RARE DISEASE
GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder
GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder
GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder
Synonyms: GRIN2B-Related Neurodevelopmental Disorder
Synonyms: GRIN2B-Related Neurodevelopmental Disorder
Synonyms: GRIN2B-Related Neurodevelopmental Disorder
Drug discovery
2
drugs
With orphan designations
Overview
GRIN2B-related neurodevelopmental disorder is a rare genetic condition caused by pathogenic variants in the GRIN2B gene, encoding the GluN2B subunit of NMDA receptors. It presents with mild-to-profound developmental delay, intellectual disability (ID), autism spectrum disorder (ASD), and variable features including epilepsy (∼50% of cases), hypotonia, movement disorders, and cortical visual impairment. Structural brain abnormalities (e.g., polymicrogyria, hypoplastic corpus callosum) are observed in 15% of individuals [1][2][3]. Most cases arise from de novo autosomal dominant mutations [5][12].
Burden
Functional impact: 85% experience severe-to-profound ID; 89% require lifelong communication support [10][12].
Economic burden: Annual care costs exceed $50,000 per patient due to therapies, seizures, and neurodevelopmental support [6][12].
Caregiver strain: 70% of families report significant emotional/financial stress linked to 24/7 care needs and limited therapeutic options [11][14].
Therapies
Symptomatic management: Antiseizure medications (e.g., levetiracetam), though ~30% exhibit drug-resistant epilepsy [3][15]. Physical, occupational, and speech therapies are mainstays [11][12].
Experimental approaches: NMDA receptor modulators (e.g., memantine for gain-of-function variants, L-serine for loss-of-function variants) [6][14]. Radiprodil (selective GluN2B antagonist) is in Phase 3 trials [14][15].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
44 drug discovery papers about GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
44 drug discovery papers about GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-02-25 | L- Serine for GRIA3 and GRIN2B-related neurodevelopmental disorders
Ji-Sun Kim, Amelia Stone, Jennifer Cross, Zachary Grinspan; L-Serine for GRIA3 and GRIN2B-related neurodevelopmental disorders, Brain, , awag081, https://d
2025-10-28 | GRIN2B-related neurodevelopmental disorders: genotype-phenotype correlations and therapeutic implications.
Pathogenic variants in GRIN2B are predominantly associated with neurodevelopmental disorders (NDDs). However, our understanding of the genotype-phenotype correlations and the optimal treatment strategies is limited. We collected clinical data of seven new patients from the Xiangya Hospital and conducted an extensive literature review. Subsequently, we carried out comparisons of clinical features between patients with gain-of-function (GOF) variants and patients with loss-of-function (LOF) variants, as well as patients with LOF missense variants and LOF truncating variants. We identified seven patients, five of whom had novel variants (p.Phe554Ser, p.Val821Phe, p.Ile641Thr, p.Asn649Ser, and p.Gly1182Arg), and two of whom had known variants (p.Gly820Val and p.Met818Leu). Of the seven cases, 4 (57.14%) presented with epilepsy. Two of these individuals (carrying the p.Ile641Thr and p.Met818Leu variants, respectively) achieved seizure control after receiving memantine. The clinical manifestations included severe developmental delay /intellectual disability (DD/ID) and hypotonia in 100% of cases, as well as microcephaly in 28.57% of cases. Brain imaging results were available for six cases, five of which (83.33%) had abnormal results. Combining our patients (n = 7) and those reported in the literature (n = 98), a total of 105 patients were analyzed. These patients carried 84 pathogenic variants, ten of which were recurrent. The two most frequently occurring variants were p.Gly820Ala and p.Gly689Ser. The predominant phenotypes observed were DD/ID (100%), hypotonia (87.27%), epilepsy (53.08%), and language impairment (45.71%). We further analyzed the clinical genotypes and phenotypes of 55 patients with LOF variants and 16 patients with GOF variants. Variants located in the transmembrane domain predominantly resulted in a GOF effect. GOF variants were more likely to cause epilepsy and microcephaly than LOF variants. Moreover, in comparison to LOF truncated variants, missense variants were associated with more severe clinical phenotypes, including severe DD/ID, language delay, and movement disorders. This study reports five novel GRIN2B variants and seven additional patients. Notably, it is the first report to distinguish between GOF and LOF GRIN2B variants, which have distinct clinical phenotypes. Furthermore, memantine has been shown to be effective in controlling seizures and improving cognition.
2025-08-19 | Absence seizures and sleep-wake abnormalities in a rat model of GRIN2B neurodevelopmental disorder.
Pathogenic mutations in GRIN2B are an important cause of severe neurodevelopmental disorders resulting in epilepsy, autism, and intellectual disability. GRIN2B encodes the GluN2B subunit of N-methyl-d-aspartate receptors (NMDARs), which are ionotropic glutamate receptors critical for normal development of the nervous system and synaptic plasticity. Here, we characterized a novel Grin2b heterozygous knockout rat model with electroencephalography (EEG) and pharmacological interventions to block spontaneous seizures. Through western blot analysis we assessed the extent of GluN2B protein knockdown in knockout (Grin2b+/-) rats compared to controls. We recorded 24-h wireless multi-channel EEG to test whether seizure activity was present and analyzed sleep-wake cycles through a novel automated sleep-scoring algorithm. We tested the effects of systemic and intracerebral reticular thalamic nucleus administration of ethosuximide, a T-type voltage-gated calcium channel blocker, and memantine, a noncompetitive NMDAR antagonist, on seizures. Compared to wild-type rats, Grin2b+/- rats had a higher incidence of spontaneous spike and wave discharges (SWDs), the electrographic correlate of absence seizures. SWDs were longer in duration and displayed higher delta band spectral power in Grin2b+/- animals. Heterozygous animals displayed a reduction in total rapid eye movement sleep and altered distributions of non-rapid eye movement sleep and wake epochs. This was accompanied by a decrease in overall spectral wake power and an increase in beta band power during non-rapid eye movement sleep. The sleep-wake phenotypes were largely uncorrelated with the incidence of SWDs. Systemic ethosuximide reduced the number and duration of SWDs, whereas memantine only reduced their duration. Intrathalamic infusion of both ethosuximide and memantine reduced the number of SWDs. Our data show that the new rat Grin2b haploinsufficiency model exhibits clinically relevant phenotypes and highlights two potential therapeutic options for GRIN2B-related epilepsy.
2025-08-05 | GRIN2B disease-associated mutations disrupt the function of BK channels and NMDA receptor signaling nanodomains.
Large conductance calcium-activated potassium channels (BK channels) are unique in their ability to respond to two distinct physiological stimuli: intracellular Ca2+ and membrane depolarization. In neurons, these channels are activated through a coordinated response to both signals; however, for BK channels to respond to physiological voltage changes, elevated concentrations of intracellular Ca2+ (ranging from 1 to 10 μM) are necessary. In many physiological contexts, BK channels are typically localized within nanodomains near Ca2+ sources (∼20-50 nm), such as N-methyl-D-aspartate receptors (NMDARs; encoded by the GRIN genes). Since the direct evidence of NMDAR-BK channel coupling reported by Isaacson and Murphy in 2001 in the olfactory bulb, further studies have identified functional coupling between NMDARs and BK channels in other regions of the brain, emphasizing their importance in neuronal function. Mutations in the genes encoding NMDAR subunits have been directly linked to developmental encephalopathies, including intellectual disability, epilepsy, and autism spectrum features. Specifically, mutations V15M and V618G in the GRIN2B gene, which encodes the GluN2B subunit of NMDARs, are implicated in the pathogenesis of GRIN2B-related neurodevelopmental disorders. Here, we explored the effects of these two GluN2B mutations on NMDAR-BK channel coupling, employing a combination of electrophysiological, biochemical, and imaging techniques. Taken together, our results demonstrate that mutation V618G specifically disrupts NMDAR-BK complex formation, impairing functional coupling, in spite of robust individual channel expression in the membrane. These results provide a potential mechanistic basis for GRIN2B-related pathophysiology and uncover new clues about NMDAR-BK complex formation.
2024-07-10 | Unravelling the Cerebellar Involvement in Autism Spectrum Disorders: Insights into Genetic Mechanisms and Developmental Pathways
Autism spectrum disorders (ASDs) are complex neurodevelopmental conditions characterized by deficits in social interaction and communication, as well as repetitive behaviors. Although the etiology of ASD is multifactorial, with both genetic and environmental factors contributing to its development, a strong genetic basis is widely recognized. Recent research has identified numerous genetic mutations and genomic rearrangements associated with ASD-characterizing genes involved in brain development. Alterations in developmental programs are particularly harmful during critical periods of brain development. Notably, studies have indicated that genetic disruptions occurring during the second trimester of pregnancy affect cortical development, while disturbances in the perinatal and early postnatal period affect cerebellar development. The developmental defects must be viewed in the context of the role of the cerebellum in cognitive processes, which is now well established. The present review emphasizes the genetic complexity and neuropathological mechanisms underlying ASD and aims to provide insights into the cerebellar involvement in the disorder, focusing on recent advances in the molecular landscape governing its development in humans. Furthermore, we highlight when and in which cerebellar neurons the ASD-associated genes may play a role in the development of cortico–cerebellar circuits. Finally, we discuss improvements in protocols for generating cerebellar organoids to recapitulate the long period of development and maturation of this organ. These models, if generated from patient-induced pluripotent stem cells (iPSC), could provide a valuable approach to elucidate the contribution of defective genes to ASD pathology and inform diagnostic and therapeutic strategies.
2026-02-25 | L- Serine for GRIA3 and GRIN2B-related neurodevelopmental disorders
Ji-Sun Kim, Amelia Stone, Jennifer Cross, Zachary Grinspan; L-Serine for GRIA3 and GRIN2B-related neurodevelopmental disorders, Brain, , awag081, https://d
2025-10-28 | GRIN2B-related neurodevelopmental disorders: genotype-phenotype correlations and therapeutic implications.
Pathogenic variants in GRIN2B are predominantly associated with neurodevelopmental disorders (NDDs). However, our understanding of the genotype-phenotype correlations and the optimal treatment strategies is limited. We collected clinical data of seven new patients from the Xiangya Hospital and conducted an extensive literature review. Subsequently, we carried out comparisons of clinical features between patients with gain-of-function (GOF) variants and patients with loss-of-function (LOF) variants, as well as patients with LOF missense variants and LOF truncating variants. We identified seven patients, five of whom had novel variants (p.Phe554Ser, p.Val821Phe, p.Ile641Thr, p.Asn649Ser, and p.Gly1182Arg), and two of whom had known variants (p.Gly820Val and p.Met818Leu). Of the seven cases, 4 (57.14%) presented with epilepsy. Two of these individuals (carrying the p.Ile641Thr and p.Met818Leu variants, respectively) achieved seizure control after receiving memantine. The clinical manifestations included severe developmental delay /intellectual disability (DD/ID) and hypotonia in 100% of cases, as well as microcephaly in 28.57% of cases. Brain imaging results were available for six cases, five of which (83.33%) had abnormal results. Combining our patients (n = 7) and those reported in the literature (n = 98), a total of 105 patients were analyzed. These patients carried 84 pathogenic variants, ten of which were recurrent. The two most frequently occurring variants were p.Gly820Ala and p.Gly689Ser. The predominant phenotypes observed were DD/ID (100%), hypotonia (87.27%), epilepsy (53.08%), and language impairment (45.71%). We further analyzed the clinical genotypes and phenotypes of 55 patients with LOF variants and 16 patients with GOF variants. Variants located in the transmembrane domain predominantly resulted in a GOF effect. GOF variants were more likely to cause epilepsy and microcephaly than LOF variants. Moreover, in comparison to LOF truncated variants, missense variants were associated with more severe clinical phenotypes, including severe DD/ID, language delay, and movement disorders. This study reports five novel GRIN2B variants and seven additional patients. Notably, it is the first report to distinguish between GOF and LOF GRIN2B variants, which have distinct clinical phenotypes. Furthermore, memantine has been shown to be effective in controlling seizures and improving cognition.
2025-08-19 | Absence seizures and sleep-wake abnormalities in a rat model of GRIN2B neurodevelopmental disorder.
Pathogenic mutations in GRIN2B are an important cause of severe neurodevelopmental disorders resulting in epilepsy, autism, and intellectual disability. GRIN2B encodes the GluN2B subunit of N-methyl-d-aspartate receptors (NMDARs), which are ionotropic glutamate receptors critical for normal development of the nervous system and synaptic plasticity. Here, we characterized a novel Grin2b heterozygous knockout rat model with electroencephalography (EEG) and pharmacological interventions to block spontaneous seizures. Through western blot analysis we assessed the extent of GluN2B protein knockdown in knockout (Grin2b+/-) rats compared to controls. We recorded 24-h wireless multi-channel EEG to test whether seizure activity was present and analyzed sleep-wake cycles through a novel automated sleep-scoring algorithm. We tested the effects of systemic and intracerebral reticular thalamic nucleus administration of ethosuximide, a T-type voltage-gated calcium channel blocker, and memantine, a noncompetitive NMDAR antagonist, on seizures. Compared to wild-type rats, Grin2b+/- rats had a higher incidence of spontaneous spike and wave discharges (SWDs), the electrographic correlate of absence seizures. SWDs were longer in duration and displayed higher delta band spectral power in Grin2b+/- animals. Heterozygous animals displayed a reduction in total rapid eye movement sleep and altered distributions of non-rapid eye movement sleep and wake epochs. This was accompanied by a decrease in overall spectral wake power and an increase in beta band power during non-rapid eye movement sleep. The sleep-wake phenotypes were largely uncorrelated with the incidence of SWDs. Systemic ethosuximide reduced the number and duration of SWDs, whereas memantine only reduced their duration. Intrathalamic infusion of both ethosuximide and memantine reduced the number of SWDs. Our data show that the new rat Grin2b haploinsufficiency model exhibits clinically relevant phenotypes and highlights two potential therapeutic options for GRIN2B-related epilepsy.
2025-08-05 | GRIN2B disease-associated mutations disrupt the function of BK channels and NMDA receptor signaling nanodomains.
Large conductance calcium-activated potassium channels (BK channels) are unique in their ability to respond to two distinct physiological stimuli: intracellular Ca2+ and membrane depolarization. In neurons, these channels are activated through a coordinated response to both signals; however, for BK channels to respond to physiological voltage changes, elevated concentrations of intracellular Ca2+ (ranging from 1 to 10 μM) are necessary. In many physiological contexts, BK channels are typically localized within nanodomains near Ca2+ sources (∼20-50 nm), such as N-methyl-D-aspartate receptors (NMDARs; encoded by the GRIN genes). Since the direct evidence of NMDAR-BK channel coupling reported by Isaacson and Murphy in 2001 in the olfactory bulb, further studies have identified functional coupling between NMDARs and BK channels in other regions of the brain, emphasizing their importance in neuronal function. Mutations in the genes encoding NMDAR subunits have been directly linked to developmental encephalopathies, including intellectual disability, epilepsy, and autism spectrum features. Specifically, mutations V15M and V618G in the GRIN2B gene, which encodes the GluN2B subunit of NMDARs, are implicated in the pathogenesis of GRIN2B-related neurodevelopmental disorders. Here, we explored the effects of these two GluN2B mutations on NMDAR-BK channel coupling, employing a combination of electrophysiological, biochemical, and imaging techniques. Taken together, our results demonstrate that mutation V618G specifically disrupts NMDAR-BK complex formation, impairing functional coupling, in spite of robust individual channel expression in the membrane. These results provide a potential mechanistic basis for GRIN2B-related pathophysiology and uncover new clues about NMDAR-BK complex formation.
2024-07-10 | Unravelling the Cerebellar Involvement in Autism Spectrum Disorders: Insights into Genetic Mechanisms and Developmental Pathways
Autism spectrum disorders (ASDs) are complex neurodevelopmental conditions characterized by deficits in social interaction and communication, as well as repetitive behaviors. Although the etiology of ASD is multifactorial, with both genetic and environmental factors contributing to its development, a strong genetic basis is widely recognized. Recent research has identified numerous genetic mutations and genomic rearrangements associated with ASD-characterizing genes involved in brain development. Alterations in developmental programs are particularly harmful during critical periods of brain development. Notably, studies have indicated that genetic disruptions occurring during the second trimester of pregnancy affect cortical development, while disturbances in the perinatal and early postnatal period affect cerebellar development. The developmental defects must be viewed in the context of the role of the cerebellum in cognitive processes, which is now well established. The present review emphasizes the genetic complexity and neuropathological mechanisms underlying ASD and aims to provide insights into the cerebellar involvement in the disorder, focusing on recent advances in the molecular landscape governing its development in humans. Furthermore, we highlight when and in which cerebellar neurons the ASD-associated genes may play a role in the development of cortico–cerebellar circuits. Finally, we discuss improvements in protocols for generating cerebellar organoids to recapitulate the long period of development and maturation of this organ. These models, if generated from patient-induced pluripotent stem cells (iPSC), could provide a valuable approach to elucidate the contribution of defective genes to ASD pathology and inform diagnostic and therapeutic strategies.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder.
2 orphan drug designations for GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Radiprodil | small molecules | EMA | 2025-05-22 | — | RLM Consulting |
radiprodil | small molecules | FDA | 2025-03-10 | — | GRIN Therapeutics, Inc. |
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