RARE DISEASE
Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
Drug discovery
0
drugs
With orphan designations
Overview
Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation is a rare neurodevelopmental disorder characterized by severe, often intractable epilepsy (focal/generalized seizures), global developmental delay, and varying degrees of intellectual disability. Pathogenic variants in GRIN2A disrupt NMDA receptor function, leading to hyperexcitability and synaptic dysfunction. Brain MRI may show progressive parenchymal volume loss and a thin corpus callosum. Speech disorders (e.g., apraxia) and EEG abnormalities (e.g., centrotemporal spikes) are common, with phenotypes spanning the epilepsy-aphasia spectrum [1][5][14].
Therapies
Antiseizure medications: Polytherapy (e.g., sodium channel blockers) for refractory seizures [5].
Targeted agents: NMDA receptor antagonists (e.g., memantine) improve seizure burden in gain-of-function variants [3][8].
Emerging therapies: NMDA modulators (e.g., L-serine, radiprodil) in clinical trials [10].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
10 drug discovery papers about Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
10 drug discovery papers about Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2023-06-02 | GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics
N-methyl-D-aspartate receptors (NMDARs) play essential roles in vital aspects of brain functions. NMDARs mediate clinical features of neurological diseases and thus, represent a potential therapeutic target for their treatments. Many findings implicated the GluN2B subunit of NMDARs in various neurological disorders including epilepsy, ischemic brain damage, and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's chorea, and amyotrophic lateral sclerosis. Although a large amount of information is growing consistently on the importance of GluN2B subunit, however, limited recent data is available on how subunit-selective ligands impact NMDAR functions, which blunts the ability to render the diagnosis or craft novel treatments tailored to patients. To bridge this gap, we have focused on and summarized recently reported GluN2B selective ligands as emerging subunit-selective antagonists and modulators of NMDAR. Herein, we have also presented an overview of the structure-function relationship for potential GluN2B/NMDAR ligands with their binding sites and connection to CNS functionalities. Understanding of design rules and roles of GluN2B selective compounds will provide the link to medicinal chemists and neuroscientists to explore novel neurotherapeutic strategies against dysfunctions of glutamatergic neurotransmission.
2021-08-19 | Application of Trio-Whole Exome Sequencing in Genetic Diagnosis and Therapy in Chinese Children With Epilepsy
Epilepsy is one of the most common neurological disorders in pediatric patients with other underlying neurological defects. Identifying the underlying etiology is crucial for better management of the disorder. We performed trio-whole exome sequencing in 221 pediatric patients with epilepsy. Probands were divided into seizures with developmental delay/intellectual disability (DD/ID) and seizures without DD/ID groups. Pathogenic (P) or likely pathogenic (LP) variants were identified in 71/110 (64.5%) patients in the seizures with DD/ID group and 21/111 (18.9%) patients in the seizures without DD/ID group ( P < 0.001). Eighty-seven distinct P/LP single nucleotide variants (SNVs)/insertion deletions (Indels) were detected, with 55.2% (48/87) of them being novel. All aneuploidy and P/LP copy number variants (CNVs) larger than 100 Kb were identifiable by both whole-exome sequencing and copy number variation sequencing (CNVseq) in 123 of individuals (41 pedigrees). Ten of P/LP CNVs in nine patients and one aneuploidy variant in one patient (Patient #56, #47, XXY) were identified by CNVseq. Herein, we identified seven genes ( NCL , SEPHS2 , PA2G4 , SLC35G2 , MYO1C , GPR158 , and POU3F1 ) with de novo variants but unknown pathogenicity that were not previously associated with epilepsy. Potential effective treatment options were available for 32 patients with a P/LP variant, based on the molecular diagnosis. Genetic testing may help identify the molecular etiology of early onset epilepsy and DD/ID and further aid to choose the appropriate treatment strategy for patients.
2020-04-23 | Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice
NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in GRIN2A encoding the GluN2A subunit are associated with a spectrum of disorders, ranging from mild speech and language delay to intractable neurodevelopmental disorders, including but not limited to developmental and epileptic encephalopathy. A de novo missense variant, p.Ser644Gly, was identified in a child with this disorder, and Grin2a knock-in mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibited altered hippocampal morphology at 2 weeks of age, and all homozygotes exhibited lethal tonic-clonic seizures by mid-third week. Heterozygous adults displayed susceptibility to induced generalized seizures, hyperactivity, repetitive and reduced anxiety behaviours, plus several unexpected features, including significant resistance to electrically-induced limbic seizures and to pentylenetetrazole induced tonic-clonic seizures. Multielectrode recordings of neuronal networks revealed hyperexcitability and altered bursting and synchronicity. In heterologous cells, mutant receptors had enhanced NMDA receptor agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. NMDA receptor-mediated synaptic currents in heterozygous hippocampal slices also showed a prolonged deactivation time course. Standard anti-epileptic drug monotherapy was ineffective in the patient. Introduction of NMDA receptor antagonists was correlated with a decrease in seizure burden. Chronic treatment of homozygous mouse pups with NMDA receptor antagonists significantly delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of using multiple experimental modalities to model and test therapies for severe neurodevelopmental disorders, while revealing significant biological complexities associated with GRIN2A developmental and epileptic encephalopathy.
2019-11-20 | Distinct roles of GRIN2A and GRIN2B variants in neurological conditions
Rapid advances in sequencing technology have led to an explosive increase in the number of genetic variants identified in patients with neurological disease and have also enabled the assembly of a robust database of variants in healthy individuals. A surprising number of variants in the GRIN genes that encode N-methyl-D-aspartate (NMDA) glutamatergic receptor subunits have been found in patients with various neuropsychiatric disorders, including autism spectrum disorders, epilepsy, intellectual disability, attention-deficit/hyperactivity disorder, and schizophrenia. This review compares and contrasts the available information describing the clinical and functional consequences of genetic variations in GRIN2A and GRIN2B. Comparison of clinical phenotypes shows that GRIN2A variants are commonly associated with an epileptic phenotype but that GRIN2B variants are commonly found in patients with neurodevelopmental disorders. These observations emphasize the distinct roles that the gene products serve in circuit function and suggest that functional analysis of GRIN2A and GRIN2B variation may provide insight into the molecular mechanisms, which will allow more accurate subclassification of clinical phenotypes. Furthermore, characterization of the pharmacological properties of variant receptors could provide the first opportunity for translational therapeutic strategies for these GRIN-related neurological and psychiatric disorders.
2019-06-20 | The human NMDA receptor GluN2AN615K variant influences channel blocker potency.
Abstract N ‐methyl‐D‐aspartate (NMDA) receptors are glutamate receptors with key roles in synaptic plasticity, due in part to their Mg 2+ mediated voltage‐dependence. A large number of genetic variants affecting NMDA receptor subunits have been found in people with a range of neurodevelopmental disorders, including GluN2A N615K ( GRIN2A C1845A ) in two unrelated individuals with severe epileptic encephalopathy. This missense variant substitutes a lysine in place of an asparagine known to be important for blockade by Mg 2+ and other small molecule channel blockers. We therefore measured the impact of GluN2A N615K on a range of NMDA receptor channel blockers using two‐electrode voltage clamp recordings made in Xenopus oocytes. We found that GluN2A N615K resulted in block by Mg 2+ 1 mmol/L being greatly reduced (89% vs 8%), block by memantine 10 μmol/L (76% vs 27%) and amantadine 100 μmol/L (45% vs 17%) being substantially reduced, block by ketamine 10 μmol/L being modestly reduced (79% vs 73%) and block by dextromethorphan 10 μmol/L being enhanced (45% vs 55%). Coapplying Mg 2+ with memantine or amantadine did not reduce the GluN2A N615K block seen with either small molecule. In addition, we measured single–channel conductance of GluN2A N615K –containing NMDA receptors in outside‐out patches pulled from Xenopus oocytes, finding a 4‐fold reduction in conductance (58 vs 15 pS). In conclusion, the GluN2A N615K variant is associated with substantial changes to important physiological and pharmacological properties of the NMDA receptor. Our findings are consistent with GluN2A N615K having a disease–causing role, and inform potential therapeutic strategies.
small molecules
2023-06-02 | GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics
N-methyl-D-aspartate receptors (NMDARs) play essential roles in vital aspects of brain functions. NMDARs mediate clinical features of neurological diseases and thus, represent a potential therapeutic target for their treatments. Many findings implicated the GluN2B subunit of NMDARs in various neurological disorders including epilepsy, ischemic brain damage, and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's chorea, and amyotrophic lateral sclerosis. Although a large amount of information is growing consistently on the importance of GluN2B subunit, however, limited recent data is available on how subunit-selective ligands impact NMDAR functions, which blunts the ability to render the diagnosis or craft novel treatments tailored to patients. To bridge this gap, we have focused on and summarized recently reported GluN2B selective ligands as emerging subunit-selective antagonists and modulators of NMDAR. Herein, we have also presented an overview of the structure-function relationship for potential GluN2B/NMDAR ligands with their binding sites and connection to CNS functionalities. Understanding of design rules and roles of GluN2B selective compounds will provide the link to medicinal chemists and neuroscientists to explore novel neurotherapeutic strategies against dysfunctions of glutamatergic neurotransmission.
2021-08-19 | Application of Trio-Whole Exome Sequencing in Genetic Diagnosis and Therapy in Chinese Children With Epilepsy
Epilepsy is one of the most common neurological disorders in pediatric patients with other underlying neurological defects. Identifying the underlying etiology is crucial for better management of the disorder. We performed trio-whole exome sequencing in 221 pediatric patients with epilepsy. Probands were divided into seizures with developmental delay/intellectual disability (DD/ID) and seizures without DD/ID groups. Pathogenic (P) or likely pathogenic (LP) variants were identified in 71/110 (64.5%) patients in the seizures with DD/ID group and 21/111 (18.9%) patients in the seizures without DD/ID group ( P < 0.001). Eighty-seven distinct P/LP single nucleotide variants (SNVs)/insertion deletions (Indels) were detected, with 55.2% (48/87) of them being novel. All aneuploidy and P/LP copy number variants (CNVs) larger than 100 Kb were identifiable by both whole-exome sequencing and copy number variation sequencing (CNVseq) in 123 of individuals (41 pedigrees). Ten of P/LP CNVs in nine patients and one aneuploidy variant in one patient (Patient #56, #47, XXY) were identified by CNVseq. Herein, we identified seven genes ( NCL , SEPHS2 , PA2G4 , SLC35G2 , MYO1C , GPR158 , and POU3F1 ) with de novo variants but unknown pathogenicity that were not previously associated with epilepsy. Potential effective treatment options were available for 32 patients with a P/LP variant, based on the molecular diagnosis. Genetic testing may help identify the molecular etiology of early onset epilepsy and DD/ID and further aid to choose the appropriate treatment strategy for patients.
2020-04-23 | Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice
NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in GRIN2A encoding the GluN2A subunit are associated with a spectrum of disorders, ranging from mild speech and language delay to intractable neurodevelopmental disorders, including but not limited to developmental and epileptic encephalopathy. A de novo missense variant, p.Ser644Gly, was identified in a child with this disorder, and Grin2a knock-in mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibited altered hippocampal morphology at 2 weeks of age, and all homozygotes exhibited lethal tonic-clonic seizures by mid-third week. Heterozygous adults displayed susceptibility to induced generalized seizures, hyperactivity, repetitive and reduced anxiety behaviours, plus several unexpected features, including significant resistance to electrically-induced limbic seizures and to pentylenetetrazole induced tonic-clonic seizures. Multielectrode recordings of neuronal networks revealed hyperexcitability and altered bursting and synchronicity. In heterologous cells, mutant receptors had enhanced NMDA receptor agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. NMDA receptor-mediated synaptic currents in heterozygous hippocampal slices also showed a prolonged deactivation time course. Standard anti-epileptic drug monotherapy was ineffective in the patient. Introduction of NMDA receptor antagonists was correlated with a decrease in seizure burden. Chronic treatment of homozygous mouse pups with NMDA receptor antagonists significantly delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of using multiple experimental modalities to model and test therapies for severe neurodevelopmental disorders, while revealing significant biological complexities associated with GRIN2A developmental and epileptic encephalopathy.
2019-11-20 | Distinct roles of GRIN2A and GRIN2B variants in neurological conditions
Rapid advances in sequencing technology have led to an explosive increase in the number of genetic variants identified in patients with neurological disease and have also enabled the assembly of a robust database of variants in healthy individuals. A surprising number of variants in the GRIN genes that encode N-methyl-D-aspartate (NMDA) glutamatergic receptor subunits have been found in patients with various neuropsychiatric disorders, including autism spectrum disorders, epilepsy, intellectual disability, attention-deficit/hyperactivity disorder, and schizophrenia. This review compares and contrasts the available information describing the clinical and functional consequences of genetic variations in GRIN2A and GRIN2B. Comparison of clinical phenotypes shows that GRIN2A variants are commonly associated with an epileptic phenotype but that GRIN2B variants are commonly found in patients with neurodevelopmental disorders. These observations emphasize the distinct roles that the gene products serve in circuit function and suggest that functional analysis of GRIN2A and GRIN2B variation may provide insight into the molecular mechanisms, which will allow more accurate subclassification of clinical phenotypes. Furthermore, characterization of the pharmacological properties of variant receptors could provide the first opportunity for translational therapeutic strategies for these GRIN-related neurological and psychiatric disorders.
2019-06-20 | The human NMDA receptor GluN2AN615K variant influences channel blocker potency.
Abstract N ‐methyl‐D‐aspartate (NMDA) receptors are glutamate receptors with key roles in synaptic plasticity, due in part to their Mg 2+ mediated voltage‐dependence. A large number of genetic variants affecting NMDA receptor subunits have been found in people with a range of neurodevelopmental disorders, including GluN2A N615K ( GRIN2A C1845A ) in two unrelated individuals with severe epileptic encephalopathy. This missense variant substitutes a lysine in place of an asparagine known to be important for blockade by Mg 2+ and other small molecule channel blockers. We therefore measured the impact of GluN2A N615K on a range of NMDA receptor channel blockers using two‐electrode voltage clamp recordings made in Xenopus oocytes. We found that GluN2A N615K resulted in block by Mg 2+ 1 mmol/L being greatly reduced (89% vs 8%), block by memantine 10 μmol/L (76% vs 27%) and amantadine 100 μmol/L (45% vs 17%) being substantially reduced, block by ketamine 10 μmol/L being modestly reduced (79% vs 73%) and block by dextromethorphan 10 μmol/L being enhanced (45% vs 55%). Coapplying Mg 2+ with memantine or amantadine did not reduce the GluN2A N615K block seen with either small molecule. In addition, we measured single–channel conductance of GluN2A N615K –containing NMDA receptors in outside‐out patches pulled from Xenopus oocytes, finding a 4‐fold reduction in conductance (58 vs 15 pS). In conclusion, the GluN2A N615K variant is associated with substantial changes to important physiological and pharmacological properties of the NMDA receptor. Our findings are consistent with GluN2A N615K having a disease–causing role, and inform potential therapeutic strategies.
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