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Classifications

Harrison's Chapter

Channelopathy

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Inheritance

1

Autosomal dominant HP:0000006

GRIN2A-related disorders are autosomal dominant. Roughly half of all probands across the GRIN2A spectrum carry a de novo variant; at the severe developmental and epileptic encephalopathy end the causative missense variants are characteristically de novo, whereas inherited (often null) variants segregate with the milder epilepsy-aphasia phenotypes, sometimes through mildly affected or apparently unaffected carriers.

Autosomal dominant inheritance

Show evidence (6 references)

PMID:27683935 SUPPORT Human Clinical

"GRIN2A-related disorders are inherited in an autosomal dominant manner."

GeneReviews states the autosomal dominant mode of inheritance.

PMID:27683935 SUPPORT Human Clinical

"Approximately 50% of individuals diagnosed with a GRIN2A-related disorder have the disorder as the result of a GRIN2A pathogenic variant that occurred as a de novo event in the affected individual"

Quantifies the de novo proportion across GRIN2A-related disorders.

PMID:27683935 SUPPORT Human Clinical

"Each child of an individual with a GRIN2A-related disorder has a 50% chance of inheriting the GRIN2A pathogenic variant."

Records the transmission risk to offspring, the counselling counterpart of the autosomal dominant mode.

+ 3 more references

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Mechanistic Hypotheses

1

Variant domain localization determines NMDA-receptor functional class, which in turn determines phenotype severity

grin2a_domain_localization_functional_class_severity CANONICAL

Evidence balance 4 support

The prevailing pathomechanistic model for the GRIN2A spectrum holds that the protein domain in which a variant falls predicts its electrophysiological consequence, and that consequence predicts clinical severity. Missense variants in the transmembrane and linker domains (misTMD+Linker) sit in the gating machinery and the ion-permeation pathway and predominantly produce NMDA-receptor gain-of-function, yielding the severe developmental and epileptic encephalopathy phenotype curated here. Missense variants in the amino-terminal or ligand-binding domains (misATD+LBD) exclusively produce loss-of-function and, together with null variants, yield the less severe epilepsy-aphasia phenotypes. This model is the basis for stratifying patients to opposite precision therapies (channel blockade versus co-agonist supplementation).

Pathograph links

GRIN2A Missense Variant in the Transmembrane and Linker Domains -> NMDA Receptor Gain-of-Function DIRECT Variants in the gating and permeation machinery predominantly increase receptor function.

GRIN2A Null or Ligand-Binding/Amino-Terminal Domain Missense Variant -> NMDA Receptor Loss-of-Function DIRECT Haploinsufficiency or impaired agonist binding reduces receptor function.

GluN2A C-Terminal Domain Truncation and Receptor Mistargeting -> NMDA Receptor Loss-of-Function DIRECT Extrasynaptic mislocalization removes GluN2A from the synapse, producing net loss of synaptic NMDA-receptor function.

Show evidence (4 references)

PMID:30544257 SUPPORT Human Clinical

"We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes"

Establishes the domain-localization to severity relationship in a discovery and a validation cohort.

PMID:30544257 SUPPORT In Vitro

"Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function."

Links the domain-localization axis to the electrophysiological gain-of-function versus loss-of-function axis.

PMID:30544257 SUPPORT Human Clinical

"This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders."

The authors frame the domain/function/severity relationship explicitly as a pathomechanistic model with precision-medicine consequences.

+ 1 more reference

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Discussions and Knowledge Gaps

3

Can a GRIN2A variant's functional class be assigned reliably enough, and early enough, to direct opposite precision therapies (NMDA-receptor channel blockade for gain-of-function versus co-agonist supplementation for loss-of-function) before irreversible developmental injury has occurred?

KNOWLEDGE GAP OPEN grin2a_dee_functional_class_precision_therapy

Attached to

pathophysiology#NMDA Receptor Gain-of-Function pathophysiology#NMDA Receptor Loss-of-Function

This disorder is unusual in that two available therapies point in opposite directions and each is potentially harmful in the wrong functional class: L-serine is explicitly contraindicated in gain-of-function variants and has caused immediate behavioral deterioration when given in error, and NMDA-receptor blockers are to be used with caution in loss-of-function and null variants. Domain localization predicts functional class only probabilistically (transmembrane and linker missense variants predominantly rather than invariably cause gain-of-function), some variants have mixed biophysical effects (p.Asn615Lys abolishes magnesium block while decreasing calcium permeability), and definitive assignment requires electrophysiological characterization unavailable for most novel variants. Meanwhile the developmental injury the therapy is meant to prevent accrues in infancy. Whether prediction can be made accurate and fast enough to be actionable is the central open translational question for this entity.

Proposed experiments

Prospective functional-class-stratified precision-therapy trial

exp_grin2a_prospective_functional_stratified_trial

Prospectively characterize newly identified GRIN2A variants with a standardized electrophysiology panel (agonist potency, deactivation kinetics, magnesium block, calcium permeability, surface expression) within a defined turnaround time, assign patients to memantine or a GluN2-subunit-selective negative allosteric modulator versus L-serine on that basis, and compare seizure, EEG, and developmental outcomes against unstratified historical controls. Include a prespecified analysis of whether domain localization alone predicts the assay result well enough to substitute for it.

Variant-to-blocker potency map

exp_grin2a_variant_to_blocker_potency_map

Systematically measure the potency of each available NMDA-receptor channel blocker (memantine, dextromethorphan, dextrorphan, amantadine, ketamine) and of GluN2-subunit-selective negative allosteric modulators against a panel of recombinant receptors carrying each reported GRIN2A gain-of-function variant, and test whether distance from the blocker binding site predicts clinical response.

Show evidence (3 references)

PMID:27683935 SUPPORT Human Clinical

"In individuals with GRIN2A-related disorders due to pathogenic missense variants activating the NMDAR (i.e., gain-of-function variants), receptor-specific agonists and other activators (e.g., L-serine) should be avoided as this could result in worsening of symptoms."

Documents the bidirectional harm potential that makes correct functional classification essential.

PMID:34997442 SUPPORT Human Clinical

"A second individual with a GoF missense variant was erroneously treated with L-serine and experienced immediate temporary behavioral deterioration further supporting the supposed functional pathomechanism."

Demonstrates that misassignment of functional class produced real clinical harm.

PMID:41489401 SUPPORT Human Clinical

"the distance from a GoF variant to the memantine binding site correlated with a positive treatment response and may, at least in part, explain different degrees of therapeutic benefit."

Shows that even within the gain-of-function class, response varies with variant position, so class assignment alone is insufficient.

Why do heterozygous Grin2a gain-of-function knock-in mice show paradoxical resistance to electrically induced limbic seizures and to pentylenetetrazole induced tonic-clonic seizures while patients with the same variant have intractable epilepsy, and does that discordance limit the model's use for preclinical drug selection?

HUMAN MODEL MISMATCH OPEN grin2a_dee_mouse_model_paradoxical_seizure_resistance

Attached to

pathophysiology#Cortical Excitation-Inhibition Imbalance and Network Hyperexcitability

The Grin2a p.Ser644Gly knock-in is the principal in vivo model of this disorder, and it does reproduce network hyperexcitability, altered hippocampal morphology, and (in homozygotes) lethal spontaneous seizures. But the heterozygous genotype that actually matches the human condition displays significant resistance to two standard induced-seizure paradigms, the opposite direction from the human drug-resistant epilepsy, and the study authors themselves flag significant biological complexities. The second GRIN2A gain-of-function model points the same way: in Grin2aN615S mice midbrain circuits are hyperexcitable while hippocampal oscillatory activity is reduced, so the direction of the excitability change is region-dependent rather than global. If induced-seizure thresholds in the heterozygote run opposite to the human phenotype, then screening candidate anti-seizure or NMDA-receptor-directed drugs against those paradigms could select the wrong compounds. Whether the discordance reflects gene-dosage effects, mouse-specific compensatory circuit remodelling, or a genuine limitation of induced-seizure models as proxies for spontaneous GRIN2A epilepsy is unresolved, and it directly conditions how much weight preclinical rescue data (including the radiprodil audiogenic-seizure result) should carry for the ongoing radiprodil clinical programme.

Proposed experiments

Spontaneous versus induced seizure phenotyping across Grin2a models

exp_grin2a_spontaneous_vs_induced_seizure_concordance

Perform long-term continuous video-EEG in heterozygous Grin2a gain-of-function knock-in mice to quantify spontaneous seizure burden, and compare that burden and its pharmacological responsiveness against the same animals' induced-seizure thresholds, to establish which readout predicts human treatment response.

Patient-derived neuronal network validation

exp_grin2a_human_neuron_circuit_validation

Compare excitability, bursting, and synchronicity phenotypes and drug responses between mouse knock-in cortical networks and isogenic patient-derived iPSC neuronal or organoid networks carrying the same GRIN2A variant, to determine whether the human cellular substrate reproduces the mouse discordance.

Show evidence (4 references)

PMID:32577763 SUPPORT Model Organism

"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."

Documents the paradoxical induced-seizure resistance in the heterozygous model.

PMID:32577763 SUPPORT Model Organism

"while revealing significant biological complexities associated with GRIN2A developmental and epileptic encephalopathy"

The authors explicitly flag the model's biological complexity as a caveat.

PMID:33420383 PARTIAL Model Organism

"Likewise, the synchronization of theta- and gamma oscillatory activity is lowered during exploration, demonstrating reduced hippocampal activity."

In the second gain-of-function model the hippocampus is hypoactive while midbrain circuits are hyperexcitable, showing the excitability change is region-dependent rather than uniformly increased.

+ 1 more reference

Is the progressive cerebral parenchymal volume loss in GRIN2A early-onset epileptic encephalopathy a consequence of NMDA-receptor-mediated excitotoxicity and calcium overload, a consequence of the seizure burden itself, or an independent developmental or neurodegenerative process?

KNOWLEDGE GAP OPEN grin2a_dee_progressive_atrophy_mechanism

Attached to

pathophysiology#Progressive Cerebral Parenchymal Volume Loss and Abnormal Myelination

Progressive atrophy with a thin corpus callosum is written into this disorder's clinical definition and is one of the features that separates it from the milder GRIN2A epilepsy-aphasia phenotypes, yet its mechanism has never been established: the causal edge from network hyperexcitability to atrophy is curated here with unknown intermediates. The distinction matters therapeutically. If the atrophy is driven by excessive NMDA-receptor calcium influx then early channel blockade might slow it independent of seizure control; if it is seizure-driven then aggressive seizure control is the priority; if it is an independent developmental program then neither will help. The index patient's cognitive ability was explicitly unchanged despite a two-thirds reduction in seizures on memantine, which is at least consistent with the atrophy and developmental impairment being partly seizure-independent. Two further observations pull in the same direction and sharpen the question. First, in an independent epilepsy-aphasia cohort the baseline spike-wave index did not correlate with intellectual disability level, and the authors concluded the neuropsychological deterioration is not driven by discharge severity alone. Second, and as a genuine counterpoint, longitudinal diffusion imaging of Grin2a knockout mice found microstructural anomalies that were TRANSIENT - present at postnatal day 30 but not at 15 days or 2 months - which is the opposite temporal profile to the progressive human atrophy. That contrast may itself be informative, since the mouse is a knockout (loss-of-function) whereas the severe human phenotype is predominantly gain-of-function, raising the possibility that progressive tissue loss is specific to the gain-of-function arm rather than a general consequence of GRIN2A disruption.

Proposed experiments

Serial volumetric MRI against seizure burden and functional class

exp_grin2a_serial_mri_seizure_burden_correlation

In a prospective GRIN2A cohort, correlate serial volumetric MRI atrophy rates with quantified seizure burden, EEG spike load, variant functional class, and treatment exposure, to test whether atrophy tracks seizures, tracks receptor gain-of-function, or progresses independently.

Neurodegeneration time course in Grin2a knock-in models with and without seizure suppression

exp_grin2a_model_neurodegeneration_timecourse

Quantify neuronal loss, dendritic morphology, and white-matter myelination over time in Grin2a gain-of-function knock-in mice, comparing animals in which seizures are suppressed by a non-NMDA-receptor anti-seizure drug against animals treated with an NMDA-receptor antagonist, to separate seizure-driven from receptor-driven neurodegeneration.

Show evidence (4 references)

PMID:24839611 SUPPORT Human Clinical

"Furthermore, the proband's myoclonic jerks ceased upon memantine treatment. His cognitive ability remained unchanged."

Seizure improvement without cognitive improvement suggests the developmental and structural injury is at least partly independent of ongoing seizures.

PMID:33240831 SUPPORT Human Clinical

"The baseline severity of the spike-wave index (SWI) was not significantly correlated with intellectual disability (ID) level."

Decouples epileptiform burden from cognitive outcome, arguing against a purely seizure-driven mechanism for the developmental and structural injury.

PMID:33240831 SUPPORT Human Clinical

"The neuropsychological deterioration in children with EAS might not only be completely affected by electric discharge severity but also genetic etiology."

The authors attribute deterioration partly to genetic etiology rather than discharge severity alone, which is the alternative this gap seeks to distinguish.

+ 1 more reference

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Pathophysiology

10

GRIN2A Missense Variant in the Transmembrane and Linker Domains

A heterozygous, typically de novo, GRIN2A missense variant falling in the transmembrane domains or the linkers that couple the ligand-binding domain to the channel (misTMD+Linker) alters the GluN2A subunit within the gating and ion-permeation machinery of the NMDA receptor. Recurrent examples include p.Leu812Met in the S2-M4 linker, p.Asn615Lys and p.Asn615Ser in the pore-lining M2 reentrant loop, and p.Ser644Gly. This variant class is the genetic entry point for the severe developmental and epileptic encephalopathy end of the GRIN2A spectrum.

Variant domain localization determines NMDA-receptor functional class, which in turn determines phenotype severity

cortical glutamatergic neuron CL:0000679

NMDA glutamate receptor activity GO:0004972 ⚠ ABNORMAL

Downstream

NMDA Receptor Gain-of-Function Variants in the gating and permeation machinery predominantly increase receptor function.

Show evidence (2 references)

PMID:30544257 SUPPORT Human Clinical

"We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes"

Identifies transmembrane/linker missense variants as the genotype class underlying the severe developmental phenotype.

PMID:24839611 SUPPORT Human Clinical

"This mutation resulted in a leucine to methionine substitution (NP_000824.1:p.L812M) in the linker region connecting the ligand-binding domain to the pore-forming transmembrane region of GluN2A"

Localizes the p.L812M early-onset epileptic encephalopathy variant to the ligand-binding-domain-to-transmembrane linker.

GRIN2A Null or Ligand-Binding/Amino-Terminal Domain Missense Variant

The alternative genotype class: GRIN2A null variants (nonsense, frameshift, splice, exon-disrupting deletions) and missense variants confined to the amino-terminal or ligand-binding domains (misATD+LBD). These act through loss of receptor function. This class predominantly produces the milder GRIN2A epilepsy-aphasia phenotypes curated separately (self-limited epilepsy with centrotemporal spikes, Landau-Kleffner syndrome), and is included here because a minority of individuals at the severe developmental end carry loss-of-function variants and because this class defines eligibility for co-agonist (L-serine) therapy.

Variant domain localization determines NMDA-receptor functional class, which in turn determines phenotype severity

cortical glutamatergic neuron CL:0000679

NMDA glutamate receptor activity GO:0004972 ↓ DECREASED

Downstream

NMDA Receptor Loss-of-Function Haploinsufficiency or impaired agonist binding reduces receptor function.

Show evidence (4 references)

PMID:30544257 SUPPORT In Vitro

"misATD+LBD exclusively caused NMDAR loss-of-function"

Assigns amino-terminal/ligand-binding-domain missense variants to the loss-of-function class.

PMID:30544257 SUPPORT In Vitro

"With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B."

Shows null variants also reduce NMDA-receptor function, without GluN2B compensation.

PMID:33240831 SUPPORT Human Clinical

"Two pathogenic de novo GRIN2A null variants were identified in patients with ABPE who had less severe ID, despite the electrical status epilepticus during slow-wave sleep (ESES)."

An independent cohort assembled at the severe end of the epilepsy-aphasia spectrum found null variants in the patients with the LESS severe intellectual disability, corroborating that this genotype class does not produce the severe developmental phenotype curated in this entry.

+ 1 more reference

GluN2A C-Terminal Domain Truncation and Receptor Mistargeting

A mechanistically distinct third route to reduced GluN2A function, separate from gene-dosage loss and from impaired agonist binding: a frameshift truncating the GluN2A intracellular C-terminal domain leaves the receptor able to reach the postsynaptic membrane but destroys its PDZ interaction with the scaffolding protein PSD-95, so the receptor is mislocalized to extrasynaptic membrane while retaining Scribble1-mediated recycling. The consequence is fewer synapses and reduced dendritic spine density. This is a trafficking and localization defect rather than a channel-gating defect, and it was identified in a patient with epileptic encephalopathy, multiple seizure types, and severe aphasia.

Variant domain localization determines NMDA-receptor functional class, which in turn determines phenotype severity

cortical glutamatergic neuron CL:0000679

protein localization to synapse GO:0035418 ⚠ ABNORMAL

Downstream

NMDA Receptor Loss-of-Function Extrasynaptic mislocalization removes GluN2A from the synapse, producing net loss of synaptic NMDA-receptor function.

Impaired Activity-Dependent Synaptic Maturation and Plasticity Mislocalized receptors leave neurons with fewer synapses and lower spine density, a direct structural hit to synaptic maturation that does not require passing through altered channel gating.

Show evidence (2 references)

PMID:38050135 SUPPORT In Vitro

"We observed that the GluN2A P1199Rfs*32-containing receptors traffic efficiently to the postsynaptic membrane but have increased extra-synaptic expression relative to WT GluN2A-containing NMDARs."

Establishes the mistargeting phenotype: trafficking to the membrane is preserved but synaptic localization is lost.

PMID:38050135 SUPPORT In Vitro

"Indeed, we observed impaired binding to the scaffolding protein postsynaptic protein-95 (PSD-95); however, we found the mutant interacts with Scribble1, which facilitates the recycling of both the mutant and the WT GluN2A."

Identifies loss of PSD-95 binding with retained Scribble1 recycling as the molecular basis of the mislocalization.

NMDA Receptor Gain-of-Function

Transmembrane and linker missense variants increase NMDA-receptor function by several convergent biophysical routes: increased agonist (glutamate and glycine) potency, slowed deactivation after synaptic glutamate is cleared, and loss of the voltage-dependent extracellular magnesium block of the channel pore, which renders receptor calcium signaling voltage-independent. The net effect is greater charge transfer per receptor activation. Notably, pore-loop variants can simultaneously reduce calcium permeability while abolishing magnesium block, so gain-of-function here denotes increased overall charge transfer and excitatory drive rather than a uniform increase in every biophysical parameter.

cortical glutamatergic neuron CL:0000679

ionotropic glutamate receptor signaling GO:0035235 ↑ INCREASED

NMDA glutamate receptor activity GO:0004972 ↑ INCREASED

Downstream

Excessive NMDA Receptor-Mediated Charge Transfer and Calcium Signaling Increased agonist potency, slowed deactivation, and loss of magnesium block all increase current flow through the receptor.

Show evidence (4 references)

PMID:24839611 SUPPORT In Vitro

"A de novo GRIN2A missense mutation (c.2434C>A; p.L812M) increased the charge transfer mediated by NMDA receptors containing the mutant GluN2A-L812M subunit."

Demonstrates increased NMDA-receptor charge transfer for a linker-domain variant causing early-onset epileptic encephalopathy.

PMID:24839611 SUPPORT In Vitro

"These data support the idea that GluN2A-L812M-containing NMDARs are overactive due to the increased activation at low concentrations of agonists."

Increased agonist potency is one biophysical route to receptor overactivity.

PMID:20890276 SUPPORT In Vitro

"receptor currents revealed a loss of the Mg²(+) block and a decrease in Ca²(+) permeability"

The pore-loop p.N615K variant abolishes the magnesium block while reducing calcium permeability, the mixed biophysical signature noted above.

+ 1 more reference

NMDA Receptor Loss-of-Function

Null variants and amino-terminal or ligand-binding-domain missense variants reduce NMDA-receptor-mediated current, through haploinsufficiency of GluN2A or impaired agonist binding, without compensatory upregulation of GluN2B. Because GluN2A-containing receptors carry much of the mature excitatory synaptic NMDA current, this too dysregulates developmentally tuned NMDA-receptor signaling, but it characteristically produces the milder epilepsy-aphasia end of the spectrum rather than this severe entity.

cortical glutamatergic neuron CL:0000679

ionotropic glutamate receptor signaling GO:0035235 ↓ DECREASED

Downstream

Dysregulated NMDA Receptor-Mediated Glutamatergic Signaling Reduced receptor function also perturbs developmentally tuned NMDA-receptor signaling, but with a characteristically milder developmental phenotype.

Show evidence (2 references)

PMID:30544257 SUPPORT In Vitro

"Grin2a+/- cortical rat neurons also had reduced NMDAR function"

Demonstrates reduced NMDA-receptor function with GRIN2A haploinsufficiency.

PMID:34997442 SUPPORT Human Clinical

"Pathogenic missense variants in GRIN2A and GRIN2B may result in gain or loss of function (GoF/LoF) of the N-methyl-D-aspartate receptor (NMDAR)."

Establishes the two-functional-class model that this node's loss-of-function arm represents.

Excessive NMDA Receptor-Mediated Charge Transfer and Calcium Signaling

The immediate cellular consequence of gain-of-function receptors is enhanced NMDA-receptor-mediated cation flux, with excessive depolarizing charge transfer and excessive calcium entry, at synapses that are simultaneously less able to terminate the signal (slow deactivation) and less protected by magnesium block at resting potential. Because calcium entry through NMDA receptors during coincident pre- and postsynaptic activity is the principal instructive signal for activity-dependent synaptic refinement, the excess is both an excitatory and a developmental-signaling insult, and the loss of its voltage dependence destroys the coincidence detection the signal depends on.

cortical glutamatergic neuron CL:0000679

calcium ion transmembrane transport GO:0070588 ↑ INCREASED glutamatergic synaptic transmission GO:0035249 ↑ INCREASED

Downstream

Dysregulated NMDA Receptor-Mediated Glutamatergic Signaling Excess and voltage-independent charge transfer is the gain-of-function route into dysregulated NMDA-receptor signaling.

Show evidence (2 references)

PMID:24839611 SUPPORT In Vitro

"The resulting enhanced excitatory drive is consistent with the production of an epileptic phenotype."

Links increased receptor activity to enhanced excitatory drive and epilepsy.

PMID:33420383 SUPPORT Model Organism

"The NMDA receptor-mediated Ca2+ signaling during simultaneous pre- and postsynaptic activity is critically involved in synaptic plasticity and thus has a key role in the nervous system."

Establishes coincidence-dependent NMDA-receptor calcium signaling as the function that magnesium-block loss subverts.

Dysregulated NMDA Receptor-Mediated Glutamatergic Signaling

The convergence point of both functional classes: NMDA-receptor-mediated glutamatergic signaling and its calcium-dependent downstream cascades fall outside the narrow range that the developing cortex requires. Because GluN2A expression rises through late infancy and childhood as GluN2B-containing receptors are replaced, the perturbation lands on a moving developmental target, which is one reason the same gene produces phenotypes ranging from isolated speech apraxia to a lethal encephalopathy.

cortical glutamatergic neuron CL:0000679 cortical GABAergic interneuron CL:0000617

regulation of glutamatergic synaptic transmission GO:0051966 ↕ DYSREGULATED ionotropic glutamate receptor signaling GO:0035235 ↕ DYSREGULATED

Downstream

Cortical Excitation-Inhibition Imbalance and Network Hyperexcitability Dysregulated NMDA-receptor signaling shifts cortical network excitability.

Impaired Activity-Dependent Synaptic Maturation and Plasticity NMDA-receptor calcium signaling instructs synapse refinement; its dysregulation impairs that program.

Show evidence (2 references)

PMID:20890276 SUPPORT Human Clinical

"Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected."

Frames the disorder as a developmental disturbance of neuronal electrophysiological balance.

PMID:33420383 SUPPORT Model Organism

"In GRIN2-variant patients alterations of this coincidence detection provoked complex clinical phenotypes, ranging from reduced muscle strength to epileptic seizures and intellectual disability."

Connects disrupted NMDA-receptor coincidence detection to the clinical spectrum of seizures and intellectual disability. The cited publication is a mouse study, hence MODEL_ORGANISM; this particular sentence is the paper's framing of the human phenotype context rather than its own primary data, and the paper's own experimental findings are cited separately elsewhere in this entry.

Cortical Excitation-Inhibition Imbalance and Network Hyperexcitability

Dysregulated NMDA-receptor signaling shifts the balance between excitation and inhibition in developing cortical, hippocampal, and midbrain networks, producing neuronal hyperexcitability with abnormal bursting and abnormal network synchronicity. This is the substrate of the multiple early-onset, predominantly drug-resistant focal and generalized seizure types that define the epileptic component of the encephalopathy. The shift is not uniform across regions: in gain-of-function models midbrain circuits become hyperexcitable while hippocampal oscillatory activity is reduced.

cortical glutamatergic neuron CL:0000679 cortical GABAergic interneuron CL:0000617

regulation of membrane potential GO:0042391 ⚠ ABNORMAL modulation of chemical synaptic transmission GO:0050804 ↕ DYSREGULATED

Downstream

Progressive Cerebral Parenchymal Volume Loss and Abnormal Myelination Sustained hyperexcitability and excessive calcium loading are the presumed but not directly demonstrated route to the progressive atrophy seen on serial MRI.

Show evidence (3 references)

PMID:32577763 SUPPORT Model Organism

"Multielectrode recordings of neuronal networks revealed hyperexcitability and altered bursting and synchronicity."

Directly demonstrates network hyperexcitability and altered synchronicity in a GRIN2A developmental and epileptic encephalopathy knock-in model.

PMID:32577763 SUPPORT Model Organism

"all homozygotes exhibited lethal tonic-clonic seizures by mid-third week"

The knock-in model develops spontaneous, ultimately lethal seizures, confirming the epileptogenic consequence.

PMID:33420383 PARTIAL Model Organism

"we show that voltage-independent glutamate-gated signaling of GluN2A-containing NMDA receptors is associated with NMDAR-dependent audiogenic seizures due to hyperexcitable midbrain circuits"

Demonstrates hyperexcitability with a specific regional locus (midbrain), supporting but regionally qualifying the excitation-inhibition imbalance claim.

Impaired Activity-Dependent Synaptic Maturation and Plasticity

NMDA-receptor calcium signaling is the instructive signal for activity-dependent synapse formation, pruning, and long-term potentiation and depression. Dysregulation on either side of the optimum disrupts dendritic and synaptic maturation and produces altered hippocampal morphology, providing the substrate for global developmental delay, intellectual disability, and the prominent speech and language impairment of GRIN2A-related disorders.

neuron CL:0000540 hippocampal pyramidal neuron CL:0000598

long-term synaptic potentiation GO:0060291 ⚠ ABNORMAL synapse organization GO:0050808 ⚠ ABNORMAL dendrite development GO:0016358 ⚠ ABNORMAL

Show evidence (2 references)

PMID:32577763 SUPPORT Model Organism

"Homozygous and heterozygous mutant mice exhibited altered hippocampal morphology at 2 weeks of age"

Structural hippocampal abnormality in the knock-in model at an early developmental stage supports impaired synaptic and circuit maturation.

PMID:27683935 SUPPORT Human Clinical

"GRIN2A-related disorders encompass a broad phenotypic spectrum that includes developmental delay evolving to intellectual disability (DD/ID), epilepsy, speech and language disorders, movement disorders, and neuropsychiatric disorders."

Developmental delay, intellectual disability, and speech-language disorder are the clinical output of impaired synaptic maturation.

Progressive Cerebral Parenchymal Volume Loss and Abnormal Myelination

Serial brain MRI in the severe GRIN2A phenotype shows widespread and progressive cerebral parenchymal volume loss with a thin corpus callosum and abnormal myelination of the terminal zones and temporal lobes, while the cerebellum and brainstem are relatively spared. This progressive structural loss distinguishes the severe developmental and epileptic encephalopathy from the structurally subtle perisylvian and hippocampal changes described in the GRIN2A epilepsy-aphasia phenotypes, and it is the anatomical correlate of the static, profoundly impaired developmental trajectory. Whether it is driven by receptor-mediated excitotoxicity, by the seizure burden, or by an independent process is unresolved.

neuron CL:0000540

Show evidence (2 references)

PMID:24839611 SUPPORT Human Clinical

"Neuroimaging revealed widespread cerebral parenchymal volume loss, a thin corpus callosum, and abnormal myelination of the terminal zones and temporal lobes bilaterally."

Documents the characteristic MRI signature of the severe GRIN2A phenotype.

PMID:24839611 SUPPORT Human Clinical

"These findings reflected progression compared to previous studies."

Establishes that the volume loss is progressive on serial imaging.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

18

Nervous System 8

Intellectual Disability VERY_FREQUENT Intellectual disability HP:0001249

Severity: SEVERE

Show evidence (2 references)

PMID:27683935 SUPPORT Human Clinical

"Intellect ranges from normal to profoundly impaired."

GeneReviews documents the range of intellectual outcome, of which this entity occupies the impaired end.

PMID:24839611 SUPPORT Human Clinical

"early-onset epileptic encephalopathy associated with profound cognitive impairment, absent motor development, and intractable seizures"

The index severe case had profound cognitive impairment.

Global Developmental Delay VERY_FREQUENT Global developmental delay HP:0001263

Show evidence (2 references)

PMID:27683935 SUPPORT Human Clinical

"developmental delay evolving to intellectual disability (DD/ID)"

Developmental delay evolving to intellectual disability is a core feature.

PMID:24839611 SUPPORT Human Clinical

"Development was static at a neonatal level without further progression or regression."

Illustrates the profound, static developmental impairment at the severe end.

Drug-Resistant Focal Seizures VERY_FREQUENT Focal-onset seizure HP:0007359

Show evidence (2 references)

PMID:27683935 SUPPORT Human Clinical

"Epilepsy is typically focal"

GeneReviews states that GRIN2A-related epilepsy is typically focal.

PMID:32577763 SUPPORT Human Clinical

"Standard anti-epileptic drug monotherapy was ineffective in the patient."

Documents drug resistance in the index GRIN2A developmental and epileptic encephalopathy patient.

Tonic Seizures Tonic seizure HP:0032792

Show evidence (1 reference)

PMID:24839611 SUPPORT Human Clinical

"Seizures evolved to involve tonic flexion or extension of all extremities lasting minutes"

Describes the tonic seizure semiology in the severe phenotype.

Progressive Cerebral Atrophy Cerebral atrophy HP:0002059

Course: PROGRESSIVE

Show evidence (2 references)

PMID:24839611 SUPPORT Human Clinical

"Neuroimaging revealed widespread cerebral parenchymal volume loss"

Documents cerebral parenchymal volume loss.

PMID:24839611 SUPPORT Human Clinical

"These findings reflected progression compared to previous studies."

Confirms the atrophy is progressive.

Cerebral Hypomyelination Cerebral hypomyelination HP:0006808

Show evidence (1 reference)

PMID:24839611 SUPPORT Human Clinical

"abnormal myelination of the terminal zones and temporal lobes bilaterally"

Documents the abnormal cerebral myelination.

Absent Speech Absent speech HP:0001344

Show evidence (1 reference)

PMID:27683935 SUPPORT Human Clinical

"Observed speech disorders include dysarthria and speech dyspraxia, and both receptive and expressive language delays"

Establishes the prominent expressive and receptive speech-language impairment of GRIN2A-related disorders.

Motor Delay Motor delay HP:0001270

Show evidence (1 reference)

PMID:24839611 SUPPORT Human Clinical

"profound cognitive impairment, absent motor development, and intractable seizures"

Documents absent motor development at the severe end.

Other 10

Developmental and Epileptic Encephalopathy VERY_FREQUENT Epileptic encephalopathy HP:0200134

Show evidence (2 references)

PMID:27683935 SUPPORT Human Clinical

"Epilepsy is typically focal and ranges from self-limited epilepsy with centrotemporal spikes to developmental and/or epileptic encephalopathies (DEE/EE)"

Places developmental and epileptic encephalopathy at the severe end of the GRIN2A epilepsy spectrum.

PMID:24839611 SUPPORT Human Clinical

"other GluN2A mutations extend the range of phenotypes beyond disorders in the epilepsy-aphasia spectrum to include early-onset epileptic encephalopathy, which is characterized by severe infantile-onset epilepsy and lack of development."

Defines the entity as distinct from, and more severe than, the epilepsy-aphasia spectrum phenotypes.

Myoclonic Seizures and Multifocal Myoclonus Myoclonic seizure HP:0032794

Show evidence (2 references)

PMID:24839611 SUPPORT Human Clinical

"the myoclonic jerks continuing to occur alone or in association with these larger seizures"

Documents myoclonic seizures in the severe GRIN2A phenotype.

PMID:24839611 SUPPORT Human Clinical

"The child exhibited frequent random multifocal myoclonic movements of his extremities."

Documents the multifocal myoclonus on examination.

Multifocal and Generalized Epileptiform EEG Abnormality Multifocal epileptiform discharges HP:0010841

Show evidence (2 references)

PMID:24839611 SUPPORT Human Clinical

"EEGs were reported to possess a diffusely slow and disorganized background with irregularly generalized or lateralized runs of spike and slow wave discharges"

Describes the interictal EEG in the severe phenotype.

PMID:24839611 SUPPORT Human Clinical

"These EEGs were noted to only have very mild activation of the right-sided discharge during sleep and were without any features of electrical status epilepticus of sleep (ESES)."

Distinguishes the severe phenotype's EEG from the sleep-activated (ESES/CSWS) pattern of the GRIN2A epilepsy-aphasia phenotypes.

Slow Disorganized EEG Background EEG with generalized slow activity HP:0010845

Show evidence (1 reference)

PMID:24839611 SUPPORT Human Clinical

"abnormal with slow activity of 3.5-4.5 hertz and 1-3 hertz delta and disorganized activity"

Documents the diffusely slow, disorganized EEG background.

Thin Corpus Callosum Thin corpus callosum HP:0033725

Show evidence (1 reference)

PMID:24839611 SUPPORT Human Clinical

"widespread cerebral parenchymal volume loss, a thin corpus callosum"

Documents the thin corpus callosum.

Axial Hypotonia Axial hypotonia HP:0008936

Show evidence (1 reference)

PMID:24839611 SUPPORT Human Clinical

"At 6 weeks of age, he had poor head control, axial hypotonia, and appendicular hypertonia."

Documents very early axial hypotonia.

Appendicular Hypertonia Limb hypertonia HP:0002509

Show evidence (1 reference)

PMID:24839611 SUPPORT Human Clinical

"He was nondysmorphic and had axial hypotonia, appendicular hypertonia, and diffuse hyporeflexia."

Documents appendicular hypertonia.

Hyporeflexia Hyporeflexia HP:0001265

Show evidence (1 reference)

PMID:24839611 SUPPORT Human Clinical

"axial hypotonia, appendicular hypertonia, and diffuse hyporeflexia"

Documents diffuse hyporeflexia.

Hyperkinetic Movement Disorder OCCASIONAL Hyperkinetic movements HP:0002487

Show evidence (1 reference)

PMID:27683935 SUPPORT Human Clinical

"Movement disorders occur less frequently and include ataxia, dystonia, and chorea."

GeneReviews reports movement disorders as a less frequent feature, supporting the OCCASIONAL frequency band.

Cerebral Visual Impairment Cerebral visual impairment HP:0100704

Show evidence (1 reference)

PMID:24839611 SUPPORT Human Clinical

"the patient did not visually track or exhibit any purposeful interaction with his environment"

Absent visual tracking with a normal eye examination indicates cerebral visual impairment.

🧬

Genetic Associations

1

GRIN2A (Causative)

Gene: GRIN2A hgnc:4585 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:27683935 SUPPORT Human Clinical

"The diagnosis of a GRIN2A-related disorder is established in a proband by the identification of a GRIN2A heterozygous pathogenic variant on molecular genetic testing."

A heterozygous GRIN2A pathogenic variant establishes the diagnosis.

PMID:30544257 SUPPORT Human Clinical

"Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals."

Establishes the size and curation basis of the GRIN2A variant-phenotype dataset supporting the genotype-severity model.

💊

Medical Actions

6

Anti-Seizure Medication

Action: Pharmacotherapy NCIT:C15986

Seizures are treated with standard anti-seizure medications, but at this severe end of the spectrum the epilepsy is characteristically refractory: monotherapy and multi-drug regimens frequently fail to control seizures.

Show evidence (2 references)

PMID:27683935 SUPPORT Human Clinical

"Seizures should be treated with anti-seizure medication (ASM)."

GeneReviews recommends standard anti-seizure medication for the epilepsy.

PMID:32577763 SUPPORT Human Clinical

"Standard anti-epileptic drug monotherapy was ineffective in the patient."

Documents the limited efficacy of standard anti-seizure monotherapy in this severe phenotype.

Memantine (NMDA Receptor Channel Blockade for Gain-of-Function Variants)

Action: Pharmacotherapy NCIT:C15986

Agent: memantine CHEBI:64312

Mechanism-directed therapy for gain-of-function GRIN2A variants: the use-dependent open-channel blocker memantine reduces the excessive NMDA-receptor current. In the index patient with the linker variant p.Leu812Met, in vitro screening confirmed retained memantine sensitivity and adjunct memantine cut seizure frequency from an average of 11.1 to 3.3 episodes per week, abolished the myoclonic jerks, and cleared the frontal spike-wave discharges from the EEG. A retrospective multicentre series of 34 individuals with GRIN variants found that 74% of those with gain-of-function variants benefited, whereas those with loss-of-function or indeterminate variants benefited significantly less. Because blocker potency varies between variants (dextromethorphan and dextrorphan are more potent on p.Asn615Lys but less potent on p.Leu812Met), and because the distance of the variant from the memantine binding site tracks the response, blocker choice should be variant-specific. GeneReviews cautions that NMDA-receptor blockers be used with care in individuals with loss-of-function or null variants.

Mechanism Target:

INHIBITS NMDA Receptor Gain-of-Function — Use-dependent open-channel blockade counteracts the excessive receptor activity of gain-of-function variants.

Show evidence (1 reference)

PMID:24839611 SUPPORT In Vitro

"memantine inhibited GluN2A-L812M-containing NMDARs with an IC50 of 12"

Direct measurement of memantine inhibition of the gain-of-function receptor, the mechanistic basis for this treatment-target edge.

Show evidence (5 references)

PMID:24839611 SUPPORT In Vitro

"In vitro analysis with NMDA receptor blockers indicated that GLuN2A-L812M-containing NMDARs retained their sensitivity to the use-dependent channel blocker memantine"

Establishes retained memantine sensitivity as the rationale for the therapy.

PMID:24839611 SUPPORT Human Clinical

"Over a 54-week period prior to memantine treatment, the proband averaged 11.1 episodes per week (SEM = 0.5). Once the full memantine dosage was achieved, there was a decrease in average seizure frequency to 3.3 per week (SEM = 0.3)."

Quantifies the clinical seizure reduction with adjunct memantine.

PMID:41489401 SUPPORT Human Clinical

"Fourteen of 19 individuals (74%) benefited from memantine, comprising improvements in behavior (71%), development (50%), and seizure frequency (39%)."

A multicentre retrospective series quantifies memantine benefit in GRIN gain-of-function variants.

+ 2 more references

L-Serine Supplementation (NMDA Receptor Co-Agonist for Loss-of-Function Variants)

Action: Pharmacotherapy NCIT:C15986

Agent: L-serine CHEBI:17115

Mechanism-directed therapy for the opposite functional class: oral L-serine is the metabolic precursor of the NMDA-receptor co-agonists D-serine and glycine, and supplementation potentiates hypofunctional receptors. A retrospective n-of-1 series of ten individuals with GRIN2A- or GRIN2B-related disorders found improvement in behaviour in 8 of 9 (89%) with loss-of-function missense or null variants, and a phase 2A open-label trial (NCT04646447) in 24 children with GRIN loss-of-function variants, 5 of whom had GRIN2A variants, reported improved adaptive behaviour, motor function, and quality of life, EEG normalization in five children, and reduced seizure frequency in one, with better response in milder phenotypes. Critically, L-serine must be avoided in individuals with gain-of-function variants: a gain-of-function patient treated in error experienced immediate behavioral deterioration.

Mechanism Target:

RESTORES NMDA Receptor Loss-of-Function — L-serine supplies NMDA-receptor co-agonist to potentiate hypofunctional receptors carrying loss-of-function variants.

Show evidence (1 reference)

PMID:34997442 SUPPORT Human Clinical

"This observation gave rise to the hypothesis of successfully treating GRIN-related disorders due to LoF variants with co-agonists of the NMDAR."

States the co-agonist rationale that this treatment-target edge encodes.

Show evidence (6 references)

PMID:27683935 SUPPORT Human Clinical

"In some individuals with pathogenic loss-of-function and null GRIN2A variants, treatment with the N-methyl-D-aspartate receptor (NMDAR) coagonist L-serine was associated with improvements in behavior, development, EEG features, and/or seizure frequency."

GeneReviews names L-serine as the targeted therapy for GRIN2A loss-of-function and null variants.

PMID:34997442 SUPPORT Human Clinical

"Among all nine individuals with LoF missense or null variants, L-serine treatment was associated with improvements in behavior in eight (89%), in development in four (44%), and/or in EEG or seizure frequency in four (44%)."

Quantifies benefit in the loss-of-function class in a GRIN2A/GRIN2B n-of-1 series.

PMID:38380699 SUPPORT Human Clinical

"Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively)."

Confirms that GRIN2A patients were included in the L-serine phase 2A trial.

+ 3 more references

Radiprodil (Investigational GluN2B-Selective Negative Allosteric Modulator)

Action: Pharmacotherapy NCIT:C15986

Agent: radiprodil NCIT:C152143

Investigational mechanism-directed therapy for the gain-of-function class, currently in an open-label phase 1b trial restricted to GRIN-related disorder with a gain-of-function variant (NCT05818943). Radiprodil is a GluN2B-selective negative allosteric modulator, which is mechanistically counterintuitive for a GRIN2A (GluN2A) disorder; the preclinical rationale is that it dose-dependently suppressed audiogenic seizures in Grin2a p.Asn615Ser gain-of-function mice, plausibly by damping total NMDA-receptor drive through the GluN2B-containing population that remains in the same circuits. Two caveats temper the expectation: the rescue was sex-dependent for reasons that are unexplained, and the wider question of how well induced-seizure paradigms in Grin2a mice predict human response is captured in the grin2a_dee_mouse_model_paradoxical_seizure_resistance discussion. No human efficacy result is available.

Mechanism Target:

INHIBITS NMDA Receptor Gain-of-Function — Negative allosteric modulation of GluN2B-containing NMDA receptors reduces overall NMDA-receptor drive in circuits carrying a GRIN2A gain-of-function variant.

Show evidence (1 reference)

PMID:38529699 SUPPORT Model Organism

"Overall, our data clearly show that radiprodil, a GluN2B selective negative allosteric modulator, may have the potential to control seizures in patients with GRIN2A GoF mutations."

States the gain-of-function-directed rationale that this treatment-target edge encodes.

Show evidence (3 references)

PMID:38529699 SUPPORT Model Organism

"Radiprodil significantly and dose-dependently reduced the onset and severity of AGS in Grin2aS/S mice."

The preclinical efficacy result underpinning the clinical programme.

clinicaltrials:NCT05818943 SUPPORT Human Clinical

"Study RAD-GRIN-101 is a phase 1B trial to assess safety, tolerability, PK, and potential efficacy of radiprodil for the treatment of GRIN-related disorder in children with a Gain-of-Function (GoF) genetic variant."

Confirms the drug is in clinical development with gain-of-function-restricted eligibility, matching the target_mechanisms edge.

PMID:38529699 PARTIAL Model Organism

"Surprisingly, the results revealed a sex-dependent difference in AGS susceptibility and in the dose-dependent protection of radiprodil in the two genders."

Records the unexplained sex-dependence of the preclinical rescue as a caveat on translating it to patients.

Speech and Language Therapy

Action: speech language therapy Ontology label: Speech Language Therapy NCIT:C159273

Speech and language deficits are the signature impairment of GRIN2A-related disorders and require ongoing intervention by a speech-language pathologist, with routine monitoring recommended particularly before school age.

Show evidence (1 reference)

PMID:27683935 SUPPORT Human Clinical

"Significant speech and language deficits require therapy from a speech-language pathologist."

GeneReviews recommends speech-language pathology intervention.

Multidisciplinary Supportive Care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Coordinated care by paediatric epilepsy, movement-disorder, speech-language, physical therapy, occupational therapy, feeding and nutrition, behavioural, and genetic counselling specialists, with ongoing developmental surveillance.

Show evidence (1 reference)

PMID:27683935 SUPPORT Human Clinical

"Multidisciplinary care is recommended by pediatric specialists in the fields of including pediatric epilepsy, movement disorders, speech-language disorders, physical therapy, occupational therapy, feeding and nutrition, behavioral disorders, and genetic counseling."

GeneReviews specifies the multidisciplinary management model.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from GRIN2A-Related Epileptic Encephalopathy and Intellectual Disability:

Landau-Kleffner Syndrome MONDO:0009509

Overlapping Features The GRIN2A epilepsy-aphasia phenotype: previously normal children who lose acquired language in association with sleep-activated continuous spike-and-wave (ESES/CSWS). Distinguished from this entity by normal early development followed by regression rather than delay from infancy, by the obligate sleep-activated EEG pattern, and mechanistically by a loss-of-function (null or ATD/LBD missense) rather than transmembrane/linker gain-of-function genotype.

Show evidence (1 reference)

PMID:24839611 SUPPORT Human Clinical

"These EEGs were noted to only have very mild activation of the right-sided discharge during sleep and were without any features of electrical status epilepticus of sleep (ESES)."

The absence of ESES separates the severe early-onset phenotype from Landau-Kleffner syndrome and CSWS.

Self-Limited Epilepsy with Centrotemporal Spikes MONDO:1060142

Overlapping Features The mildest GRIN2A-associated epilepsy phenotype, with normal or near-normal development, mild focal epilepsy and speech delay or apraxia, and spontaneous remission. Occupies the opposite pole of the same gene's spectrum. Bound to the GRIN2A-specific MONDO term rather than the generic self-limited epilepsy with centrotemporal spikes (MONDO:0007295) because this differential is scoped to the GRIN2A-associated form; note that GRIN2A explains only a minority of centrotemporal-spike epilepsy overall, so the broader term remains the right one for the syndrome in general.

Show evidence (2 references)

PMID:30544257 SUPPORT Human Clinical

"The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum."

Defines the two poles of the GRIN2A spectrum that must be distinguished.

PMID:23933819 SUPPORT Human Clinical

"Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy"

The founding GRIN2A study establishes the rolandic-spike focal epilepsy phenotype as a common childhood epilepsy, and therefore as the highest-yield differential at the mild pole of the GRIN2A spectrum.

GRIN2B-Related Developmental and Epileptic Encephalopathy MONDO:0700350

Overlapping Features The paralogous NMDA-receptor subunit disorder, likewise presenting with developmental delay, intellectual disability, seizures, movement disorder, and cortical visual impairment, and likewise partitioned into gain-of-function and loss-of-function variant classes. Distinguished only by the gene; GluN2B-containing receptors predominate earlier in development, which shifts the timing of the insult. Granularity note: the bound MONDO term is the gene-level GRIN2B-related complex neurodevelopmental disorder, which is BROADER than the developmental and epileptic encephalopathy named here (the dismech entry for the DEE end binds MONDO:0014505, developmental and epileptic encephalopathy 27); the broader term is used because it is the closest non-obsolete MONDO class covering the whole GRIN2B spectrum this differential spans.

Show evidence (1 reference)

PMID:20890276 SUPPORT Human Clinical

"Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected."

Explicitly contrasts the GRIN2A and GRIN2B phenotypes as subunit-dependent.

🔬

Clinical Trials

2

NCT04646447 PHASE_II COMPLETED

Phase 2A, open-label, single-arm, 52-week trial of oral L-serine in children aged 2-18 years with GRIN loss-of-function variants (GRIN1, GRIN2A, GRIN2B), with adaptive behaviour, motor function, quality of life, seizure frequency, and EEG as endpoints.

Target Phenotypes: Intellectual disability HP:0001249 Seizure HP:0001250

Show evidence (1 reference)

PMID:38380699 SUPPORT Human Clinical

"Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function."

Identifies the trial, its design, and its loss-of-function eligibility criterion.

NCT05818943 PHASE_I ACTIVE_NOT_RECRUITING

RAD-GRIN-101: open-label phase 1b study of individually titrated radiprodil, a GluN2B-selective NMDA-receptor negative allosteric modulator, in children with GRIN-related disorder carrying a gain-of-function variant, assessing safety, tolerability, pharmacokinetics, and effects on seizures and behavioural symptoms. It is the first clinical test of the gain-of-function-directed pharmacology supported by the Grin2aN615S mouse rescue data.

Target Phenotypes: Seizure HP:0001250

Show evidence (1 reference)

clinicaltrials:NCT05818943 SUPPORT Human Clinical

"Study RAD-GRIN-101 is a phase 1B trial to assess safety, tolerability, PK, and potential efficacy of radiprodil for the treatment of GRIN-related disorder in children with a Gain-of-Function (GoF) genetic variant."

Confirms the trial's phase, drug, and gain-of-function eligibility criterion.

{ }

Source YAML

click to show

name: GRIN2A-Related Epileptic Encephalopathy and Intellectual Disability
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
synonyms:
- Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
- GRIN2A-related developmental and epileptic encephalopathy
- GRIN2A-related early-onset epileptic encephalopathy
- GRIN2A encephalopathy
description: >-
  The severe end of the GRIN2A phenotypic spectrum: an early-onset developmental
  and epileptic encephalopathy with global developmental delay evolving to mild
  to profound intellectual disability, multiple usually drug-resistant focal and
  generalized seizure types with variably abnormal EEG, and progressive cerebral
  parenchymal volume loss with a thin corpus callosum on brain MRI. It is caused
  by heterozygous, typically de novo, variants in GRIN2A, which encodes the
  GluN2A (NR2A) subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor.
  Mechanistically the disorder is distinguished from the milder GRIN2A-related
  epilepsy-aphasia phenotypes (self-limited epilepsy with centrotemporal spikes,
  Landau-Kleffner syndrome, epileptic encephalopathy with continuous
  spike-and-wave during sleep) by where in the protein the variant falls:
  missense variants in the transmembrane and linker domains predominantly confer
  NMDA-receptor gain-of-function and severe developmental phenotypes, whereas
  missense variants in the amino-terminal or ligand-binding domains and null
  variants cause loss-of-function and less severe phenotypes. A third,
  trafficking-based route to loss of function - C-terminal-domain truncation that
  mislocalizes the receptor away from the synapse - is modelled as its own
  pathophysiology node. Excessive
  NMDA-receptor-mediated charge transfer and calcium influx during a critical
  developmental window drives cortical excitation-inhibition imbalance
  (seizures), impaired activity-dependent synaptic maturation (developmental
  delay and intellectual disability), and progressive neuronal loss. The
  functional class of the variant is directly actionable and bidirectionally
  consequential: gain-of-function receptors retain sensitivity to use-dependent
  NMDA-receptor channel blockers such as memantine and are the target of
  GluN2B-selective negative allosteric modulators now in trial, whereas
  loss-of-function variants are the target of co-agonist supplementation with
  L-serine, a therapy that has caused immediate behavioral deterioration when
  given in error to a gain-of-function patient.
disease_term:
  preferred_term: early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
  term:
    id: MONDO:0017325
    label: early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      An early-onset developmental and epileptic encephalopathy of the central
      nervous system with intellectual disability, seizures, movement
      abnormalities, and progressive brain atrophy.
  channelopathy_category:
    classification_value: neurological channelopathy
    notes: >-
      GRIN2A encodes the GluN2A subunit of the NMDA-receptor cation channel;
      pathogenic variants alter channel gating, agonist potency, and divalent
      cation permeation and block, making this a neurological channelopathy.
parents:
- childhood-onset epilepsy syndrome
- GRIN2A-related complex neurodevelopmental disorder
- Neurodevelopmental Disorder
- Genetic Disease
references:
- reference: PMID:27683935
  title: "GRIN2A-Related Disorders."
  tags:
  - GeneReviews
- reference: PMID:30544257
  title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
inheritance:
- name: Autosomal dominant
  description: >-
    GRIN2A-related disorders are autosomal dominant. Roughly half of all
    probands across the GRIN2A spectrum carry a de novo variant; at the severe
    developmental and epileptic encephalopathy end the causative missense
    variants are characteristically de novo, whereas inherited (often null)
    variants segregate with the milder epilepsy-aphasia phenotypes, sometimes
    through mildly affected or apparently unaffected carriers.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GRIN2A-related disorders are inherited in an autosomal dominant manner."
    explanation: >-
      GeneReviews states the autosomal dominant mode of inheritance.
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 50% of individuals diagnosed with a GRIN2A-related disorder
      have the disorder as the result of a GRIN2A pathogenic variant that
      occurred as a de novo event in the affected individual
    explanation: >-
      Quantifies the de novo proportion across GRIN2A-related disorders.
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with a GRIN2A-related disorder has a 50% chance
      of inheriting the GRIN2A pathogenic variant.
    explanation: >-
      Records the transmission risk to offspring, the counselling counterpart of
      the autosomal dominant mode.
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once the GRIN2A pathogenic variant has been identified in an affected family
      member, prenatal and preimplantation genetic testing are possible.
    explanation: >-
      Documents the reproductive-option consequence of molecular confirmation.
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some individuals diagnosed with a GRIN2A-related disorder have the disorder
      as the result of a pathogenic variant inherited from an affected parent.
    explanation: >-
      Establishes that a proportion of variants are inherited from an affected
      parent, which is why parental testing changes recurrence risk.
  - reference: PMID:20890276
    reference_title: "Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a girl with early-onset epileptic encephalopathy, we identified the de
      novo GRIN2A mutation c.1845C>A predicting the amino acid substitution
      p.N615K.
    explanation: >-
      The index case of GRIN2A early-onset epileptic encephalopathy carried a de
      novo variant, illustrating the de novo origin at the severe end.
mechanistic_hypotheses:
- hypothesis_group_id: grin2a_domain_localization_functional_class_severity
  hypothesis_label: >-
    Variant domain localization determines NMDA-receptor functional class, which
    in turn determines phenotype severity
  status: CANONICAL
  description: >-
    The prevailing pathomechanistic model for the GRIN2A spectrum holds that the
    protein domain in which a variant falls predicts its electrophysiological
    consequence, and that consequence predicts clinical severity. Missense
    variants in the transmembrane and linker domains (misTMD+Linker) sit in the
    gating machinery and the ion-permeation pathway and predominantly produce
    NMDA-receptor gain-of-function, yielding the severe developmental and
    epileptic encephalopathy phenotype curated here. Missense variants in the
    amino-terminal or ligand-binding domains (misATD+LBD) exclusively produce
    loss-of-function and, together with null variants, yield the less severe
    epilepsy-aphasia phenotypes. This model is the basis for stratifying
    patients to opposite precision therapies (channel blockade versus co-agonist
    supplementation).
  evidence:
  - reference: PMID:30544257
    reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that pathogenic missense variants in transmembrane and linker
      domains (misTMD+Linker) were associated with severe developmental
      phenotypes, whereas missense variants within amino terminal or
      ligand-binding domains (misATD+LBD) and null variants led to less severe
      developmental phenotypes
    explanation: >-
      Establishes the domain-localization to severity relationship in a
      discovery and a validation cohort.
  - reference: PMID:30544257
    reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Notably, this was paralleled by electrophysiology data, where
      misTMD+Linker predominantly led to NMDAR gain-of-function, while
      misATD+LBD exclusively caused NMDAR loss-of-function.
    explanation: >-
      Links the domain-localization axis to the electrophysiological
      gain-of-function versus loss-of-function axis.
  - reference: PMID:30544257
    reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This new pathomechanistic model may ultimately help in predicting
      phenotype severity as well as eligibility for potential precision medicine
      approaches in GRIN2A-related disorders.
    explanation: >-
      The authors frame the domain/function/severity relationship explicitly as
      a pathomechanistic model with precision-medicine consequences.
  - reference: PMID:33240831
    reference_title: "Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our finding also enforced the current genotype-phenotype relationship theory"
    explanation: >-
      An independent cohort and literature review explicitly reports its findings
      as reinforcing the GRIN2A genotype-phenotype model, which is the
      corroboration this CANONICAL status rests on.
pathophysiology:
- name: GRIN2A Missense Variant in the Transmembrane and Linker Domains
  description: >-
    A heterozygous, typically de novo, GRIN2A missense variant falling in the
    transmembrane domains or the linkers that couple the ligand-binding domain
    to the channel (misTMD+Linker) alters the GluN2A subunit within the gating
    and ion-permeation machinery of the NMDA receptor. Recurrent examples
    include p.Leu812Met in the S2-M4 linker, p.Asn615Lys and p.Asn615Ser in the
    pore-lining M2 reentrant loop, and p.Ser644Gly. This variant class is the
    genetic entry point for the severe developmental and epileptic
    encephalopathy end of the GRIN2A spectrum.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: cortical glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  molecular_functions:
  - preferred_term: NMDA glutamate receptor activity
    term:
      id: GO:0004972
      label: NMDA glutamate receptor activity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30544257
    reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that pathogenic missense variants in transmembrane and linker
      domains (misTMD+Linker) were associated with severe developmental
      phenotypes
    explanation: >-
      Identifies transmembrane/linker missense variants as the genotype class
      underlying the severe developmental phenotype.
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This mutation resulted in a leucine to methionine substitution
      (NP_000824.1:p.L812M) in the linker region connecting the ligand-binding
      domain to the pore-forming transmembrane region of GluN2A
    explanation: >-
      Localizes the p.L812M early-onset epileptic encephalopathy variant to the
      ligand-binding-domain-to-transmembrane linker.
  downstream:
  - target: NMDA Receptor Gain-of-Function
    causal_link_type: DIRECT
    hypothesis_groups:
    - grin2a_domain_localization_functional_class_severity
    description: >-
      Variants in the gating and permeation machinery predominantly increase
      receptor function.
    evidence:
    - reference: PMID:30544257
      reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "misTMD+Linker predominantly led to NMDAR gain-of-function"
      explanation: >-
        Electrophysiology links this variant class to gain-of-function.
- name: GRIN2A Null or Ligand-Binding/Amino-Terminal Domain Missense Variant
  description: >-
    The alternative genotype class: GRIN2A null variants (nonsense, frameshift,
    splice, exon-disrupting deletions) and missense variants confined to the
    amino-terminal or ligand-binding domains (misATD+LBD). These act through
    loss of receptor function. This class predominantly produces the milder
    GRIN2A epilepsy-aphasia phenotypes curated separately (self-limited epilepsy
    with centrotemporal spikes, Landau-Kleffner syndrome), and is included here
    because a minority of individuals at the severe developmental end carry
    loss-of-function variants and because this class defines eligibility for
    co-agonist (L-serine) therapy.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: cortical glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  molecular_functions:
  - preferred_term: NMDA glutamate receptor activity
    term:
      id: GO:0004972
      label: NMDA glutamate receptor activity
    modifier: DECREASED
  evidence:
  - reference: PMID:30544257
    reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "misATD+LBD exclusively caused NMDAR loss-of-function"
    explanation: >-
      Assigns amino-terminal/ligand-binding-domain missense variants to the
      loss-of-function class.
  - reference: PMID:30544257
    reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      With respect to null variants, we show that Grin2a+/- cortical rat neurons
      also had reduced NMDAR function and there was no evidence of previously
      postulated compensatory overexpression of GluN2B.
    explanation: >-
      Shows null variants also reduce NMDA-receptor function, without GluN2B
      compensation.
  - reference: PMID:33240831
    reference_title: "Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two pathogenic de novo GRIN2A null variants were identified in patients with
      ABPE who had less severe ID, despite the electrical status epilepticus during
      slow-wave sleep (ESES).
    explanation: >-
      An independent cohort assembled at the severe end of the epilepsy-aphasia
      spectrum found null variants in the patients with the LESS severe
      intellectual disability, corroborating that this genotype class does not
      produce the severe developmental phenotype curated in this entry.
  - reference: PMID:33240831
    reference_title: "Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of these mutations, 9 (31.0%) are situated in amino (N)-terminal domain, 6
      (20.7%) in linger-binding domain S1, and 10 (34.5%) in linger-binding domain
      S2.
    explanation: >-
      A literature-wide tally of GRIN2A loss-of-function variants places the large
      majority in the amino-terminal and ligand-binding domains, independently
      corroborating the domain localization assigned to this genotype class. (The
      source misspells "ligand-binding" as "linger-binding"; the snippet reproduces
      the published text verbatim.)
  downstream:
  - target: NMDA Receptor Loss-of-Function
    causal_link_type: DIRECT
    hypothesis_groups:
    - grin2a_domain_localization_functional_class_severity
    description: >-
      Haploinsufficiency or impaired agonist binding reduces receptor function.
    evidence:
    - reference: PMID:30544257
      reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "misATD+LBD exclusively caused NMDAR loss-of-function"
      explanation: >-
        Electrophysiology assigns this variant class to loss-of-function.
- name: GluN2A C-Terminal Domain Truncation and Receptor Mistargeting
  description: >-
    A mechanistically distinct third route to reduced GluN2A function, separate
    from gene-dosage loss and from impaired agonist binding: a frameshift
    truncating the GluN2A intracellular C-terminal domain leaves the receptor able
    to reach the postsynaptic membrane but destroys its PDZ interaction with the
    scaffolding protein PSD-95, so the receptor is mislocalized to extrasynaptic
    membrane while retaining Scribble1-mediated recycling. The consequence is
    fewer synapses and reduced dendritic spine density. This is a trafficking and
    localization defect rather than a channel-gating defect, and it was identified
    in a patient with epileptic encephalopathy, multiple seizure types, and severe
    aphasia.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: cortical glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: protein localization to synapse
    term:
      id: GO:0035418
      label: protein localization to synapse
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38050135
    reference_title: "A Frameshift Variant of GluN2A Identified in an Epilepsy Patient Results in NMDA Receptor Mistargeting."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We observed that the GluN2A P1199Rfs*32-containing receptors traffic
      efficiently to the postsynaptic membrane but have increased extra-synaptic
      expression relative to WT GluN2A-containing NMDARs.
    explanation: >-
      Establishes the mistargeting phenotype: trafficking to the membrane is
      preserved but synaptic localization is lost.
  - reference: PMID:38050135
    reference_title: "A Frameshift Variant of GluN2A Identified in an Epilepsy Patient Results in NMDA Receptor Mistargeting."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Indeed, we observed impaired binding to the scaffolding protein postsynaptic
      protein-95 (PSD-95); however, we found the mutant interacts with Scribble1,
      which facilitates the recycling of both the mutant and the WT GluN2A.
    explanation: >-
      Identifies loss of PSD-95 binding with retained Scribble1 recycling as the
      molecular basis of the mislocalization.
  downstream:
  - target: NMDA Receptor Loss-of-Function
    causal_link_type: DIRECT
    hypothesis_groups:
    - grin2a_domain_localization_functional_class_severity
    description: >-
      Extrasynaptic mislocalization removes GluN2A from the synapse, producing net
      loss of synaptic NMDA-receptor function.
    evidence:
    - reference: PMID:38050135
      reference_title: "A Frameshift Variant of GluN2A Identified in an Epilepsy Patient Results in NMDA Receptor Mistargeting."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Overall, our data show that GluN2A P1199Rfs*32 is a loss-of-function
        variant with altered membrane localization in neurons
      explanation: >-
        The authors classify the trafficking defect as loss-of-function.
  - target: Impaired Activity-Dependent Synaptic Maturation and Plasticity
    causal_link_type: DIRECT
    description: >-
      Mislocalized receptors leave neurons with fewer synapses and lower spine
      density, a direct structural hit to synaptic maturation that does not require
      passing through altered channel gating.
    evidence:
    - reference: PMID:38050135
      reference_title: "A Frameshift Variant of GluN2A Identified in an Epilepsy Patient Results in NMDA Receptor Mistargeting."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we found that neurons expressing GluN2A P1199Rfs*32 have fewer synapses and
        decreased spine density, indicating compromised synaptic transmission in
        these neurons
      explanation: >-
        Measures the structural synaptic consequence directly in neurons.
- name: NMDA Receptor Gain-of-Function
  description: >-
    Transmembrane and linker missense variants increase NMDA-receptor function
    by several convergent biophysical routes: increased agonist (glutamate and
    glycine) potency, slowed deactivation after synaptic glutamate is cleared,
    and loss of the voltage-dependent extracellular magnesium block of the
    channel pore, which renders receptor calcium signaling voltage-independent.
    The net effect is greater charge transfer per receptor activation. Notably,
    pore-loop variants can simultaneously reduce calcium permeability while
    abolishing magnesium block, so gain-of-function here denotes increased
    overall charge transfer and excitatory drive rather than a uniform increase
    in every biophysical parameter.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: cortical glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  molecular_functions:
  - preferred_term: NMDA glutamate receptor activity
    term:
      id: GO:0004972
      label: NMDA glutamate receptor activity
    modifier: INCREASED
  biological_processes:
  - preferred_term: ionotropic glutamate receptor signaling
    term:
      id: GO:0035235
      label: ionotropic glutamate receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A de novo GRIN2A missense mutation (c.2434C>A; p.L812M) increased the
      charge transfer mediated by NMDA receptors containing the mutant
      GluN2A-L812M subunit.
    explanation: >-
      Demonstrates increased NMDA-receptor charge transfer for a linker-domain
      variant causing early-onset epileptic encephalopathy.
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These data support the idea that GluN2A-L812M-containing NMDARs are
      overactive due to the increased activation at low concentrations of
      agonists.
    explanation: >-
      Increased agonist potency is one biophysical route to receptor
      overactivity.
  - reference: PMID:20890276
    reference_title: "Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      receptor currents revealed a loss of the Mg²(+) block and a decrease in
      Ca²(+) permeability
    explanation: >-
      The pore-loop p.N615K variant abolishes the magnesium block while reducing
      calcium permeability, the mixed biophysical signature noted above.
  - reference: PMID:32577763
    reference_title: "Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In heterologous cells, mutant receptors had enhanced NMDA receptor agonist
      potency and slow deactivation following rapid removal of glutamate, as
      occurs at synapses.
    explanation: >-
      Adds slowed deactivation as a second gain-of-function route, for the
      p.Ser644Gly developmental and epileptic encephalopathy variant.
  downstream:
  - target: Excessive NMDA Receptor-Mediated Charge Transfer and Calcium Signaling
    causal_link_type: DIRECT
    description: >-
      Increased agonist potency, slowed deactivation, and loss of magnesium
      block all increase current flow through the receptor.
    evidence:
    - reference: PMID:24839611
      reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        increased the charge transfer mediated by NMDA receptors containing the
        mutant GluN2A-L812M subunit
      explanation: >-
        Directly measures increased charge transfer as the consequence of the
        gain-of-function variant.
- name: NMDA Receptor Loss-of-Function
  description: >-
    Null variants and amino-terminal or ligand-binding-domain missense variants
    reduce NMDA-receptor-mediated current, through haploinsufficiency of GluN2A
    or impaired agonist binding, without compensatory upregulation of GluN2B.
    Because GluN2A-containing receptors carry much of the mature excitatory
    synaptic NMDA current, this too dysregulates developmentally tuned
    NMDA-receptor signaling, but it characteristically produces the milder
    epilepsy-aphasia end of the spectrum rather than this severe entity.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: cortical glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: ionotropic glutamate receptor signaling
    term:
      id: GO:0035235
      label: ionotropic glutamate receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:30544257
    reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Grin2a+/- cortical rat neurons also had reduced NMDAR function"
    explanation: >-
      Demonstrates reduced NMDA-receptor function with GRIN2A
      haploinsufficiency.
  - reference: PMID:34997442
    reference_title: "L-Serine Treatment is Associated with Improvements in Behavior, EEG, and Seizure Frequency in Individuals with GRIN-Related Disorders Due to Null Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic missense variants in GRIN2A and GRIN2B may result in gain or
      loss of function (GoF/LoF) of the N-methyl-D-aspartate receptor (NMDAR).
    explanation: >-
      Establishes the two-functional-class model that this node's
      loss-of-function arm represents.
  downstream:
  - target: Dysregulated NMDA Receptor-Mediated Glutamatergic Signaling
    causal_link_type: DIRECT
    description: >-
      Reduced receptor function also perturbs developmentally tuned
      NMDA-receptor signaling, but with a characteristically milder
      developmental phenotype.
    evidence:
    - reference: PMID:30544257
      reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Grin2a+/- cortical rat neurons also had reduced NMDAR function"
      explanation: >-
        Reduced NMDA-receptor function in Grin2a-haploinsufficient neurons is the
        perturbation this edge carries forward.
- name: Excessive NMDA Receptor-Mediated Charge Transfer and Calcium Signaling
  description: >-
    The immediate cellular consequence of gain-of-function receptors is enhanced
    NMDA-receptor-mediated cation flux, with excessive depolarizing charge
    transfer and excessive calcium entry, at synapses that are simultaneously
    less able to terminate the signal (slow deactivation) and less protected by
    magnesium block at resting potential. Because calcium entry through NMDA
    receptors during coincident pre- and postsynaptic activity is the principal
    instructive signal for activity-dependent synaptic refinement, the excess is
    both an excitatory and a developmental-signaling insult, and the loss of its
    voltage dependence destroys the coincidence detection the signal depends on.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cortical glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: calcium ion transmembrane transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
    modifier: INCREASED
  - preferred_term: glutamatergic synaptic transmission
    term:
      id: GO:0035249
      label: synaptic transmission, glutamatergic
    modifier: INCREASED
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The resulting enhanced excitatory drive is consistent with the production
      of an epileptic phenotype.
    explanation: >-
      Links increased receptor activity to enhanced excitatory drive and
      epilepsy.
  - reference: PMID:33420383
    reference_title: "Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The NMDA receptor-mediated Ca2+ signaling during simultaneous pre- and
      postsynaptic activity is critically involved in synaptic plasticity and
      thus has a key role in the nervous system.
    explanation: >-
      Establishes coincidence-dependent NMDA-receptor calcium signaling as the
      function that magnesium-block loss subverts.
  downstream:
  - target: Dysregulated NMDA Receptor-Mediated Glutamatergic Signaling
    causal_link_type: DIRECT
    description: >-
      Excess and voltage-independent charge transfer is the gain-of-function
      route into dysregulated NMDA-receptor signaling.
    evidence:
    - reference: PMID:24839611
      reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The resulting enhanced excitatory drive is consistent with the production
        of an epileptic phenotype.
      explanation: >-
        Enhanced excitatory drive is the dysregulated-signaling state this edge
        produces.
- name: Dysregulated NMDA Receptor-Mediated Glutamatergic Signaling
  description: >-
    The convergence point of both functional classes: NMDA-receptor-mediated
    glutamatergic signaling and its calcium-dependent downstream cascades fall
    outside the narrow range that the developing cortex requires. Because GluN2A
    expression rises through late infancy and childhood as GluN2B-containing
    receptors are replaced, the perturbation lands on a moving developmental
    target, which is one reason the same gene produces phenotypes ranging from
    isolated speech apraxia to a lethal encephalopathy.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cortical glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  - preferred_term: cortical GABAergic interneuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: regulation of glutamatergic synaptic transmission
    term:
      id: GO:0051966
      label: regulation of synaptic transmission, glutamatergic
    modifier: DYSREGULATED
  - preferred_term: ionotropic glutamate receptor signaling
    term:
      id: GO:0035235
      label: ionotropic glutamate receptor signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:20890276
    reference_title: "Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings suggest that disturbances in the neuronal
      electrophysiological balance during development result in variable
      neurological phenotypes depending on which NR2 subunit of NMDA receptors
      is affected.
    explanation: >-
      Frames the disorder as a developmental disturbance of neuronal
      electrophysiological balance.
  - reference: PMID:33420383
    reference_title: "Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In GRIN2-variant patients alterations of this coincidence detection
      provoked complex clinical phenotypes, ranging from reduced muscle strength
      to epileptic seizures and intellectual disability.
    explanation: >-
      Connects disrupted NMDA-receptor coincidence detection to the clinical
      spectrum of seizures and intellectual disability. The cited publication is
      a mouse study, hence MODEL_ORGANISM; this particular sentence is the
      paper's framing of the human phenotype context rather than its own primary
      data, and the paper's own experimental findings are cited separately
      elsewhere in this entry.
  downstream:
  - target: Cortical Excitation-Inhibition Imbalance and Network Hyperexcitability
    causal_link_type: DIRECT
    description: >-
      Dysregulated NMDA-receptor signaling shifts cortical network excitability.
    evidence:
    - reference: PMID:32577763
      reference_title: "Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Multielectrode recordings of neuronal networks revealed hyperexcitability
        and altered bursting and synchronicity.
      explanation: >-
        Network hyperexcitability is measured directly downstream of the
        dysregulated receptor in a patient-variant knock-in model.
  - target: Impaired Activity-Dependent Synaptic Maturation and Plasticity
    causal_link_type: DIRECT
    description: >-
      NMDA-receptor calcium signaling instructs synapse refinement; its
      dysregulation impairs that program.
    evidence:
    - reference: PMID:33420383
      reference_title: "Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The NMDA receptor-mediated Ca2+ signaling during simultaneous pre- and
        postsynaptic activity is critically involved in synaptic plasticity
      explanation: >-
        Establishes that the dysregulated signal is the one that instructs
        synaptic plasticity.
- name: Cortical Excitation-Inhibition Imbalance and Network Hyperexcitability
  description: >-
    Dysregulated NMDA-receptor signaling shifts the balance between excitation
    and inhibition in developing cortical, hippocampal, and midbrain networks,
    producing neuronal hyperexcitability with abnormal bursting and abnormal
    network synchronicity. This is the substrate of the multiple early-onset,
    predominantly drug-resistant focal and generalized seizure types that define
    the epileptic component of the encephalopathy. The shift is not uniform
    across regions: in gain-of-function models midbrain circuits become
    hyperexcitable while hippocampal oscillatory activity is reduced.
  biological_scale: CELLULAR
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance"
  cell_types:
  - preferred_term: cortical glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  - preferred_term: cortical GABAergic interneuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: regulation of membrane potential
    term:
      id: GO:0042391
      label: regulation of membrane potential
    modifier: ABNORMAL
  - preferred_term: modulation of chemical synaptic transmission
    term:
      id: GO:0050804
      label: modulation of chemical synaptic transmission
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:32577763
    reference_title: "Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Multielectrode recordings of neuronal networks revealed hyperexcitability
      and altered bursting and synchronicity.
    explanation: >-
      Directly demonstrates network hyperexcitability and altered synchronicity
      in a GRIN2A developmental and epileptic encephalopathy knock-in model.
  - reference: PMID:32577763
    reference_title: "Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      all homozygotes exhibited lethal tonic-clonic seizures by mid-third week
    explanation: >-
      The knock-in model develops spontaneous, ultimately lethal seizures,
      confirming the epileptogenic consequence.
  - reference: PMID:33420383
    reference_title: "Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we show that voltage-independent glutamate-gated signaling of
      GluN2A-containing NMDA receptors is associated with NMDAR-dependent
      audiogenic seizures due to hyperexcitable midbrain circuits
    explanation: >-
      Demonstrates hyperexcitability with a specific regional locus (midbrain),
      supporting but regionally qualifying the excitation-inhibition imbalance
      claim.
  downstream:
  - target: Progressive Cerebral Parenchymal Volume Loss and Abnormal Myelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Sustained hyperexcitability and excessive calcium loading are the presumed
      but not directly demonstrated route to the progressive atrophy seen on
      serial MRI.
    evidence:
    - reference: PMID:24839611
      reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "These findings reflected progression compared to previous studies."
      explanation: >-
        Serial imaging establishes that the atrophy is progressive in a patient
        with intractable seizures, but the intervening mechanism linking network
        hyperexcitability to tissue loss is not demonstrated; see the
        grin2a_dee_progressive_atrophy_mechanism discussion.
- name: Impaired Activity-Dependent Synaptic Maturation and Plasticity
  description: >-
    NMDA-receptor calcium signaling is the instructive signal for
    activity-dependent synapse formation, pruning, and long-term potentiation
    and depression. Dysregulation on either side of the optimum disrupts
    dendritic and synaptic maturation and produces altered hippocampal
    morphology, providing the substrate for global developmental delay,
    intellectual disability, and the prominent speech and language impairment of
    GRIN2A-related disorders.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: hippocampal pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: long-term synaptic potentiation
    term:
      id: GO:0060291
      label: long-term synaptic potentiation
    modifier: ABNORMAL
  - preferred_term: synapse organization
    term:
      id: GO:0050808
      label: synapse organization
    modifier: ABNORMAL
  - preferred_term: dendrite development
    term:
      id: GO:0016358
      label: dendrite development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32577763
    reference_title: "Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous and heterozygous mutant mice exhibited altered hippocampal
      morphology at 2 weeks of age
    explanation: >-
      Structural hippocampal abnormality in the knock-in model at an early
      developmental stage supports impaired synaptic and circuit maturation.
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GRIN2A-related disorders encompass a broad phenotypic spectrum that
      includes developmental delay evolving to intellectual disability (DD/ID),
      epilepsy, speech and language disorders, movement disorders, and
      neuropsychiatric disorders.
    explanation: >-
      Developmental delay, intellectual disability, and speech-language disorder
      are the clinical output of impaired synaptic maturation.
- name: Progressive Cerebral Parenchymal Volume Loss and Abnormal Myelination
  description: >-
    Serial brain MRI in the severe GRIN2A phenotype shows widespread and
    progressive cerebral parenchymal volume loss with a thin corpus callosum and
    abnormal myelination of the terminal zones and temporal lobes, while the
    cerebellum and brainstem are relatively spared. This progressive structural
    loss distinguishes the severe developmental and epileptic encephalopathy
    from the structurally subtle perisylvian and hippocampal changes described in
    the GRIN2A epilepsy-aphasia phenotypes, and it is the anatomical correlate
    of the static, profoundly impaired developmental trajectory. Whether it is
    driven by receptor-mediated excitotoxicity, by the seizure burden, or by an
    independent process is unresolved.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neuroimaging revealed widespread cerebral parenchymal volume loss, a thin
      corpus callosum, and abnormal myelination of the terminal zones and
      temporal lobes bilaterally.
    explanation: >-
      Documents the characteristic MRI signature of the severe GRIN2A phenotype.
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings reflected progression compared to previous studies."
    explanation: >-
      Establishes that the volume loss is progressive on serial imaging.
phenotypes:
- category: Neurologic
  name: Developmental and Epileptic Encephalopathy
  description: >-
    The defining phenotype: an early-onset epileptic encephalopathy in which
    frequent seizures and abundant epileptiform activity compound an
    independently abnormal developmental trajectory. Within the GRIN2A spectrum
    this sits at the opposite pole from self-limited epilepsy with centrotemporal
    spikes.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epilepsy is typically focal and ranges from self-limited epilepsy with
      centrotemporal spikes to developmental and/or epileptic encephalopathies
      (DEE/EE)
    explanation: >-
      Places developmental and epileptic encephalopathy at the severe end of the
      GRIN2A epilepsy spectrum.
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      other GluN2A mutations extend the range of phenotypes beyond disorders in
      the epilepsy-aphasia spectrum to include early-onset epileptic
      encephalopathy, which is characterized by severe infantile-onset epilepsy
      and lack of development.
    explanation: >-
      Defines the entity as distinct from, and more severe than, the
      epilepsy-aphasia spectrum phenotypes.
- category: Neurodevelopmental
  name: Intellectual Disability
  description: >-
    Intellectual disability that in this severe subgroup ranges from moderate to
    profound; across the wider GRIN2A spectrum intellect ranges from normal to
    profoundly impaired.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
    severity: SEVERE
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellect ranges from normal to profoundly impaired."
    explanation: >-
      GeneReviews documents the range of intellectual outcome, of which this
      entity occupies the impaired end.
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      early-onset epileptic encephalopathy associated with profound cognitive
      impairment, absent motor development, and intractable seizures
    explanation: >-
      The index severe case had profound cognitive impairment.
- category: Neurodevelopmental
  name: Global Developmental Delay
  description: >-
    Global developmental delay is present from infancy and evolves into
    intellectual disability. In the most severe cases development is static at a
    neonatal level rather than regressive.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delay evolving to intellectual disability (DD/ID)"
    explanation: >-
      Developmental delay evolving to intellectual disability is a core feature.
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Development was static at a neonatal level without further progression or
      regression.
    explanation: >-
      Illustrates the profound, static developmental impairment at the severe
      end.
- category: Neurologic
  name: Drug-Resistant Focal Seizures
  description: >-
    GRIN2A-related epilepsy is typically focal. At the severe end seizures begin
    in infancy or early childhood and are usually refractory to multiple
    anti-seizure medications.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy is typically focal"
    explanation: >-
      GeneReviews states that GRIN2A-related epilepsy is typically focal.
  - reference: PMID:32577763
    reference_title: "Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Standard anti-epileptic drug monotherapy was ineffective in the patient."
    explanation: >-
      Documents drug resistance in the index GRIN2A developmental and epileptic
      encephalopathy patient.
- category: Neurologic
  name: Tonic Seizures
  description: >-
    Tonic seizures with flexion or extension of all extremities, lasting seconds
    to minutes, occurring at up to near-daily frequency.
  phenotype_term:
    preferred_term: Tonic seizure
    term:
      id: HP:0032792
      label: Tonic seizure
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures evolved to involve tonic flexion or extension of all extremities
      lasting minutes
    explanation: >-
      Describes the tonic seizure semiology in the severe phenotype.
- category: Neurologic
  name: Myoclonic Seizures and Multifocal Myoclonus
  description: >-
    Frequent myoclonic jerks, occurring alone or as the initiating event of
    larger tonic seizures, together with near-continuous random multifocal
    myoclonic movements of the extremities.
  phenotype_term:
    preferred_term: Myoclonic seizure
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the myoclonic jerks continuing to occur alone or in association with these
      larger seizures
    explanation: >-
      Documents myoclonic seizures in the severe GRIN2A phenotype.
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The child exhibited frequent random multifocal myoclonic movements of his
      extremities.
    explanation: >-
      Documents the multifocal myoclonus on examination.
- category: Neurologic
  name: Multifocal and Generalized Epileptiform EEG Abnormality
  description: >-
    EEG shows a diffusely slow, disorganized background with irregular
    generalized or lateralized runs of spike-and-slow-wave discharges. Notably,
    in the severe phenotype the discharges need not be sleep-activated: unlike
    the GRIN2A epilepsy-aphasia phenotypes, features of electrical status
    epilepticus in sleep may be absent entirely.
  phenotype_term:
    preferred_term: Multifocal epileptiform discharges
    term:
      id: HP:0010841
      label: Multifocal epileptiform discharges
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      EEGs were reported to possess a diffusely slow and disorganized background
      with irregularly generalized or lateralized runs of spike and slow wave
      discharges
    explanation: >-
      Describes the interictal EEG in the severe phenotype.
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These EEGs were noted to only have very mild activation of the right-sided
      discharge during sleep and were without any features of electrical status
      epilepticus of sleep (ESES).
    explanation: >-
      Distinguishes the severe phenotype's EEG from the sleep-activated
      (ESES/CSWS) pattern of the GRIN2A epilepsy-aphasia phenotypes.
- category: Neurologic
  name: Slow Disorganized EEG Background
  description: >-
    A diffusely slow, poorly organized waking background with delta activity,
    reflecting the encephalopathic state independent of individual seizures.
  phenotype_term:
    preferred_term: EEG with generalized slow activity
    term:
      id: HP:0010845
      label: EEG with generalized slow activity
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal with slow activity of 3.5-4.5 hertz and 1-3 hertz delta and
      disorganized activity
    explanation: >-
      Documents the diffusely slow, disorganized EEG background.
- category: Neurologic
  name: Progressive Cerebral Atrophy
  description: >-
    Widespread cerebral parenchymal volume loss that progresses on serial MRI,
    with relative sparing of cerebellum and brainstem.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroimaging revealed widespread cerebral parenchymal volume loss"
    explanation: >-
      Documents cerebral parenchymal volume loss.
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings reflected progression compared to previous studies."
    explanation: >-
      Confirms the atrophy is progressive.
- category: Neurologic
  name: Thin Corpus Callosum
  description: >-
    A thin corpus callosum accompanies the cerebral volume loss and is part of
    the MRI signature named in the disorder's clinical definition.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "widespread cerebral parenchymal volume loss, a thin corpus callosum"
    explanation: >-
      Documents the thin corpus callosum.
- category: Neurologic
  name: Cerebral Hypomyelination
  description: >-
    Abnormal myelination affecting the terminal zones and temporal lobes
    bilaterally, on a background of cerebral volume loss.
  phenotype_term:
    preferred_term: Cerebral hypomyelination
    term:
      id: HP:0006808
      label: Cerebral hypomyelination
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal myelination of the terminal zones and temporal lobes bilaterally
    explanation: >-
      Documents the abnormal cerebral myelination.
- category: Neurologic
  name: Axial Hypotonia
  description: >-
    Axial hypotonia is evident within the first weeks of life, together with
    poor head control.
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 6 weeks of age, he had poor head control, axial hypotonia, and
      appendicular hypertonia.
    explanation: >-
      Documents very early axial hypotonia.
- category: Neurologic
  name: Appendicular Hypertonia
  description: >-
    Appendicular (limb) hypertonia coexists with the axial hypotonia, a
    dissociated tone pattern present from infancy.
  phenotype_term:
    preferred_term: Limb hypertonia
    term:
      id: HP:0002509
      label: Limb hypertonia
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was nondysmorphic and had axial hypotonia, appendicular hypertonia, and
      diffuse hyporeflexia.
    explanation: >-
      Documents appendicular hypertonia.
- category: Neurologic
  name: Hyporeflexia
  description: >-
    Diffusely reduced deep tendon reflexes are described alongside the
    dissociated tone abnormality.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "axial hypotonia, appendicular hypertonia, and diffuse hyporeflexia"
    explanation: >-
      Documents diffuse hyporeflexia.
- category: Neurologic
  name: Hyperkinetic Movement Disorder
  description: >-
    Movement disorders occur across the GRIN2A spectrum and include ataxia,
    dystonia, and chorea; in the severe phenotype near-continuous involuntary
    flinging movements of the extremities have been described.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hyperkinetic movements
    term:
      id: HP:0002487
      label: Hyperkinetic movements
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Movement disorders occur less frequently and include ataxia, dystonia, and
      chorea.
    explanation: >-
      GeneReviews reports movement disorders as a less frequent feature,
      supporting the OCCASIONAL frequency band.
- category: Neurodevelopmental
  name: Absent Speech
  description: >-
    Speech and language impairment is the signature of GRIN2A-related disorders,
    ranging from subtly reduced conversational intelligibility to dysarthria and
    speech dyspraxia; at this severe end expressive speech may be entirely
    absent.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Observed speech disorders include dysarthria and speech dyspraxia, and
      both receptive and expressive language delays
    explanation: >-
      Establishes the prominent expressive and receptive speech-language
      impairment of GRIN2A-related disorders.
- category: Neurologic
  name: Motor Delay
  description: >-
    Gross and fine motor development is delayed and, in the most severely
    affected, purposeful motor development is absent.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      profound cognitive impairment, absent motor development, and intractable
      seizures
    explanation: >-
      Documents absent motor development at the severe end.
- category: Ophthalmologic
  name: Cerebral Visual Impairment
  description: >-
    Absent visual tracking with a structurally normal ophthalmological
    examination indicates a cortical or cerebral rather than ocular basis for the
    visual impairment.
  phenotype_term:
    preferred_term: Cerebral visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the patient did not visually track or exhibit any purposeful interaction
      with his environment
    explanation: >-
      Absent visual tracking with a normal eye examination indicates cerebral
      visual impairment.
imaging_findings:
- name: Progressive Cerebral Volume Loss with Thin Corpus Callosum on MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  located_in:
    preferred_term: Cerebral hemisphere
    term:
      id: UBERON:0001869
      label: cerebral hemisphere
  laterality: BILATERAL
  description: >-
    Serial brain MRI shows widespread and progressive cerebral parenchymal
    volume loss with a thin corpus callosum and subtle white-matter abnormality
    including hypomyelination of the terminal zones and temporal lobes, with
    relative sparing of the cerebellum and brainstem. This combination is named
    in the clinical definition of the disorder and helps separate it from the
    GRIN2A epilepsy-aphasia phenotypes, in which routine MRI is often normal.
  diagnostic: false
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      showed progressive cerebral atrophy and a thin corpus callosum associated
      with subtle abnormalities of the white matter including hypomyelination of
      the terminal zones and the temporal lobes
    explanation: >-
      The MRI report for the index severe case describes exactly this
      constellation.
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cerebellum and brainstem were relatively spared"
    explanation: >-
      Records the relative sparing of infratentorial structures.
  - reference: PMID:30544257
    reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other phenotypes such as MRI abnormalities and epilepsy types were also
      significantly different between the two groups.
    explanation: >-
      MRI abnormality differs significantly between the severe
      (transmembrane/linker missense) and mild (ATD/LBD missense and null)
      genotype groups.
genetic:
- name: GRIN2A
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: GRIN2A
    term:
      id: hgnc:4585
      label: GRIN2A
  notes: >-
    Heterozygous GRIN2A variants cause the disorder. At this severe end the
    variants are characteristically de novo missense changes in the
    transmembrane domains or the linkers coupling the ligand-binding domain to
    the channel, which predominantly confer NMDA-receptor gain-of-function. Null
    variants and missense variants in the amino-terminal or ligand-binding
    domains confer loss-of-function and predominantly produce the milder
    epilepsy-aphasia phenotypes. Assigning the functional class is a
    prerequisite for mechanism-directed treatment, because the two available
    precision therapies act in opposite directions.
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of a GRIN2A-related disorder is established in a proband by
      the identification of a GRIN2A heterozygous pathogenic variant on
      molecular genetic testing.
    explanation: >-
      A heterozygous GRIN2A pathogenic variant establishes the diagnosis.
  - reference: PMID:30544257
    reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Applying the criteria of the American College of Medical Genetics and
      Genomics to all published variants yielded 156 additional cases with
      pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of
      248 individuals.
    explanation: >-
      Establishes the size and curation basis of the GRIN2A variant-phenotype
      dataset supporting the genotype-severity model.
variants:
- name: GRIN2A p.Leu812Met (c.2434C>A)
  gene:
    preferred_term: GRIN2A
    term:
      id: hgnc:4585
      label: GRIN2A
  type: missense
  clinical_significance: PATHOGENIC
  description: >-
    De novo missense variant in the linker connecting the ligand-binding domain
    to the M4 transmembrane region. Increases NMDA-receptor charge transfer via
    an approximately eightfold increase in glutamate potency and a comparable
    increase in glycine potency, with a partial reduction in magnesium block.
    Receptors carrying it remain sensitive to memantine, which was the basis for
    successful adjunct memantine therapy in the index patient.
  functional_effects:
  - function: NMDA glutamate receptor activity
    type: gain-of-function
    description: >-
      Increased agonist potency and increased charge transfer through
      GluN2A-L812M-containing NMDA receptors.
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Receptors containing GluN2A-L812M showed an eightfold reduction in EC50
      (i.e., increased potency) for glutamate
    explanation: >-
      Quantifies the gain-of-function effect on glutamate potency.
- name: GRIN2A p.Asn615Lys (c.1845C>A)
  gene:
    preferred_term: GRIN2A
    term:
      id: hgnc:4585
      label: GRIN2A
  type: missense
  clinical_significance: PATHOGENIC
  description: >-
    De novo missense variant near the apex of the pore-lining M2 reentrant loop,
    identified in the index girl with GRIN2A early-onset epileptic
    encephalopathy. It eliminates the voltage-dependent extracellular magnesium
    block at physiological concentrations while also reducing calcium
    permeability. Unlike p.Leu812Met, agonist potency is unchanged, and
    dextromethorphan and dextrorphan are more rather than less potent on
    N615K-containing receptors, illustrating that channel-blocker choice is
    variant-specific.
  functional_effects:
  - function: NMDA glutamate receptor voltage-dependent magnesium block
    type: gain-of-function
    description: >-
      Loss of the voltage-dependent magnesium block, permitting
      NMDA-receptor-mediated current at resting membrane potentials, with a
      concomitant decrease in calcium permeability.
  evidence:
  - reference: PMID:20890276
    reference_title: "Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      receptor currents revealed a loss of the Mg²(+) block and a decrease in
      Ca²(+) permeability
    explanation: >-
      Defines the biophysical consequence of p.N615K.
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      showed enhanced potency on N615K-containing NMDARs in comparison to
      wild-type NMDARs
    explanation: >-
      Shows that channel-blocker pharmacology differs between GRIN2A
      gain-of-function variants, so blocker selection is variant-specific.
- name: GRIN2A p.Ser644Gly
  gene:
    preferred_term: GRIN2A
    term:
      id: hgnc:4585
      label: GRIN2A
  type: missense
  clinical_significance: PATHOGENIC
  description: >-
    De novo missense variant identified in a child with GRIN2A developmental and
    epileptic encephalopathy and modelled with a knock-in mouse. Confers
    enhanced agonist potency and markedly slowed deactivation after synaptic
    glutamate clearance, prolonging NMDA-receptor-mediated synaptic currents.
  functional_effects:
  - function: NMDA glutamate receptor deactivation kinetics
    type: gain-of-function
    description: >-
      Enhanced agonist potency and slow deactivation, with prolonged
      NMDA-receptor-mediated synaptic current deactivation in heterozygous
      hippocampal slices.
  evidence:
  - reference: PMID:32577763
    reference_title: "Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      NMDA receptor-mediated synaptic currents in heterozygous hippocampal
      slices also showed a prolonged deactivation time course.
    explanation: >-
      Confirms the slowed-deactivation gain-of-function mechanism at native
      synapses.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    An ultra-rare disorder. Across the whole GRIN2A phenotypic spectrum (of
    which this severe developmental and epileptic encephalopathy is a minority)
    a comprehensive 2019 curation assembled 248 individuals with pathogenic or
    likely pathogenic variants. No population-based prevalence or incidence
    estimate specific to the severe GRIN2A encephalopathy has been published.
  evidence:
  - reference: PMID:30544257
    reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "resulting in a total of 248 individuals"
    explanation: >-
      Total reported individuals across the GRIN2A spectrum, indicating
      ultra-rare occurrence.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    The diagnosis is established by identifying a heterozygous pathogenic
    GRIN2A variant, usually via exome or genome sequencing or an epilepsy gene
    panel. Because treatment direction depends on functional class, the variant
    should be localized to a protein domain and, where possible, functionally
    characterized.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of a GRIN2A-related disorder is established in a proband by
      the identification of a GRIN2A heterozygous pathogenic variant on
      molecular genetic testing.
    explanation: >-
      Defines the molecular diagnostic criterion.
- name: NMDA Receptor Functional Assay for Variant Classification
  description: >-
    In vitro electrophysiological characterization (agonist potency,
    deactivation kinetics, magnesium block, calcium permeability, surface
    expression) assigns a GRIN2A variant to the gain-of-function or
    loss-of-function class. This assignment is a prerequisite for
    mechanism-directed therapy, because channel blockers and co-agonist
    supplementation are indicated in opposite functional classes.
  evidence:
  - reference: PMID:41489401
    reference_title: "Memantine treatment in individuals with GRIN gain-of-function variants is associated with improvements in behavior, development, and seizure frequency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our retrospective observational study outlines the importance of correct
      classification of GRIN variants with regard to pathogenicity and
      functional consequence prior to applying memantine or other precision
      medicine approaches in clinical trials.
    explanation: >-
      Establishes functional classification as a prerequisite for precision
      therapy.
  - reference: PMID:34997442
    reference_title: "L-Serine Treatment is Associated with Improvements in Behavior, EEG, and Seizure Frequency in Individuals with GRIN-Related Disorders Due to Null Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A second individual with a GoF missense variant was erroneously treated
      with L-serine and experienced immediate temporary behavioral deterioration
      further supporting the supposed functional pathomechanism.
    explanation: >-
      A misclassified variant led to clinical deterioration, showing that
      functional-class assignment is safety-critical, not merely academic.
differential_diagnoses:
- name: Landau-Kleffner Syndrome
  disease_term:
    preferred_term: Landau-Kleffner syndrome
    term:
      id: MONDO:0009509
      label: Landau-Kleffner syndrome
  description: >-
    The GRIN2A epilepsy-aphasia phenotype: previously normal children who lose
    acquired language in association with sleep-activated continuous
    spike-and-wave (ESES/CSWS). Distinguished from this entity by normal early
    development followed by regression rather than delay from infancy, by the
    obligate sleep-activated EEG pattern, and mechanistically by a
    loss-of-function (null or ATD/LBD missense) rather than transmembrane/linker
    gain-of-function genotype.
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These EEGs were noted to only have very mild activation of the right-sided
      discharge during sleep and were without any features of electrical status
      epilepticus of sleep (ESES).
    explanation: >-
      The absence of ESES separates the severe early-onset phenotype from
      Landau-Kleffner syndrome and CSWS.
- name: Self-Limited Epilepsy with Centrotemporal Spikes
  disease_term:
    preferred_term: GRIN2A-related self-limited epilepsy with centrotemporal spikes
    term:
      id: MONDO:1060142
      label: GRIN2A-related self-limited epilepsy with centrotemporal spikes
  description: >-
    The mildest GRIN2A-associated epilepsy phenotype, with normal or near-normal
    development, mild focal epilepsy and speech delay or apraxia, and
    spontaneous remission. Occupies the opposite pole of the same gene's
    spectrum. Bound to the GRIN2A-specific MONDO term rather than the generic
    self-limited epilepsy with centrotemporal spikes (MONDO:0007295) because this
    differential is scoped to the GRIN2A-associated form; note that GRIN2A
    explains only a minority of centrotemporal-spike epilepsy overall, so the
    broader term remains the right one for the syndrome in general.
  evidence:
  - reference: PMID:30544257
    reference_title: "GRIN2A-related disorders: genotype and functional consequence predict phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotypic spectrum ranged from normal or near-normal development with
      mild epilepsy and speech delay/apraxia to severe developmental and
      epileptic encephalopathy, often within the epilepsy-aphasia spectrum.
    explanation: >-
      Defines the two poles of the GRIN2A spectrum that must be distinguished.
  - reference: PMID:23933819
    reference_title: "Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common
      childhood epilepsy
    explanation: >-
      The founding GRIN2A study establishes the rolandic-spike focal epilepsy
      phenotype as a common childhood epilepsy, and therefore as the highest-yield
      differential at the mild pole of the GRIN2A spectrum.
- name: GRIN2B-Related Developmental and Epileptic Encephalopathy
  disease_term:
    preferred_term: GRIN2B-related complex neurodevelopmental disorder
    term:
      id: MONDO:0700350
      label: GRIN2B-related complex neurodevelopmental disorder
  description: >-
    The paralogous NMDA-receptor subunit disorder, likewise presenting with
    developmental delay, intellectual disability, seizures, movement disorder,
    and cortical visual impairment, and likewise partitioned into
    gain-of-function and loss-of-function variant classes. Distinguished only by
    the gene; GluN2B-containing receptors predominate earlier in development,
    which shifts the timing of the insult. Granularity note: the bound MONDO term
    is the gene-level GRIN2B-related complex neurodevelopmental disorder, which is
    BROADER than the developmental and epileptic encephalopathy named here (the
    dismech entry for the DEE end binds MONDO:0014505, developmental and epileptic
    encephalopathy 27); the broader term is used because it is the closest
    non-obsolete MONDO class covering the whole GRIN2B spectrum this differential
    spans.
  evidence:
  - reference: PMID:20890276
    reference_title: "Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings suggest that disturbances in the neuronal
      electrophysiological balance during development result in variable
      neurological phenotypes depending on which NR2 subunit of NMDA receptors
      is affected.
    explanation: >-
      Explicitly contrasts the GRIN2A and GRIN2B phenotypes as subunit-dependent.
treatments:
- name: Anti-Seizure Medication
  description: >-
    Seizures are treated with standard anti-seizure medications, but at this
    severe end of the spectrum the epilepsy is characteristically refractory:
    monotherapy and multi-drug regimens frequently fail to control seizures.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures should be treated with anti-seizure medication (ASM)."
    explanation: >-
      GeneReviews recommends standard anti-seizure medication for the epilepsy.
  - reference: PMID:32577763
    reference_title: "Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Standard anti-epileptic drug monotherapy was ineffective in the patient."
    explanation: >-
      Documents the limited efficacy of standard anti-seizure monotherapy in
      this severe phenotype.
- name: Memantine (NMDA Receptor Channel Blockade for Gain-of-Function Variants)
  description: >-
    Mechanism-directed therapy for gain-of-function GRIN2A variants: the
    use-dependent open-channel blocker memantine reduces the excessive
    NMDA-receptor current. In the index patient with the linker variant
    p.Leu812Met, in vitro screening confirmed retained memantine sensitivity and
    adjunct memantine cut seizure frequency from an average of 11.1 to 3.3
    episodes per week, abolished the myoclonic jerks, and cleared the frontal
    spike-wave discharges from the EEG. A retrospective multicentre series of 34
    individuals with GRIN variants found that 74% of those with gain-of-function
    variants benefited, whereas those with loss-of-function or indeterminate
    variants benefited significantly less. Because blocker potency varies
    between variants (dextromethorphan and dextrorphan are more potent on
    p.Asn615Lys but less potent on p.Leu812Met), and because the distance of the
    variant from the memantine binding site tracks the response, blocker choice
    should be variant-specific. GeneReviews cautions that NMDA-receptor blockers
    be used with care in individuals with loss-of-function or null variants.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: memantine
      term:
        id: CHEBI:64312
        label: memantine
  target_mechanisms:
  - target: NMDA Receptor Gain-of-Function
    treatment_effect: INHIBITS
    description: >-
      Use-dependent open-channel blockade counteracts the excessive receptor
      activity of gain-of-function variants.
    evidence:
    - reference: PMID:24839611
      reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        memantine inhibited GluN2A-L812M-containing NMDARs with an IC50 of 12
      explanation: >-
        Direct measurement of memantine inhibition of the gain-of-function
        receptor, the mechanistic basis for this treatment-target edge.
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro analysis with NMDA receptor blockers indicated that
      GLuN2A-L812M-containing NMDARs retained their sensitivity to the
      use-dependent channel blocker memantine
    explanation: >-
      Establishes retained memantine sensitivity as the rationale for the
      therapy.
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over a 54-week period prior to memantine treatment, the proband averaged
      11.1 episodes per week (SEM = 0.5). Once the full memantine dosage was
      achieved, there was a decrease in average seizure frequency to 3.3 per
      week (SEM = 0.3).
    explanation: >-
      Quantifies the clinical seizure reduction with adjunct memantine.
  - reference: PMID:41489401
    reference_title: "Memantine treatment in individuals with GRIN gain-of-function variants is associated with improvements in behavior, development, and seizure frequency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fourteen of 19 individuals (74%) benefited from memantine, comprising
      improvements in behavior (71%), development (50%), and seizure frequency
      (39%).
    explanation: >-
      A multicentre retrospective series quantifies memantine benefit in GRIN
      gain-of-function variants.
  - reference: PMID:41489401
    reference_title: "Memantine treatment in individuals with GRIN gain-of-function variants is associated with improvements in behavior, development, and seizure frequency."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with either LoF or a functionally indeterminate or no effect
      GRIN variant (15/34 individuals) showed significantly less benefit from
      memantine treatment
    explanation: >-
      Restricts the indication: the benefit is confined to the gain-of-function
      class, so functional classification must precede treatment.
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In individuals with pathogenic missense variants inhibiting the NMDAR as
      well as null variants, NMDA receptor blockers should be used with caution
      (e.g., memantine, dextromethorphan, ketamine).
    explanation: >-
      Records the reciprocal caution: channel blockers are not appropriate for
      the loss-of-function class.
- name: L-Serine Supplementation (NMDA Receptor Co-Agonist for Loss-of-Function Variants)
  description: >-
    Mechanism-directed therapy for the opposite functional class: oral L-serine
    is the metabolic precursor of the NMDA-receptor co-agonists D-serine and
    glycine, and supplementation potentiates hypofunctional receptors. A
    retrospective n-of-1 series of ten individuals with GRIN2A- or
    GRIN2B-related disorders found improvement in behaviour in 8 of 9 (89%) with
    loss-of-function missense or null variants, and a phase 2A open-label trial
    (NCT04646447) in 24 children with GRIN loss-of-function variants, 5 of whom
    had GRIN2A variants, reported improved adaptive behaviour, motor function,
    and quality of life, EEG normalization in five children, and reduced seizure
    frequency in one, with better response in milder phenotypes. Critically,
    L-serine must be avoided in individuals with gain-of-function variants: a
    gain-of-function patient treated in error experienced immediate behavioral
    deterioration.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: L-serine
      term:
        id: CHEBI:17115
        label: L-serine
  target_mechanisms:
  - target: NMDA Receptor Loss-of-Function
    treatment_effect: RESTORES
    description: >-
      L-serine supplies NMDA-receptor co-agonist to potentiate hypofunctional
      receptors carrying loss-of-function variants.
    evidence:
    - reference: PMID:34997442
      reference_title: "L-Serine Treatment is Associated with Improvements in Behavior, EEG, and Seizure Frequency in Individuals with GRIN-Related Disorders Due to Null Variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This observation gave rise to the hypothesis of successfully treating
        GRIN-related disorders due to LoF variants with co-agonists of the NMDAR.
      explanation: >-
        States the co-agonist rationale that this treatment-target edge encodes.
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In some individuals with pathogenic loss-of-function and null GRIN2A
      variants, treatment with the N-methyl-D-aspartate receptor (NMDAR)
      coagonist L-serine was associated with improvements in behavior,
      development, EEG features, and/or seizure frequency.
    explanation: >-
      GeneReviews names L-serine as the targeted therapy for GRIN2A
      loss-of-function and null variants.
  - reference: PMID:34997442
    reference_title: "L-Serine Treatment is Associated with Improvements in Behavior, EEG, and Seizure Frequency in Individuals with GRIN-Related Disorders Due to Null Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among all nine individuals with LoF missense or null variants, L-serine
      treatment was associated with improvements in behavior in eight (89%), in
      development in four (44%), and/or in EEG or seizure frequency in four
      (44%).
    explanation: >-
      Quantifies benefit in the loss-of-function class in a GRIN2A/GRIN2B
      n-of-1 series.
  - reference: PMID:38380699
    reference_title: "L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases,
      respectively).
    explanation: >-
      Confirms that GRIN2A patients were included in the L-serine phase 2A
      trial.
  - reference: PMID:38380699
    reference_title: "L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The trial provides evidence that L-serine is a safe treatment for children
      with GRIN loss-of-function variants, having the potential to improve
      adaptive behaviour, motor function and quality of life, with a better
      response to the treatment in mild phenotypes.
    explanation: >-
      Establishes safety and probable benefit, but with a better response in
      mild phenotypes, which tempers the expected benefit in this severe entity.
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In individuals with GRIN2A-related disorders due to pathogenic missense
      variants activating the NMDAR (i.e., gain-of-function variants),
      receptor-specific agonists and other activators (e.g., L-serine) should be
      avoided as this could result in worsening of symptoms.
    explanation: >-
      Explicitly contraindicates L-serine in the gain-of-function class that
      predominates in this severe entity, so this treatment applies only to the
      loss-of-function minority.
  - reference: PMID:34997442
    reference_title: "L-Serine Treatment is Associated with Improvements in Behavior, EEG, and Seizure Frequency in Individuals with GRIN-Related Disorders Due to Null Variants."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A second individual with a GoF missense variant was erroneously treated
      with L-serine and experienced immediate temporary behavioral deterioration
      further supporting the supposed functional pathomechanism.
    explanation: >-
      Direct human evidence of harm from L-serine in a gain-of-function variant,
      the class that predominates in this severe entity.
- name: Radiprodil (Investigational GluN2B-Selective Negative Allosteric Modulator)
  description: >-
    Investigational mechanism-directed therapy for the gain-of-function class,
    currently in an open-label phase 1b trial restricted to GRIN-related disorder
    with a gain-of-function variant (NCT05818943). Radiprodil is a
    GluN2B-selective negative allosteric modulator, which is mechanistically
    counterintuitive for a GRIN2A (GluN2A) disorder; the preclinical rationale is
    that it dose-dependently suppressed audiogenic seizures in Grin2a p.Asn615Ser
    gain-of-function mice, plausibly by damping total NMDA-receptor drive through
    the GluN2B-containing population that remains in the same circuits. Two
    caveats temper the expectation: the rescue was sex-dependent for reasons that
    are unexplained, and the wider question of how well induced-seizure paradigms
    in Grin2a mice predict human response is captured in the
    grin2a_dee_mouse_model_paradoxical_seizure_resistance discussion. No human
    efficacy result is available.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: radiprodil
      term:
        id: NCIT:C152143
        label: Radiprodil
  target_mechanisms:
  - target: NMDA Receptor Gain-of-Function
    treatment_effect: INHIBITS
    description: >-
      Negative allosteric modulation of GluN2B-containing NMDA receptors reduces
      overall NMDA-receptor drive in circuits carrying a GRIN2A gain-of-function
      variant.
    evidence:
    - reference: PMID:38529699
      reference_title: "Radiprodil, a selective GluN2B negative allosteric modulator, rescues audiogenic seizures in mice carrying the GluN2A(N615S) mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Overall, our data clearly show that radiprodil, a GluN2B selective negative
        allosteric modulator, may have the potential to control seizures in
        patients with GRIN2A GoF mutations.
      explanation: >-
        States the gain-of-function-directed rationale that this treatment-target
        edge encodes.
  evidence:
  - reference: PMID:38529699
    reference_title: "Radiprodil, a selective GluN2B negative allosteric modulator, rescues audiogenic seizures in mice carrying the GluN2A(N615S) mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Radiprodil significantly and dose-dependently reduced the onset and severity
      of AGS in Grin2aS/S mice.
    explanation: >-
      The preclinical efficacy result underpinning the clinical programme.
  - reference: clinicaltrials:NCT05818943
    reference_title: "A Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effect on Seizures and Behavioral Symptoms of Multiple Individually Titrated Doses of Radiprodil in Children with GRIN-related Disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Study RAD-GRIN-101 is a phase 1B trial to assess safety, tolerability, PK,
      and potential efficacy of radiprodil for the treatment of GRIN-related
      disorder in children with a Gain-of-Function (GoF) genetic variant.
    explanation: >-
      Confirms the drug is in clinical development with gain-of-function-restricted
      eligibility, matching the target_mechanisms edge.
  - reference: PMID:38529699
    reference_title: "Radiprodil, a selective GluN2B negative allosteric modulator, rescues audiogenic seizures in mice carrying the GluN2A(N615S) mutation."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Surprisingly, the results revealed a sex-dependent difference in AGS
      susceptibility and in the dose-dependent protection of radiprodil in the two
      genders.
    explanation: >-
      Records the unexplained sex-dependence of the preclinical rescue as a caveat
      on translating it to patients.
- name: Speech and Language Therapy
  description: >-
    Speech and language deficits are the signature impairment of GRIN2A-related
    disorders and require ongoing intervention by a speech-language pathologist,
    with routine monitoring recommended particularly before school age.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significant speech and language deficits require therapy from a
      speech-language pathologist.
    explanation: >-
      GeneReviews recommends speech-language pathology intervention.
- name: Multidisciplinary Supportive Care
  description: >-
    Coordinated care by paediatric epilepsy, movement-disorder,
    speech-language, physical therapy, occupational therapy, feeding and
    nutrition, behavioural, and genetic counselling specialists, with ongoing
    developmental surveillance.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Multidisciplinary care is recommended by pediatric specialists in the
      fields of including pediatric epilepsy, movement disorders,
      speech-language disorders, physical therapy, occupational therapy, feeding
      and nutrition, behavioral disorders, and genetic counseling.
    explanation: >-
      GeneReviews specifies the multidisciplinary management model.
animal_models:
- species: Mus musculus (mouse)
  genotype: Grin2a p.Ser644Gly knock-in (heterozygous and homozygous)
  category: GENETIC
  genes:
  - preferred_term: GRIN2A
    term:
      id: hgnc:4585
      label: GRIN2A
  description: >-
    Knock-in mouse carrying the patient-derived gain-of-function Grin2a
    p.Ser644Gly variant. Homozygotes show altered hippocampal morphology by 2
    weeks and uniformly lethal tonic-clonic seizures by the middle of the third
    week; heterozygous adults are susceptible to induced generalized seizures
    and show hyperactivity and repetitive behaviours. Network recordings
    demonstrate hyperexcitability with altered bursting and synchronicity, and
    NMDA receptor antagonists delay the onset of the lethal seizures. It is the
    principal in vivo model of GRIN2A developmental and epileptic
    encephalopathy.
  evidence:
  - reference: PMID:32577763
    reference_title: "Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      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.
    explanation: >-
      Establishes the model and its derivation from a patient variant.
  - reference: PMID:32577763
    reference_title: "Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Chronic treatment of homozygous mouse pups with NMDA receptor antagonists
      significantly delayed the onset of lethal seizures but did not prevent
      them.
    explanation: >-
      Demonstrates partial, mechanism-consistent rescue with NMDA-receptor
      antagonists.
- species: Mus musculus (mouse)
  genotype: Grin2a p.Asn615Ser knock-in (Grin2aN615S; homozygous Grin2aS/S)
  category: GENETIC
  genes:
  - preferred_term: GRIN2A
    term:
      id: hgnc:4585
      label: GRIN2A
  description: >-
    Knock-in mouse carrying the pore-loop gain-of-function Grin2a p.Asn615Ser
    variant, which renders GluN2A-type NMDA-receptor calcium signaling
    voltage-independent. It is one of only two Grin mouse lines with a
    spontaneous epileptic phenotype: audiogenic seizures arise from
    hyperexcitable midbrain circuits, while hippocampal oscillatory activity is
    paradoxically reduced, accompanied by exploratory hyperactivity and
    dysregulated attention that impairs associative learning. Audiogenic
    seizures are dose-dependently suppressed by radiprodil, a GluN2B-selective
    negative allosteric modulator, with an unexplained sex difference in drug
    response.
  evidence:
  - reference: PMID:33420383
    reference_title: "Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      By using our gene-targeted mouse line (Grin2aN615S), we show that
      voltage-independent glutamate-gated signaling of GluN2A-containing NMDA
      receptors is associated with NMDAR-dependent audiogenic seizures due to
      hyperexcitable midbrain circuits.
    explanation: >-
      Establishes the model and its seizure phenotype arising from
      voltage-independent receptor calcium signaling.
  - reference: PMID:33420383
    reference_title: "Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This is associated with exploratory hyperactivity and aberrantly increased
      and dysregulated levels of attention that can interfere with associative
      learning
    explanation: >-
      Documents the cognitive and attentional phenotype of the model.
  - reference: PMID:38529699
    reference_title: "Radiprodil, a selective GluN2B negative allosteric modulator, rescues audiogenic seizures in mice carrying the GluN2A(N615S) mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Radiprodil significantly and dose-dependently reduced the onset and
      severity of AGS in Grin2aS/S mice.
    explanation: >-
      Demonstrates pharmacological rescue of seizures in this GRIN2A
      gain-of-function mouse model.
  - reference: PMID:38529699
    reference_title: "Radiprodil, a selective GluN2B negative allosteric modulator, rescues audiogenic seizures in mice carrying the GluN2A(N615S) mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Although several hundred GRIN mutations have been identified in humans,
      until recently none of the mouse models carrying Grin mutations/deletions
      showed an epileptic phenotype. The two recent exceptions both carry
      mutations of GluN2A.
    explanation: >-
      Establishes the scarcity of epileptic Grin mouse models and this model's
      significance.
- species: Mus musculus (mouse)
  genotype: Grin2a constitutive knockout
  category: GENETIC
  genes:
  - preferred_term: GRIN2A
    term:
      id: hgnc:4585
      label: GRIN2A
  description: >-
    The loss-of-function comparator to the two gain-of-function knock-ins.
    Longitudinal diffusion tensor imaging detects microstructural alterations in
    neocortex, corpus callosum, hippocampus, and thalamus, and EEG detects
    epileptiform discharges in the third postnatal week. Critically the imaging
    alterations are TRANSIENT, peaking at postnatal day 30 and absent at 15 days
    and 2 months, an age-dependent course the authors relate to the childhood onset
    and variable adolescent outcome of the epilepsy-aphasia phenotypes rather than
    to the progressive atrophy of the severe gain-of-function phenotype. Included
    here as the structural counterpoint referenced by the
    grin2a_dee_progressive_atrophy_mechanism discussion.
  evidence:
  - reference: PMID:30146685
    reference_title: "Transient microstructural brain anomalies and epileptiform discharges in mice defective for epilepsy and language-related NMDA receptor subunit gene Grin2a."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Microstructural alterations were detected in the neocortex, the corpus
      callosum, the hippocampus, and the thalamus of Grin2a KO mice.
    explanation: >-
      Establishes that GRIN2A loss produces detectable brain microstructural
      change.
  - reference: PMID:30146685
    reference_title: "Transient microstructural brain anomalies and epileptiform discharges in mice defective for epilepsy and language-related NMDA receptor subunit gene Grin2a."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      EEG analysis detected epileptiform discharges in Grin2a KO mice in the third
      postnatal week.
    explanation: >-
      Confirms an epileptiform phenotype in the loss-of-function model.
  - reference: PMID:30146685
    reference_title: "Transient microstructural brain anomalies and epileptiform discharges in mice defective for epilepsy and language-related NMDA receptor subunit gene Grin2a."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      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.
    explanation: >-
      The transient, age-dependent profile matches the epilepsy-aphasia phenotypes
      rather than the progressive atrophy of this severe entity, which is why this
      model is a counterpoint rather than direct support.
discussions:
- discussion_id: grin2a_dee_functional_class_precision_therapy
  prompt: >-
    Can a GRIN2A variant's functional class be assigned reliably enough, and
    early enough, to direct opposite precision therapies (NMDA-receptor channel
    blockade for gain-of-function versus co-agonist supplementation for
    loss-of-function) before irreversible developmental injury has occurred?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#NMDA Receptor Gain-of-Function
  - pathophysiology#NMDA Receptor Loss-of-Function
  rationale: >-
    This disorder is unusual in that two available therapies point in opposite
    directions and each is potentially harmful in the wrong functional class:
    L-serine is explicitly contraindicated in gain-of-function variants and has
    caused immediate behavioral deterioration when given in error, and
    NMDA-receptor blockers are to be used with caution in loss-of-function and
    null variants. Domain localization predicts functional class only
    probabilistically (transmembrane and linker missense variants predominantly
    rather than invariably cause gain-of-function), some variants have mixed
    biophysical effects (p.Asn615Lys abolishes magnesium block while decreasing
    calcium permeability), and definitive assignment requires
    electrophysiological characterization unavailable for most novel variants.
    Meanwhile the developmental injury the therapy is meant to prevent accrues in
    infancy. Whether prediction can be made accurate and fast enough to be
    actionable is the central open translational question for this entity.
  proposed_experiments:
  - experiment_id: exp_grin2a_prospective_functional_stratified_trial
    name: Prospective functional-class-stratified precision-therapy trial
    description: >-
      Prospectively characterize newly identified GRIN2A variants with a
      standardized electrophysiology panel (agonist potency, deactivation
      kinetics, magnesium block, calcium permeability, surface expression)
      within a defined turnaround time, assign patients to memantine or a
      GluN2-subunit-selective negative allosteric modulator versus L-serine on
      that basis, and compare seizure, EEG, and developmental outcomes against
      unstratified historical controls. Include a prespecified analysis of
      whether domain localization alone predicts the assay result well enough to
      substitute for it.
  - experiment_id: exp_grin2a_variant_to_blocker_potency_map
    name: Variant-to-blocker potency map
    description: >-
      Systematically measure the potency of each available NMDA-receptor channel
      blocker (memantine, dextromethorphan, dextrorphan, amantadine, ketamine)
      and of GluN2-subunit-selective negative allosteric modulators against a
      panel of recombinant receptors carrying each reported GRIN2A
      gain-of-function variant, and test whether distance from the blocker
      binding site predicts clinical response.
  evidence:
  - reference: PMID:27683935
    reference_title: "GRIN2A-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In individuals with GRIN2A-related disorders due to pathogenic missense
      variants activating the NMDAR (i.e., gain-of-function variants),
      receptor-specific agonists and other activators (e.g., L-serine) should be
      avoided as this could result in worsening of symptoms.
    explanation: >-
      Documents the bidirectional harm potential that makes correct functional
      classification essential.
  - reference: PMID:34997442
    reference_title: "L-Serine Treatment is Associated with Improvements in Behavior, EEG, and Seizure Frequency in Individuals with GRIN-Related Disorders Due to Null Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A second individual with a GoF missense variant was erroneously treated
      with L-serine and experienced immediate temporary behavioral deterioration
      further supporting the supposed functional pathomechanism.
    explanation: >-
      Demonstrates that misassignment of functional class produced real clinical
      harm.
  - reference: PMID:41489401
    reference_title: "Memantine treatment in individuals with GRIN gain-of-function variants is associated with improvements in behavior, development, and seizure frequency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the distance from a GoF variant to the memantine binding site correlated
      with a positive treatment response and may, at least in part, explain
      different degrees of therapeutic benefit.
    explanation: >-
      Shows that even within the gain-of-function class, response varies with
      variant position, so class assignment alone is insufficient.
- discussion_id: grin2a_dee_mouse_model_paradoxical_seizure_resistance
  prompt: >-
    Why do heterozygous Grin2a gain-of-function knock-in mice show paradoxical
    resistance to electrically induced limbic seizures and to pentylenetetrazole
    induced tonic-clonic seizures while patients with the same variant have
    intractable epilepsy, and does that discordance limit the model's use for
    preclinical drug selection?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Cortical Excitation-Inhibition Imbalance and Network Hyperexcitability
  rationale: >-
    The Grin2a p.Ser644Gly knock-in is the principal in vivo model of this
    disorder, and it does reproduce network hyperexcitability, altered
    hippocampal morphology, and (in homozygotes) lethal spontaneous seizures.
    But the heterozygous genotype that actually matches the human condition
    displays significant resistance to two standard induced-seizure paradigms,
    the opposite direction from the human drug-resistant epilepsy, and the study
    authors themselves flag significant biological complexities. The second
    GRIN2A gain-of-function model points the same way: in Grin2aN615S mice
    midbrain circuits are hyperexcitable while hippocampal oscillatory activity
    is reduced, so the direction of the excitability change is region-dependent
    rather than global. If induced-seizure thresholds in the heterozygote run
    opposite to the human phenotype, then screening candidate anti-seizure or
    NMDA-receptor-directed drugs against those paradigms could select the wrong
    compounds. Whether the discordance reflects gene-dosage effects,
    mouse-specific compensatory circuit remodelling, or a genuine limitation of
    induced-seizure models as proxies for spontaneous GRIN2A epilepsy is
    unresolved, and it directly conditions how much weight preclinical rescue
    data (including the radiprodil audiogenic-seizure result) should carry for
    the ongoing radiprodil clinical programme.
  proposed_experiments:
  - experiment_id: exp_grin2a_spontaneous_vs_induced_seizure_concordance
    name: Spontaneous versus induced seizure phenotyping across Grin2a models
    description: >-
      Perform long-term continuous video-EEG in heterozygous Grin2a
      gain-of-function knock-in mice to quantify spontaneous seizure burden, and
      compare that burden and its pharmacological responsiveness against the
      same animals' induced-seizure thresholds, to establish which readout
      predicts human treatment response.
  - experiment_id: exp_grin2a_human_neuron_circuit_validation
    name: Patient-derived neuronal network validation
    description: >-
      Compare excitability, bursting, and synchronicity phenotypes and drug
      responses between mouse knock-in cortical networks and isogenic
      patient-derived iPSC neuronal or organoid networks carrying the same
      GRIN2A variant, to determine whether the human cellular substrate
      reproduces the mouse discordance.
  evidence:
  - reference: PMID:32577763
    reference_title: "Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      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.
    explanation: >-
      Documents the paradoxical induced-seizure resistance in the heterozygous
      model.
  - reference: PMID:32577763
    reference_title: "Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      while revealing significant biological complexities associated with GRIN2A
      developmental and epileptic encephalopathy
    explanation: >-
      The authors explicitly flag the model's biological complexity as a caveat.
  - reference: PMID:33420383
    reference_title: "Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Likewise, the synchronization of theta- and gamma oscillatory activity is
      lowered during exploration, demonstrating reduced hippocampal activity.
    explanation: >-
      In the second gain-of-function model the hippocampus is hypoactive while
      midbrain circuits are hyperexcitable, showing the excitability change is
      region-dependent rather than uniformly increased.
  - reference: PMID:38529699
    reference_title: "Radiprodil, a selective GluN2B negative allosteric modulator, rescues audiogenic seizures in mice carrying the GluN2A(N615S) mutation."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Surprisingly, the results revealed a sex-dependent difference in AGS
      susceptibility and in the dose-dependent protection of radiprodil in the
      two genders.
    explanation: >-
      An unexplained sex-dependent drug response in the second GRIN2A model adds
      to the uncertainty about translating preclinical rescue to patients.
- discussion_id: grin2a_dee_progressive_atrophy_mechanism
  prompt: >-
    Is the progressive cerebral parenchymal volume loss in GRIN2A early-onset
    epileptic encephalopathy a consequence of NMDA-receptor-mediated
    excitotoxicity and calcium overload, a consequence of the seizure burden
    itself, or an independent developmental or neurodegenerative process?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Progressive Cerebral Parenchymal Volume Loss and Abnormal Myelination
  rationale: >-
    Progressive atrophy with a thin corpus callosum is written into this
    disorder's clinical definition and is one of the features that separates it
    from the milder GRIN2A epilepsy-aphasia phenotypes, yet its mechanism has
    never been established: the causal edge from network hyperexcitability to
    atrophy is curated here with unknown intermediates. The distinction matters
    therapeutically. If the atrophy is driven by excessive NMDA-receptor calcium
    influx then early channel blockade might slow it independent of seizure
    control; if it is seizure-driven then aggressive seizure control is the
    priority; if it is an independent developmental program then neither will
    help. The index patient's cognitive ability was explicitly unchanged despite
    a two-thirds reduction in seizures on memantine, which is at least
    consistent with the atrophy and developmental impairment being partly
    seizure-independent. Two further observations pull in the same direction and
    sharpen the question. First, in an independent epilepsy-aphasia cohort the
    baseline spike-wave index did not correlate with intellectual disability
    level, and the authors concluded the neuropsychological deterioration is not
    driven by discharge severity alone. Second, and as a genuine counterpoint,
    longitudinal diffusion imaging of Grin2a knockout mice found microstructural
    anomalies that were TRANSIENT - present at postnatal day 30 but not at 15 days
    or 2 months - which is the opposite temporal profile to the progressive human
    atrophy. That contrast may itself be informative, since the mouse is a
    knockout (loss-of-function) whereas the severe human phenotype is
    predominantly gain-of-function, raising the possibility that progressive tissue
    loss is specific to the gain-of-function arm rather than a general consequence
    of GRIN2A disruption.
  proposed_experiments:
  - experiment_id: exp_grin2a_serial_mri_seizure_burden_correlation
    name: Serial volumetric MRI against seizure burden and functional class
    description: >-
      In a prospective GRIN2A cohort, correlate serial volumetric MRI atrophy
      rates with quantified seizure burden, EEG spike load, variant functional
      class, and treatment exposure, to test whether atrophy tracks seizures,
      tracks receptor gain-of-function, or progresses independently.
  - experiment_id: exp_grin2a_model_neurodegeneration_timecourse
    name: Neurodegeneration time course in Grin2a knock-in models with and without seizure suppression
    description: >-
      Quantify neuronal loss, dendritic morphology, and white-matter myelination
      over time in Grin2a gain-of-function knock-in mice, comparing animals in
      which seizures are suppressed by a non-NMDA-receptor anti-seizure drug
      against animals treated with an NMDA-receptor antagonist, to separate
      seizure-driven from receptor-driven neurodegeneration.
  evidence:
  - reference: PMID:24839611
    reference_title: "GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, the proband's myoclonic jerks ceased upon memantine
      treatment. His cognitive ability remained unchanged.
    explanation: >-
      Seizure improvement without cognitive improvement suggests the
      developmental and structural injury is at least partly independent of
      ongoing seizures.
  - reference: PMID:33240831
    reference_title: "Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The baseline severity of the spike-wave index (SWI) was not significantly
      correlated with intellectual disability (ID) level.
    explanation: >-
      Decouples epileptiform burden from cognitive outcome, arguing against a
      purely seizure-driven mechanism for the developmental and structural injury.
  - reference: PMID:33240831
    reference_title: "Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The neuropsychological deterioration in children with EAS might not only be
      completely affected by electric discharge severity but also genetic etiology.
    explanation: >-
      The authors attribute deterioration partly to genetic etiology rather than
      discharge severity alone, which is the alternative this gap seeks to
      distinguish.
  - reference: PMID:30146685
    reference_title: "Transient microstructural brain anomalies and epileptiform discharges in mice defective for epilepsy and language-related NMDA receptor subunit gene Grin2a."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      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.
    explanation: >-
      A direct counterpoint: in the Grin2a knockout mouse the microstructural
      anomalies are transient rather than progressive, the opposite temporal
      profile to the human severe phenotype. Because the model is a knockout
      (loss-of-function) and the severe human phenotype is predominantly
      gain-of-function, this discordance may localize progressive tissue loss to
      the gain-of-function arm.
clinical_trials:
- name: NCT04646447
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Phase 2A, open-label, single-arm, 52-week trial of oral L-serine in children
    aged 2-18 years with GRIN loss-of-function variants (GRIN1, GRIN2A, GRIN2B),
    with adaptive behaviour, motor function, quality of life, seizure frequency,
    and EEG as endpoints.
  target_phenotypes:
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:38380699
    reference_title: "L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we present the first non-randomized, open-label, single-arm trial
      (NCT04646447) designed to evaluate the tolerability and efficacy of
      L-serine in children with GRIN genetic variants leading to
      loss-of-function.
    explanation: >-
      Identifies the trial, its design, and its loss-of-function eligibility
      criterion.
- name: NCT05818943
  phase: PHASE_I
  status: ACTIVE_NOT_RECRUITING
  description: >-
    RAD-GRIN-101: open-label phase 1b study of individually titrated radiprodil,
    a GluN2B-selective NMDA-receptor negative allosteric modulator, in children
    with GRIN-related disorder carrying a gain-of-function variant, assessing
    safety, tolerability, pharmacokinetics, and effects on seizures and
    behavioural symptoms. It is the first clinical test of the
    gain-of-function-directed pharmacology supported by the Grin2aN615S mouse
    rescue data.
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: clinicaltrials:NCT05818943
    reference_title: "A Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Effect on Seizures and Behavioral Symptoms of Multiple Individually Titrated Doses of Radiprodil in Children with GRIN-related Disorder"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Study RAD-GRIN-101 is a phase 1B trial to assess safety, tolerability, PK,
      and potential efficacy of radiprodil for the treatment of GRIN-related
      disorder in children with a Gain-of-Function (GoF) genetic variant.
    explanation: >-
      Confirms the trial's phase, drug, and gain-of-function eligibility
      criterion.
biochemical: []
datasets: []

📚

References & Deep Research

References

2

PMID:27683935

GRIN2A-Related Disorders.

No top-level findings curated for this source.

PMID:30544257

GRIN2A-related disorders: genotype and functional consequence predict phenotype.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 22 citations 2026-08-01T11:55:33.400998

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: GRIN2A-Related Epileptic Encephalopathy and Intellectual Disability
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on GRIN2A-Related Epileptic Encephalopathy and Intellectual Disability covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

GRIN2A-Related Epileptic Encephalopathy and Intellectual Disability

Executive summary

GRIN2A-related disorder is an autosomal-dominant, variably penetrant neurodevelopmental synaptopathy caused by pathogenic variants in GRIN2A, which encodes the GluN2A subunit of the NMDA-type ionotropic glutamate receptor. It is better regarded as a spectrum than as one narrowly defined syndrome. Manifestations range from self-limited childhood focal epilepsy with speech dyspraxia to Landau–Kleffner syndrome, developmental/epileptic encephalopathy with spike-wave activation in sleep (D/EE-SWAS), severe intellectual disability, and early-onset developmental and epileptic encephalopathy. The largest aggregated study comprised 248 individuals and found epilepsy and speech disorder in more than 80% and intellectual disability/developmental impairment in 62.7%. Variant location and functional effect are major determinants of severity. Transmembrane/linker missense variants are usually de novo, frequently gain-of-function (GoF), and associated with severe disease; amino-terminal/ligand-binding-domain missense and protein-null variants more often cause loss-of-function (LoF) and milder epilepsy–aphasia phenotypes. This distinction is clinically important because proposed precision therapies act in opposite directions. (strehlow2019grin2arelateddisordersgenotype pages 1-1, strehlow2019grin2arelateddisordersgenotype pages 11-11)

The compact knowledge-base mapping below summarizes major findings and ontology suggestions.

Domain	Core finding/statistic	Suggested ontology terms	Evidence type/source
Disease identity	GRIN2A-related disorder spans mild focal epilepsy/speech disorder to severe developmental and epileptic encephalopathy within the epilepsy-aphasia spectrum; largest aggregated cohort included 248 affected individuals. Orphanet entry referenced as 289266 in trial registry material. (strehlow2019grin2arelateddisordersgenotype pages 1-1, NCT04646447 chunk 1)	MONDO: GRIN2A-related disorder (if mapped); Orphanet: 289266; HP:0001250 Seizure; HP:0000750 Delayed speech and language development	Human aggregated cohort; trial registry background (Brain 2019; ClinicalTrials.gov)
Gene/protein	Causal gene is GRIN2A encoding GluN2A, an NMDA receptor subunit; pathogenic variation affects receptor function, trafficking, and localization. (vieira2024aframeshiftvariant pages 1-2, tumdam2024nmdareceptorsin pages 4-6)	HGNC: GRIN2A; NCBI Gene: GRIN2A; UniProt: GluN2A; GO:0004972 NMDA glutamate receptor activity	Human molecular genetics; review/in vitro mechanistic synthesis
Epilepsy/EEG	In the 2019 cohort, 27/219 (12.3%) had no seizures; among 152 with EEG, 143/152 (94.1%) had epileptiform discharges, including centrotemporal spikes (34), multifocal discharges (28), and CSWS/SWAS (51). (strehlow2019grin2arelateddisordersgenotype pages 6-7)	HP:0001250 Seizure; HP:0011175 Focal-onset seizure; HP:0010848 Abnormality of EEG; HP:0011185 Centrotemporal spike waves; HP:0011187 Continuous spike-wave during slow-wave sleep	Human cohort (Brain 2019)
Speech-language	Speech disorder was the dominant phenotype: 129/140 (92.1%) had impairment; reported subgroups included moderate dysarthria/dyspraxia (55), aphasia with speech loss (26), delayed speech development (26), and temporary regression (8). (strehlow2019grin2arelateddisordersgenotype pages 6-7)	HP:0000750 Delayed speech and language development; HP:0002167 Dysarthria; HP:0002376 Developmental regression; HP:0031988 Aphasia	Human cohort
ID/development	Intellectual disability/developmental delay present in 62.7% overall; severity ranged from none to profound, with misTMD+linker variants associated with markedly greater severity than misATD+LBD variants. (strehlow2019grin2arelateddisordersgenotype pages 11-11, strehlow2019grin2arelateddisordersgenotype pages 6-7)	HP:0001249 Intellectual disability; HP:0011342 Developmental delay; HP:0010864 Global developmental delay	Human cohort with genotype-phenotype analysis
Motor/behavior	Hypotonia in 40/139 (28.8%); movement disorders in 19/72 (26.4%), including ataxic/dystonic/spastic/choreatic features; neuropsychiatric comorbidity in 17/70 (24.3%), including ADHD (6), autism (6), schizophrenia (2), anxiety (1). (strehlow2019grin2arelateddisordersgenotype pages 6-7)	HP:0001252 Hypotonia; HP:0001251 Ataxia; HP:0001332 Dystonia; HP:0002317 Unsteady gait/ataxia-related; HP:0007018 Attention deficit hyperactivity disorder; HP:0000717 Autism	Human cohort
Anatomy	Imaging abnormalities were reported in 12/85 (14.1%) in the human cohort; mouse knockout imaging showed transient abnormalities in neocortex, corpus callosum, hippocampus, and thalamus, strongest around postnatal day 30. (strehlow2019grin2arelateddisordersgenotype pages 6-7, salmi2018transientmicrostructuralbrain pages 1-2)	UBERON:0000955 brain; UBERON:0001950 cerebral cortex/neocortex; UBERON:0000956 corpus callosum; UBERON:0002421 hippocampus; UBERON:0001897 thalamus	Human cohort; mouse MRI/DTI model
Mechanism (GoF/LoF)	Variant class/domain predicts function and phenotype: missense variants in transmembrane/linker regions are associated with severe developmental phenotypes and NMDAR gain-of-function; missense variants in ATD/LBD and null variants more often associate with NMDAR loss-of-function and milder developmental phenotypes. Severe GoF can also result from specific missense variants such as L812M. (strehlow2019grin2arelateddisordersgenotype pages 1-1, strehlow2019grin2arelateddisordersgenotype pages 3-3)	GO:0004972 NMDA glutamate receptor activity; GO:0050890 cognition/synaptic signaling-related; SO:0001583 missense_variant; SO:0001587 stop_gained; SO:0001909 frameshift_variant	Human cohort integrated with electrophysiology; case functional study
Protein/trafficking dysfunction	A de novo *P1199Rfs32** frameshift truncating the GluN2A CTD caused impaired PSD-95 binding, preserved Scribble1 interaction, increased extrasynaptic expression, fewer synapses, decreased spine density, and was interpreted as loss-of-function. (vieira2024aframeshiftvariant pages 1-2)	GO:0098978 glutamatergic synapse; GO:0043197 dendritic spine; GO:0006897 endocytosis/recycling trafficking; HP:0001250 Seizure	Human case plus heterologous-cell and rat-neuron in vitro study
Diagnosis	Recommended diagnosis is molecular: pathogenic/likely pathogenic GRIN2A variant in an individual with epilepsy, sleep-activated epileptiform EEG/SWAS, speech-language disorder, and/or developmental impairment; functional annotation is important because treatment direction differs for GoF vs LoF variants. (strehlow2019grin2arelateddisordersgenotype pages 11-11, krey2022lserinetreatmentis pages 1-2)	NCIT: Genetic Testing; HP:0010848 Abnormality of EEG; HP:0000750 Delayed speech and language development	Human cohort; retrospective treatment series
Inheritance	Unlike several other GRIN-associated disorders, inherited variants are common: 60.2% of GRIN2A variants were inherited overall; all 32 misTMD+linker variants were de novo, while 18/47 misATD+LBD variants were de novo. Apparent penetrance is incomplete, with only three individuals reported as apparently normal. (strehlow2019grin2arelateddisordersgenotype pages 11-11, strehlow2019grin2arelateddisordersgenotype pages 6-7)	HP:0000006 Autosomal dominant inheritance; HP:0003829 Variable expressivity; HP:0003828 Reduced penetrance	Human cohort
Temporal course	EAS/GRIN2A phenotypes are age-dependent childhood disorders; in mouse knockout, structural abnormalities were transient and most evident at ~1 month, paralleling the childhood onset and variable adolescent outcome described for EAS. (salmi2018transientmicrostructuralbrain pages 1-2)	HP:0011463 Childhood onset; HP:0002376 Developmental regression; HP:0012378 Episodic course	Mouse model with human syndrome framing
Recent SWAS relevance	In a 2024 D/EE-SWAS study, genetic etiology was found in 31/91 (34%) of the core cohort; GRIN genes are part of the etiologic landscape of SWAS disorders, reinforcing GRIN2A testing in relevant EEG-language-regression phenotypes. (viswanathan2024solvingtheetiology pages 1-3)	HP:0011187 Continuous spike-wave during slow-wave sleep; HP:0001288 Aphasia; HP:0001249 Intellectual disability	Human 2024 syndrome cohort
Treatment	Precision treatment remains experimental and mechanism-dependent. In a 10-patient retrospective GRIN2A/GRIN2B series, among 9 LoF/null cases, L-serine was associated with improvement in behavior in 8/9 (89%), development in 4/9 (44%), and EEG or seizure frequency in 4/9 (44%); no side effects were reported in these 9. A GoF case worsened transiently with L-serine. (krey2022lserinetreatmentis pages 1-2)	NCIT:C61742 Serine; NCIT:Anticonvulsant Therapy; HP:0010848 Abnormality of EEG	Human retrospective n-of-1/case-series evidence
Clinical trials	NCT04646447: L-serine in GRIN-related encephalopathy, interventional single-group, estimated enrollment 20, last known recruiting, focused on LoF variants. NCT05818943 Honeycomb: radiprodil (NR2B negative allosteric modulator), phase 1, open-label, active not recruiting, estimated enrollment 24, for pediatric GoF GRIN-related disorder. (NCT04646447 chunk 1, NCT05818943 chunk 1, NCT05818943 chunk 2)	NCIT:C61742 Serine; NCIT:C000626801 radiprodil; NCIT:Clinical Trial	Trial registry
Animal/cellular models	Grin2a KO mouse: transient microstructural brain anomalies and epileptiform discharges in third postnatal week. Grin2a N615S mouse: voltage-independent Ca2+ signaling caused audiogenic seizures, exploratory hyperactivity, attentional/cognitive abnormalities, and altered hippocampal activity. Rat primary neurons/heterologous cells: P1199Rfs*32 caused trafficking/synaptic defects. (salmi2018transientmicrostructuralbrain pages 1-2, bertocchi2021voltageindependentglun2atypenmda pages 1-2, vieira2024aframeshiftvariant pages 1-2)	MGI:Grin2a; GO:0007611 learning or memory; GO:0051930 regulation of sensory perception; CL:0000540 neuron	Mouse model; in vitro neuronal/cell-system evidence
Major evidence gaps	No robust prevalence/incidence estimates specific to GRIN2A-related epileptic encephalopathy/ID were identified; no standardized diagnostic criteria unique to GRIN2A disorder; no approved disease-modifying therapy; treatment evidence remains small, retrospective, and mechanism-stratified; limited data on biomarkers, long-term prognosis, and protective/environmental modifiers. (strehlow2019grin2arelateddisordersgenotype pages 11-11, krey2022lserinetreatmentis pages 1-2, NCT04646447 chunk 1, NCT05818943 chunk 1)	NCIT:Evidence Gap; HP:0000007 Autosomal dominant; GO:0007268 synaptic transmission	Evidence synthesis across cohort, case series, and trial registries

Table: This table maps the main disease-characteristic domains for GRIN2A-related epileptic encephalopathy/intellectual disability to concise evidence-backed findings and suggested ontology terms. It is designed as a compact knowledge-base scaffold that distinguishes cohort, mechanistic, model, and trial-registry evidence.

1. Disease information

Definition and scope

GRIN2A-related disorder is a monogenic disorder of glutamatergic neurotransmission. The historical clinical center of gravity is the epilepsy–aphasia spectrum (EAS), including epilepsy with centrotemporal spikes, atypical childhood epilepsy with centrotemporal spikes, Landau–Kleffner syndrome, and continuous spike-wave during sleep/SWAS. Severe cases qualify as developmental and epileptic encephalopathy, because both the underlying molecular defect and epileptiform activity impair development. EAS is described as an age-dependent childhood disorder with sleep-activated discharges, often infrequent seizures, and language, cognitive, or behavioral deficits. (strehlow2019grin2arelateddisordersgenotype pages 6-7, salmi2018transientmicrostructuralbrain pages 1-2)

The 2022 ILAE framework distinguishes DEE-SWAS, in which developmental impairment predates SWAS, from EE-SWAS, in which development was previously normal and regression or plateauing accompanies SWAS. Developmental sequelae may persist after seizures and SWAS remit. (viswanathan2024solvingtheetiology pages 1-3)

Identifiers and synonyms

Gene: GRIN2A; gene-level OMIM identifier OMIM 138253 is stated in the trial registry. (NCT04646447 chunk 1)
Orphanet: ORPHA:289266, cited for GRIN2A-related encephalopathy in the registry. (NCT04646447 chunk 1)
MONDO: a single confidently verified MONDO identifier was not recovered from the available literature; the knowledge base should map at the broader “GRIN2A-related disorder” level and retain syndrome-level child terms where available.
OMIM phenotype: GRIN2A is historically associated with focal epilepsy with speech disorder, with or without intellectual disability; the exact current phenotype-record number should be verified directly in OMIM before database deposition.
ICD-10/ICD-11 and MeSH: there is no specific GRIN2A code. Cases are coded under genetic/developmental and epileptic encephalopathy, focal epilepsy, Landau–Kleffner syndrome, intellectual disability, and speech/language disorder as clinically appropriate.
Synonyms: GRIN2A-related neurodevelopmental disorder; GRIN2A-related epilepsy; GRIN2A-related epilepsy–aphasia spectrum; focal epilepsy with speech disorder with or without intellectual disability; GRIN2A encephalopathy; GRIN2A-related D/EE-SWAS.

The evidence base is predominantly aggregated disease-level research cohorts, literature-ascertained cases, laboratory functional studies, and registries, rather than routine EHR-derived population surveillance. The landmark cohort combined 92 new cases with 156 published individuals. (strehlow2019grin2arelateddisordersgenotype pages 1-1)

2. Etiology, risk, and protective factors

Causal factor

The primary cause is a heterozygous germline pathogenic or likely pathogenic GRIN2A variant. Relevant classes include missense, nonsense, frameshift, splice-altering variants, exon/multiexon deletions, and larger deletions involving GRIN2A. Variants may be de novo or inherited from an affected, mildly affected, or apparently unaffected parent. In the largest cohort, 60.2% were inherited, while all 32 assessed transmembrane/linker missense variants were de novo; 18/47 amino-terminal/ligand-binding-domain missense variants were de novo. (strehlow2019grin2arelateddisordersgenotype pages 11-11, strehlow2019grin2arelateddisordersgenotype pages 6-7)

Risk factors and modifiers

Genetic: variant domain and functional direction are the strongest established severity predictors. Severe GoF changes cluster around transmembrane/linker/pore regions; null and ATD/LBD LoF variants generally have milder average developmental effects, although exceptions occur. (strehlow2019grin2arelateddisordersgenotype pages 1-1)
Epileptiform activity during development: sleep-activated discharges/SWAS are plausibly secondary contributors to language and cognitive regression. This is an interaction between an upstream genetic synaptopathy and a developmentally timed network insult, not a conventional environmental exposure. (salmi2018transientmicrostructuralbrain pages 1-2, viswanathan2024solvingtheetiology pages 1-3)
Family history: relevant because inherited variants are common and expression may be mild or apparently absent. (strehlow2019grin2arelateddisordersgenotype pages 11-11)
Sex, ancestry, lifestyle, toxins, occupation, diet, or infectious exposure: no replicated disease-specific risk association was identified.

No validated protective allele, modifier gene, environmental protective factor, or conventional gene–environment interaction has been established. Avoid inferring protection from the presence of mildly affected carriers; that may reflect reduced penetrance, variant effect, ascertainment, polygenic background, or unmeasured modifiers.

3. Phenotypes

Core clinical frequencies

In the 2019 aggregate cohort, 27/219 individuals with available data (12.3%) had no seizures. EEG was abnormal in 143/152 (94.1%): 34 had centrotemporal spikes, 28 multifocal discharges, and 51 continuous spike-wave during sleep. Speech disorder occurred in 129/140 (92.1%): moderate dysarthria/dyspraxia in 55, aphasia with speech loss in 26, delayed speech in 26, and temporary regression in 8; only 11 had normal speech. Intellectual disability/developmental impairment affected 62.7%, with severity from mild to profound. (strehlow2019grin2arelateddisordersgenotype pages 11-11, strehlow2019grin2arelateddisordersgenotype pages 6-7)

Other reported findings were hypotonia in 40/139 (28.8%), movement disorder in 19/72 (26.4%), neuropsychiatric comorbidity in 17/70 (24.3%), and MRI abnormalities in 12/85 (14.1%). The neuropsychiatric subset included ADHD (6), autism (6), schizophrenia (2), and anxiety (1); movement findings included ataxic, dystonic, spastic, and choreatic abnormalities. (strehlow2019grin2arelateddisordersgenotype pages 6-7)

Phenotype annotations

Seizures: focal, multifocal, generalized, and mixed seizure types; severity ranges from infrequent childhood seizures to drug-resistant DEE. Suggested HPO: HP:0001250 Seizure, HP:0011175 Focal-onset seizure.
Sleep-activated epileptiform EEG: centrotemporal spikes, multifocal discharges, CSWS/SWAS. Suggested HPO: HP:0010848 Abnormality of EEG, HP:0011187 Continuous spike-wave during slow-wave sleep.
Speech/language disorder: delayed language, verbal dyspraxia, dysarthria, aphasia, acquired language loss, or transient regression. Suggested HPO: HP:0000750 Delayed speech and language development, HP:0002167 Dysarthria, HP:0002376 Developmental regression, aphasia term as locally mapped.
Developmental delay/ID: variable from normal cognition to profound ID. Suggested HPO: HP:0011342 Developmental delay, HP:0010864 Global developmental delay, HP:0001249 Intellectual disability.
Motor findings: hypotonia, dyspraxia, ataxia, dystonia, spasticity, choreiform movement. Suggested HPO: HP:0001252 Hypotonia, HP:0001251 Ataxia, HP:0001332 Dystonia, plus phenotype-specific terms.
Behavior/psychiatry: ADHD, autism, anxiety, aggression, and occasionally psychosis/schizophrenia. Suggested HPO: HP:0007018 ADHD, HP:0000717 Autism, HP:0000739 Anxiety.

Quality-of-life effects have not been quantified with a GRIN2A-specific validated instrument. Clinically, aphasia, cognitive disability, seizures, motor impairment, disturbed sleep, and behavioral dysregulation impair education, communication, independence, family functioning, and caregiver well-being. PedsQL and caregiver burden are outcomes in the ongoing radiprodil program, but no completed GRIN2A-specific estimates were recovered. (NCT05818943 chunk 1, NCT05818943 chunk 2)

4. Genetic and molecular information

GRIN2A encodes GluN2A, a component of heterotetrameric NMDA receptors, typically assembled with two obligatory GluN1 subunits and GluN2/GluN3 subunits. GluN2A-containing receptors are prominent in forebrain excitatory synapses and have developmentally regulated expression. (vieira2024aframeshiftvariant pages 1-2)

Variant interpretation

Pathogenicity assessment should combine ACMG/AMP evidence with inheritance, population rarity, constraint, domain, phenotype, and—where feasible—functional testing. Pathogenic variants causing severe disease are generally absent or extremely rare in population databases; a universal allele-frequency threshold cannot substitute for variant-specific curation. Disease-causing variants are normally germline. Somatic mosaicism is possible in neurodevelopmental genetics but is not established as a major GRIN2A mechanism in the retrieved cohort.

Functional classes include:

Haploinsufficiency/null LoF: nonsense, frameshift, splice, and deletions reduce functional GluN2A dosage.
Missense LoF: altered agonist sensitivity, reduced current, impaired surface/synaptic localization, or defective trafficking.
Missense GoF: increased agonist potency/open probability, reduced magnesium/proton/zinc inhibition, prolonged responses, or excess current.
Mixed/complex effects: trafficking and channel-gating effects may coexist; “null equals simple hypofunction” and “missense equals GoF” are unsafe assumptions.

The cohort-level correlation was explicit: transmembrane/linker missense variants were associated with severe developmental phenotypes and GoF, whereas ATD/LBD missense and null variants were associated on average with LoF and milder phenotypes. (strehlow2019grin2arelateddisordersgenotype pages 1-1, strehlow2019grin2arelateddisordersgenotype pages 6-7)

A mechanistically informative 2024 study examined de novo GluN2A p.P1199Rfs*32, which truncates approximately half the C-terminal domain. The authors reported increased extrasynaptic receptor localization, impaired PSD-95 binding, retained Scribble1-mediated recycling, fewer synapses, and decreased dendritic-spine density. Their abstract concludes: “Overall, our data show that GluN2A P1199Rfs*32 is a loss-of-function variant with altered membrane localization in neurons.” (vieira2024aframeshiftvariant pages 1-2)

No validated GRIN2A modifier gene or reproducible disease-specific epigenetic signature is established. Large deletions/CNVs involving GRIN2A can cause disease, but karyotype-level aneuploidy, balanced translocation, repeat expansion, and mitochondrial mechanisms are not characteristic.

5. Environmental information

There is no evidence that toxins, radiation, pollution, occupation, smoking, alcohol, diet, exercise, or infectious agents cause the Mendelian disorder. Fever, sleep deprivation, illness, or medication nonadherence may trigger seizures in susceptible individuals, as in epilepsy generally, but this is not equivalent to causing GRIN2A disease. Lifestyle measures support seizure safety and general health but do not reverse the genotype.

6. Mechanism and pathophysiology

Upstream-to-downstream causal chain

Upstream trigger: pathogenic GRIN2A variant.
Protein effect: altered GluN2A abundance, folding, gating, magnesium block, agonist sensitivity, intracellular interactions, recycling, or synaptic targeting.
Receptor effect: NMDA-receptor hypo- or hyperfunction and disturbed Ca²⁺/Na⁺ influx.
Synaptic effect: abnormal coincidence detection, excitatory transmission, long-term potentiation, dendritic-spine maintenance, synapse formation, and activity-dependent gene regulation.
Circuit effect: disturbed excitatory–inhibitory balance and maturation of cortical/thalamocortical, hippocampal, language, attention, and sensory circuits.
Clinical effect: seizures and sleep-activated epileptiform activity, language delay/regression, ID, behavior abnormalities, and movement dysfunction. Recurrent epileptiform activity can then become a downstream amplifier of developmental impairment.

NMDAR activation normally requires glutamate plus a co-agonist and postsynaptic depolarization sufficient to relieve the magnesium pore block. Resulting calcium influx activates signaling underlying synaptic plasticity, dendritic organization, and gene regulation. Disease variants can cause either receptor hypofunction or hyperfunction, explaining why both insufficient and excessive glutamatergic signaling produce epilepsy and developmental disability. (tumdam2024nmdareceptorsin pages 4-6)

The p.P1199Rfs*32 work provides a trafficking-to-phenotype chain: CTD truncation → loss of PSD-95 interactions with preserved Scribble1 recycling → excess extrasynaptic relative to synaptic localization → reduced spine/synapse density → compromised synaptic transmission → epilepsy, aphasia, and behavioral/developmental disease. This evidence combines one human case with heterologous cells and rat primary neurons; it is not a clinical cohort. (vieira2024aframeshiftvariant pages 1-2)

Suggested terms include GO:0004972 NMDA glutamate receptor activity, GO:0035249 synaptic transmission, glutamatergic, GO:0098978 glutamatergic synapse, GO:0043197 dendritic spine, GO:0007611 learning or memory, CL:0000540 neuron, excitatory-neuron and cortical-pyramidal-neuron child terms where supported.

No replicated GRIN2A-specific metabolomic, lipidomic, immune, inflammatory, or tissue-necrosis signature is established. The biochemical abnormality is receptor/channel dysfunction, not an enzyme deficiency. Patient single-cell or spatial-transcriptomic atlases and systematic multi-omics studies remain major gaps.

7. Anatomical structures affected

The primary organ is the central nervous system, particularly cortical and thalamocortical networks responsible for language and sleep-activated epileptiform synchronization, plus hippocampal circuits involved in memory. Suggested UBERON terms include UBERON:0000955 brain, cerebral cortex/neocortex, UBERON:0000956 corpus callosum, UBERON:0002421 hippocampus, and UBERON:0001897 thalamus.

Routine MRI is often normal; abnormalities were reported in only 12/85 individuals in the aggregate cohort. (strehlow2019grin2arelateddisordersgenotype pages 6-7) Grin2a-knockout mouse diffusion imaging showed transient microstructural abnormalities in neocortex, corpus callosum, hippocampus, and thalamus, strongest at postnatal day 30. (salmi2018transientmicrostructuralbrain pages 1-2) There is no consistent lateralization, peripheral-organ pathology, or characteristic biopsy finding.

At the cellular/subcellular level, the principal sites are excitatory postsynaptic membranes, postsynaptic density, dendritic spines, and extrasynaptic neuronal membrane. Suggested GO cellular-component terms include glutamatergic synapse, postsynaptic density, dendritic spine, and plasma membrane.

8. Temporal development

Onset is usually pediatric and often follows apparently normal early development in classic EAS. Seizures and sleep-activated discharges emerge during childhood; language delay may precede seizures, whereas acquired aphasia or broader regression may coincide with increasing sleep epileptiform activity. Severe GoF variants can cause much earlier DEE.

Course is variable and lifelong at the genetic level. Seizures and SWAS may remit with age, but speech, cognitive, behavioral, or motor sequelae can persist. The 2024 SWAS cohort found that DEE-SWAS was associated with longer epilepsy duration and poorer intellectual outcome than EE-SWAS. (viswanathan2024solvingtheetiology pages 1-3)

The Grin2a-knockout mouse recapitulates developmental timing: epileptiform discharges appeared in the third postnatal week and MRI abnormalities peaked at approximately one month before becoming less evident later. The authors interpreted this as evidence for early maturation abnormalities in neocortical and thalamocortical systems. (salmi2018transientmicrostructuralbrain pages 1-2)

9. Inheritance and population

Inheritance is autosomal dominant, with both de novo and inherited variants. Expressivity is strikingly variable. Apparent penetrance is incomplete: only three individuals in the aggregate cohort were described as apparently normal, but subtle language, EEG, psychiatric, or learning phenotypes may be missed. (strehlow2019grin2arelateddisordersgenotype pages 11-11)

Parental testing is essential. A clinically unaffected parent carrying the variant changes recurrence risk substantially. Germline mosaicism remains possible even after apparently de novo occurrence, so recurrence risk is above population baseline. There is no anticipation mechanism, established founder effect, consanguinity dependence, or meaningful “carrier frequency” analogous to a recessive disorder.

Robust incidence and prevalence per 100,000 are unavailable. One study noted that GRIN2A defects had been identified in up to 20% of selected EAS patients/families; this is an etiologic fraction in an enriched phenotype, not population prevalence. (salmi2018transientmicrostructuralbrain pages 1-2) Another study stated that monogenic GRIN2A variants account for more than 5% of rolandic epilepsy cases, again not general-population prevalence. No reproducible sex, ethnic, or geographic enrichment is established.

10. Diagnostics

Clinical evaluation

Diagnosis should be considered in a child with focal or mixed epilepsy plus speech dyspraxia/dysarthria, delayed language, acquired aphasia, intellectual disability, or regression—especially when EEG shows centrotemporal spikes, multifocal discharges, or marked activation in non-REM sleep.

Recommended evaluation includes:

detailed seizure and developmental history, three-generation pedigree, and dysmorphology/neurologic examination;
prolonged EEG including adequate non-REM sleep; video-EEG where seizure classification is uncertain;
formal speech-language, neuropsychological, motor, behavioral, and autism/ADHD assessment;
brain MRI to exclude structural etiologies, despite frequently normal imaging;
hearing evaluation in language regression and targeted metabolic/infectious testing only where clinically indicated.

There is no diagnostic blood, urine, CSF, protein, or metabolite biomarker. EEG is the principal functional biomarker but is not gene-specific.

Genetic testing strategy

Use a comprehensive epilepsy/DEE/epilepsy–aphasia panel or trio exome/genome sequencing with GRIN2A and other SWAS genes.
Ensure copy-number calling; use chromosomal microarray if exome/panel CNV sensitivity is limited or syndromic findings suggest a chromosomal lesion.
Confirm the variant and test parents. Deep sequencing can be considered if mosaicism is suspected.
Interpret with ACMG/AMP criteria and ClinVar/ClinGen evidence, avoiding treatment assignment from in-silico prediction alone.
For candidate missense variants, receptor electrophysiology and trafficking assays can be decisive because GoF versus LoF determines the logic of experimental therapy.

Karyotyping/FISH are reserved for suspected large rearrangements. Mitochondrial, repeat-expansion, liquid-biopsy, proteomic, and metabolomic tests have no routine role.

Differentials include structural D/EE-SWAS, non-GRIN2A epilepsy–aphasia disorders, and other monogenic epilepsies. The 2024 D/EE-SWAS cohort found an etiology in 42/91 (46%), including a genetic cause in 31/91 (34%) and structural cause in 12/91 (13%), demonstrating substantial etiologic heterogeneity. (viswanathan2024solvingtheetiology pages 1-3)

Population newborn screening is not available. Cascade testing is appropriate after a familial variant is identified. Prenatal diagnosis and preimplantation genetic testing are technically possible for a known familial pathogenic variant.

11. Outcome and prognosis

No reliable disease-specific survival curve, life expectancy, or mortality rate is available. Most morbidity derives from communication disability, cognitive impairment, seizures, behavioral/psychiatric complications, motor dysfunction, and caregiver burden. Severe drug-resistant epilepsy may carry the general risks of injury, status epilepticus, and sudden unexpected death in epilepsy, but GRIN2A-specific rates are unknown.

Prognosis is strongly variable. More favorable indicators include null or ATD/LBD LoF variants, milder early development, infrequent seizures, and absence of prolonged SWAS. Worse outcomes correlate with transmembrane/linker GoF variants, early DEE, severe ID, and prolonged D/EE-SWAS. These are group-level associations rather than deterministic individual predictions. (strehlow2019grin2arelateddisordersgenotype pages 1-1, strehlow2019grin2arelateddisordersgenotype pages 6-7, viswanathan2024solvingtheetiology pages 1-3)

Speech and cognitive recovery may be incomplete even after electrographic and seizure remission. There is no validated molecular prognostic biomarker beyond variant class/domain and functional characterization.

12. Treatment

Standard symptomatic care

No GRIN2A-specific drug is approved. Treatment is individualized by epilepsy syndrome and seizure type and may include conventional antiseizure medicines, rescue medication and status-epilepticus planning, and—when SWAS is present—therapies used for ESES/SWAS such as benzodiazepines, corticosteroids, or other specialist-directed regimens. Ketogenic diet, vagus-nerve stimulation, or epilepsy surgery may be considered for refractory disease, although surgery is most rational when a focal structural/epileptogenic lesion is demonstrated rather than for a diffuse germline synaptopathy.

Speech-language therapy, augmentative communication, occupational/physical therapy, educational accommodations, behavioral treatment, sleep management, and psychiatric care are central. Suggested NCIT mappings include Anticonvulsant Therapy, Speech Therapy, Occupational Therapy, Physical Therapy, Ketogenic Diet, Vagus Nerve Stimulation, and Genetic Counseling.

Mechanism-directed experimental therapy

L-serine for LoF/null variants. L-serine is converted to D-serine, an NMDAR co-agonist. In a retrospective series of ten GRIN2A/GRIN2B patients treated as independent n-of-1 trials, nine had LoF/null variants. Eight of nine (89%) had reported behavioral improvement, four (44%) developmental improvement, and four (44%) EEG or seizure-frequency improvement; none of these nine had reported adverse findings. The single erroneously treated GoF case had immediate, temporary behavioral deterioration. Doses ranged from 100–850 mg/kg/day, usually in three or four divided doses, and most patients received concomitant antiseizure medication. These uncontrolled, partly subjective observations are hypothesis-generating, not proof of efficacy. (krey2022lserinetreatmentis pages 1-2)

The relevant abstract states: “Among all nine individuals with LoF missense or null variants, L-serine treatment was associated with improvements in behavior in eight (89%), in development in four (44%), and/or in EEG or seizure frequency in four (44%).” (krey2022lserinetreatmentis pages 1-2)

NCT04646447 is an open-label, single-group study of L-serine in functionally annotated LoF GRIN-related encephalopathy, planned enrollment 20, age over two years. The registry record’s last known status was recruiting but had not been recently verified. It proposed approximately 500 mg/kg/day based on prior experience. ClinicalTrials.gov: NCT04646447. (NCT04646447 chunk 1)

NMDAR antagonism for GoF variants. Memantine has mechanistic and anecdotal support for selected GoF variants, but efficacy cannot be generalized because variant pharmacology differs. Functional testing and specialist oversight are essential. A 2024 expert review summarized memantine for GoF and L-serine for LoF as potentially available personalized approaches while emphasizing that effectiveness requires trials. The severe functional consequences of pore/linker GoF variants support this precision strategy, but not empirical antagonist use in every GRIN2A patient. (strehlow2019grin2arelateddisordersgenotype pages 1-1)

Radiprodil. Honeycomb, NCT05818943, is an open-label phase 1 study of radiprodil in 24 children aged 6 months–12 years with functionally confirmed GoF GRIN variants. Radiprodil is an orally active negative allosteric modulator of the GluN2B/NR2B subunit; outcomes include safety, pharmacokinetics, video-EEG seizure burden, seizure frequency, behavior, motor function, sleep, PedsQL, and caregiver burden. As of the registry’s November 2024 verification it was active, not recruiting. This is a pan-GRIN mechanistic trial, not evidence of established GRIN2A efficacy. ClinicalTrials.gov: NCT05818943. (NCT05818943 chunk 1, NCT05818943 chunk 2)

Gene replacement, CRISPR editing, antisense/RNA therapy, and cell therapy remain preclinical concepts; no approved or disease-specific clinical implementation was identified.

13. Prevention

Primary prevention through lifestyle or vaccination is not applicable to a dominantly inherited/de novo disorder. Relevant prevention is reproductive and complication-focused:

preconception and prenatal genetic counseling;
parental/cascade testing;
prenatal diagnosis or PGT-M for a known pathogenic familial variant;
early EEG including sleep and rapid treatment of escalating SWAS or seizures;
seizure first-aid plans, water/heights precautions, medication adherence, rescue therapy, and SUDEP counseling according to epilepsy risk;
early speech, developmental, behavioral, and educational intervention.

No prophylactic medication is recommended for an asymptomatic carrier solely on genotype. There is no population or newborn-screening program.

14. Other species and natural disease

GRIN2A/Grin2a orthologs are evolutionarily conserved across mammals and vertebrates because NMDA-receptor signaling is fundamental to synaptic plasticity. No well-established naturally occurring veterinary syndrome directly homologous to human GRIN2A epilepsy–aphasia disorder was recovered. There is no infectious transmission or zoonotic potential.

Suggested taxonomy annotations include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Rattus norvegicus (10116), and Danio rerio (7955) for experimental systems. Breed ontology is not applicable without a confirmed natural animal disease.

15. Model organisms and experimental systems

Grin2a knockout mouse

Longitudinal diffusion MRI found transient microstructural changes in neocortex, corpus callosum, hippocampus, and thalamus, mainly at postnatal day 30, while EEG showed neocortical epileptiform discharges in the third postnatal week. The abstract states: “Grin2a KO mice replicated several anomalies found in patients with EAS disorders.” The model supports study of developmental thalamocortical/cortical maturation and treatment timing, but it models complete loss rather than heterozygous human domain-specific GoF variants and cannot recapitulate human language. Epilepsia 2018; DOI 10.1111/epi.14543. (salmi2018transientmicrostructuralbrain pages 1-2)

Grin2a N615S knock-in mouse

This pore-region model reduces voltage-dependent magnesium block. It developed NMDAR-dependent audiogenic seizures from hyperexcitable midbrain circuits, exploratory hyperactivity, dysregulated attention and associative learning, reduced hippocampal c-Fos response, and impaired theta–gamma synchronization. It is valuable for GoF pore physiology and circuit-specific consequences but does not model typical haploinsufficiency. Communications Biology 2021; DOI 10.1038/s42003-020-01538-4. (bertocchi2021voltageindependentglun2atypenmda pages 1-2)

Cellular systems

Heterologous expression, Xenopus-oocyte/two-electrode voltage clamp, and mammalian electrophysiology define agonist potency, current density, magnesium block, deactivation, open probability, surface expression, and drug response. Rat primary cortical neurons assess receptor localization, dendritic spines, and synapses. These systems are indispensable for variant classification and precision-treatment logic but lack whole-brain developmental and pharmacokinetic context. The p.P1199Rfs*32 study is a recent exemplar. Journal of Neuroscience, published January 24, 2024; DOI 10.1523/JNEUROSCI.0557-23.2023. (vieira2024aframeshiftvariant pages 1-2)

Patient-derived iPSC neurons, cerebral organoids, zebrafish knockouts, and CRISPR isogenic lines are promising for cell-type-specific phenotyping and drug screening, but mature GRIN2A-specific datasets were not established in the retrieved 2023–2024 literature.

Evidence limitations and curation recommendations

The strongest natural-history evidence remains the 2019 248-person aggregate cohort; ascertainment was referral- and publication-based, denominators vary by phenotype, and frequencies should not be treated as population prevalence. (strehlow2019grin2arelateddisordersgenotype pages 1-1, strehlow2019grin2arelateddisordersgenotype pages 6-7) Recent 2023–2024 advances are predominantly mechanistic—especially C-terminal trafficking—and syndrome-level genomic work in D/EE-SWAS rather than new large GRIN2A-specific prospective cohorts. (vieira2024aframeshiftvariant pages 1-2, viswanathan2024solvingtheetiology pages 1-3)

For knowledge-base curation, record variant-specific functional direction, assay system, inheritance, EEG state during sleep, developmental status before seizures/SWAS, speech phenotype, and treatment exposure. Do not annotate L-serine, memantine, or radiprodil as established effective therapy; label them experimental and mechanism-stratified. PMID values were not consistently present in the retrieved full texts, so DOI and trial URLs are provided rather than risking incorrect PMID assignment.

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(strehlow2019grin2arelateddisordersgenotype pages 6-7): Vincent Strehlow, Henrike O Heyne, Danique R M Vlaskamp, Katie F M Marwick, Gabrielle Rudolf, Julitta de Bellescize, Saskia Biskup, Eva H Brilstra, Oebele F Brouwer, Petra M C Callenbach, Julia Hentschel, Edouard Hirsch, Peter C Kind, Cyril Mignot, Konrad Platzer, Patrick Rump, Paul A Skehel, David J A Wyllie, Giles E Hardingham, Conny M A van Ravenswaaij-Arts, Gaetan Lesca, Johannes R Lemke, Alexis Arzimanoglou, Paul B Augustijn, Patrick Van Bogaert, Helene Bourry, Peter Burfeind, Yoyo Chu, Brian Chung, Diane Doummar, Patrick Edery, Aviva Fattal-Valevski, Mélanie Fradin, Marion Gerard, Christa de Geus, Boudewijn Gunning, Danielle Hasaerts, Ingo Helbig, Katherine L Helbig, Rami Jamra, Mélanie Jennesson Lyver, Jolien S Klein Wassink-Ruiter, David A Koolen, Damien Lederer, Roelineke J Lunsing, Mikaël Mathot, Hélène Maurey, Shay Menascu, Anne Michel, Ghayda Mirzaa, Diana Mitter, Hiltrud Muhle, Rikke S Møller, Caroline Nava, Margaret O’Brien, Evelyn van Pinxteren-Nagler, Anne van Riesen, Christelle Rougeot, Damien Sanlaville, Jolanda H Schieving, Steffen Syrbe, Hermine E Veenstra-Knol, Nienke Verbeek, Dorothée Ville, Yvonne J Vos, Pascal Vrielynck, Sabrina Wagner, Sarah Weckhuysen, and Marjolein H Willemsen. Grin2a-related disorders: genotype and functional consequence predict phenotype. Brain, 142:80-92, Dec 2019. URL: https://doi.org/10.1093/brain/awy304, doi:10.1093/brain/awy304. This article has 282 citations and is from a highest quality peer-reviewed journal.
(salmi2018transientmicrostructuralbrain pages 1-2): Manal Salmi, Radu Bolbos, Sylvian Bauer, Marat Minlebaev, Nail Burnashev, and Pierre Szepetowski. Transient microstructural brain anomalies and epileptiform discharges in mice defective for epilepsy and language‐related nmda receptor subunit gene grin2a. Epilepsia, 59:1919-1930, Aug 2018. URL: https://doi.org/10.1111/epi.14543, doi:10.1111/epi.14543. This article has 47 citations and is from a domain leading peer-reviewed journal.
(strehlow2019grin2arelateddisordersgenotype pages 3-3): Vincent Strehlow, Henrike O Heyne, Danique R M Vlaskamp, Katie F M Marwick, Gabrielle Rudolf, Julitta de Bellescize, Saskia Biskup, Eva H Brilstra, Oebele F Brouwer, Petra M C Callenbach, Julia Hentschel, Edouard Hirsch, Peter C Kind, Cyril Mignot, Konrad Platzer, Patrick Rump, Paul A Skehel, David J A Wyllie, Giles E Hardingham, Conny M A van Ravenswaaij-Arts, Gaetan Lesca, Johannes R Lemke, Alexis Arzimanoglou, Paul B Augustijn, Patrick Van Bogaert, Helene Bourry, Peter Burfeind, Yoyo Chu, Brian Chung, Diane Doummar, Patrick Edery, Aviva Fattal-Valevski, Mélanie Fradin, Marion Gerard, Christa de Geus, Boudewijn Gunning, Danielle Hasaerts, Ingo Helbig, Katherine L Helbig, Rami Jamra, Mélanie Jennesson Lyver, Jolien S Klein Wassink-Ruiter, David A Koolen, Damien Lederer, Roelineke J Lunsing, Mikaël Mathot, Hélène Maurey, Shay Menascu, Anne Michel, Ghayda Mirzaa, Diana Mitter, Hiltrud Muhle, Rikke S Møller, Caroline Nava, Margaret O’Brien, Evelyn van Pinxteren-Nagler, Anne van Riesen, Christelle Rougeot, Damien Sanlaville, Jolanda H Schieving, Steffen Syrbe, Hermine E Veenstra-Knol, Nienke Verbeek, Dorothée Ville, Yvonne J Vos, Pascal Vrielynck, Sabrina Wagner, Sarah Weckhuysen, and Marjolein H Willemsen. Grin2a-related disorders: genotype and functional consequence predict phenotype. Brain, 142:80-92, Dec 2019. URL: https://doi.org/10.1093/brain/awy304, doi:10.1093/brain/awy304. This article has 282 citations and is from a highest quality peer-reviewed journal.
(krey2022lserinetreatmentis pages 1-2): Ilona Krey, Sarah von Spiczak, Kathrine M. Johannesen, Christiane Hikel, Gerhard Kurlemann, Hiltrud Muhle, Diane Beysen, Tobias Dietel, Rikke S. Møller, Johannes R. Lemke, and Steffen Syrbe. L-serine treatment is associated with improvements in behavior, eeg, and seizure frequency in individuals with grin-related disorders due to null variants. Neurotherapeutics, 19:334-341, Jan 2022. URL: https://doi.org/10.1007/s13311-021-01173-9, doi:10.1007/s13311-021-01173-9. This article has 68 citations and is from a peer-reviewed journal.
(viswanathan2024solvingtheetiology pages 1-3): Sindhu Viswanathan, Karen L. Oliver, Brigid M. Regan, Amy L. Schneider, Candace T. Myers, Michele G. Mehaffey, Amy J. LaCroix, Jayne Antony, Richard Webster, Michael Cardamone, Gopinath M. Subramanian, Annie T.G. Chiu, Eugenia Roza, Raluca I. Teleanu, Stephen Malone, Richard J. Leventer, Deepak Gill, Samuel F. Berkovic, Michael S. Hildebrand, Beatrice S. Goad, Katherine B. Howell, Joseph D. Symonds, Andreas Brunklaus, Lynette G. Sadleir, Sameer M. Zuberi, Heather C. Mefford, and Ingrid E. Scheffer. Solving the etiology of developmental and epileptic encephalopathy with spike–wave activation in sleep (d/ee‐swas). Annals of Neurology, 96:932-943, Aug 2024. URL: https://doi.org/10.1002/ana.27041, doi:10.1002/ana.27041. This article has 21 citations and is from a highest quality peer-reviewed journal.
(NCT05818943 chunk 1): Honeycomb: Evaluation of Radiprodil in Children with GRIN-related Disorder. GRIN Therapeutics, Inc.. 2023. ClinicalTrials.gov Identifier: NCT05818943
(NCT05818943 chunk 2): Honeycomb: Evaluation of Radiprodil in Children with GRIN-related Disorder. GRIN Therapeutics, Inc.. 2023. ClinicalTrials.gov Identifier: NCT05818943
(bertocchi2021voltageindependentglun2atypenmda pages 1-2): Ilaria Bertocchi, Ahmed Eltokhi, Andrey Rozov, Vivan Nguyễn Chi, Vidar Jensen, Thorsten Bus, Verena Pawlak, Marta Serafino, Hannah Sonntag, Boyi Yang, Nail Burnashev, Shi-Bin Li, Horst A. Obenhaus, Martin Both, Burkhard Niewoehner, Frank N. Single, Michael Briese, Thomas Boerner, Peter Gass, John Nick P. Rawlins, Georg Köhr, David M. Bannerman, and Rolf Sprengel. Voltage-independent glun2a-type nmda receptor ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice. Communications Biology, Jan 2021. URL: https://doi.org/10.1038/s42003-020-01538-4, doi:10.1038/s42003-020-01538-4. This article has 45 citations and is from a peer-reviewed journal.

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Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Differential Diagnoses

Clinical Trials

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

GRIN2A-Related Epileptic Encephalopathy and Intellectual Disability

Executive summary

1. Disease information

Definition and scope

Identifiers and synonyms

2. Etiology, risk, and protective factors

Causal factor

Risk factors and modifiers

3. Phenotypes

Core clinical frequencies

Phenotype annotations

4. Genetic and molecular information

Variant interpretation

5. Environmental information

6. Mechanism and pathophysiology

Upstream-to-downstream causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical evaluation

Genetic testing strategy

11. Outcome and prognosis

12. Treatment

Standard symptomatic care

Mechanism-directed experimental therapy

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Grin2a knockout mouse

Grin2a N615S knock-in mouse

Cellular systems

Evidence limitations and curation recommendations

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