• comorbidities
• genetic association

• Dravet syndrome
• Early infantile epilepsy
• Epilepsy phenotype
• Epilepsy syndromes
• GLUT-1 deficiency
• Nonketotic hyperglycinemia
• Precision medicine in epilepsy

Glutamate, the major excitatory neurotransmitter, plays a ubiquitous role in most aspects of normal brain functioning. Its indispensable position is paradoxically doubled by a high excitotoxic potential following disruption of its dynamic equilibrium. Several lines of evidence have suggested the involvement of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) in learning, memory formation, and human cognition. Furthermore, NMDARs play a pivotal role in various neuropsychiatric disorders, recently being identified as an important locus for disease-associated genomic variation. The GRIN2A gene encodes the NMDAR’s GluN2A subunit. Genetic alterations of GRIN2A result in phenotypic pleiotropy, predisposing to a broad range of epilepsy syndromes, with an elusive and unpredictable evolution and response to treatment. The archetypal GRIN2A-related phenotype comprises the idiopathic focal epilepsies (IFEs), with a higher incidence of GRIN2A mutants among entities at the more severe end of the spectrum. We report the case of a patient heterozygous for GRIN2A, c.1081C>T, presenting with febrile convulsions and later superimposed atonic seizures, expressive language delay, and macrocephaly. As the number of reported GRIN2A variants is continuously increasing, the phenotypic boundaries gradually grow faint. Therefore, it is fundamental to maintain an acute critical awareness of the possible genetic etiology of different epilepsy syndromes. So far, therapeutic strategies rely on empirical observations relating genotypes to specific drugs, but the overall success of treatment remains unpredictable. Deciphering the functional consequences of individual GRIN2A variants could lead to the development of precision therapeutic approaches for patients carrying NMDAR mutations.

• GRIN2A gene
• N-methyl-D-aspartate receptor (NMDAR)
• child
• genetic epilepsy

Recently, the electroencephalogram pattern of electrical status epilepticus during sleep (ESES) had been reported in some genetic disorders, and most of them were noted with developmental and epileptic encephalopathy (DEE) or epileptic encephalopathy (EE). This study aimed to determine the genetic etiologies and clinical characteristics of ESES in DEE/EE.

We performed a cohort study in cases of DEE or EE with ESES. Tio-based genetic testing was performed in 74 cases and was analyzed to identify underlying variants.

Pathogenic or likely pathogenic variants were identified in 17/74 cases, including KCNQ2 (n = 6), KCNA2 (n = 5), GRIN2A (n = 3), SLC9A6 (n = 1), HIVEP2 (n = 1), and RARS2 (n = 1). Eleven were boys. The median age at seizure onset was 6 months. ESES occurred at the mean age of 2.0 ± 1.2 years, predominant in the Rolandic region in 14 years. Twelve of 17 cases had the first stage of different epilepsy preceding ESES: 2/12 were diagnosed as Ohtahara syndrome, 2/12 were diagnosed as infantile spasms, 3/12 were diagnosed as DEE, and 5/12 were diagnosed as EE without the epileptic syndrome.

Monogenic variants explained over 20% of DEE/EE with ESES. ESES could be an age-related feature in genetic disorders and occurred after the first stage of different epilepsy. Both age-related factors and genetic etiology were suggested to play a role in the occurrence of ESES in genetic DEE/EE.

• electrical status epilepticus during sleep
• encephalopathy
• epilepsy
• etiology
• genetic

• cognitive impairment
• electroencephalogram
• encephalopathy related to status epilepticus during slow sleep
• status epilepticus during sleep
• treatment

• BECTS
• CECTS
• DTI
• diffusion tensor imaging
• probabilistic tractography

• C-terminal domain
• GRIN1
• GRIN2A
• GRIN2B
• GRIN2C
• GRIN2D
• NMDA receptor
• amino-terminal domain
• gating hinge
• ligand-binding domain
• pre-active
• pre-gating
• precision medicine
• transmembrane domain

• Epilepsy
• GRIN2A
• human induced pluripotent stem cells

• Excitotoxicity
• NMDA receptor
• Neurodegeneration
• Parkinson's disease
• glutamate ionotropic receptor NMDA type subunit 2A
• rs4998386 polymorphism

The mutation in CNKSR2 leads to a broad spectrum of phenotypic variability and manifests as an X-linked intellectual disability. However, we reported that the male patient in this study not only had intellectual disability but also epileptic seizures. In addition, there were progressive language impairment, attention deficit hyperactivity disorder and autism. Electroencephalograms showed continuous spike-and-wave during sleep. Genetic testing revealed a de novo mutation of the CNKSR2 gene (c.2185C>T, p.Arg729Ter) in the child that was not detected in the parents. Therefore, the child was diagnosed with X-linked epilepsy aphasia syndrome. Deletion of the CNKSR2 gene has been rarely reported in epilepsy aphasia syndrome, but no de novo mutation has been found in this gene. This report not only adds to the spectrum of epilepsy aphasia syndrome but also helps clinicians in diagnosis and genetic counseling.

• Epilepsy
• Language impairment
• Mental retardation
• De novo mutation of CNKSR2
• X-linked epilepsy-aphasia syndrome