GRIN1-Related Neurodevelopmental Disorder

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Classifications

Harrison's Chapter

Channelopathy

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Mappings

MONDO

MONDO:1060123 GRIN1-related complex neurodevelopmental disorder

This entry is deliberately anchored on the gene-level MONDO umbrella MONDO:1060123 (GRIN1-related complex neurodevelopmental disorder), whose MONDO definition names GRIN1 (HGNC:4584) as the causal gene, rather than on a single clinical subtype. The umbrella subsumes the phenotypic and inheritance breadth of the disorder (de novo autosomal dominant and biallelic autosomal recessive; gain- and loss-of-function), matching the unified mechanism-based scope of this dismech entry.

MONDO:0030727 developmental and epileptic encephalopathy 101 Not Yet Curated

DEE101 (MONDO:0030727) is a GRIN1 child of the umbrella, representing the developmental-and-epileptic-encephalopathy end of the spectrum.

MONDO:0013655 neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant Not Yet Curated

The autosomal dominant (de novo) GRIN1 child of the umbrella, capturing the heterozygous-variant, hyperkinetic-movement presentation.

MONDO:0060629 neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive Not Yet Curated

The autosomal recessive GRIN1 child of the umbrella, capturing the biallelic (homozygous) loss-of-function presentation.

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Inheritance

2

Autosomal dominant HP:0000006

Most affected individuals have a heterozygous de novo GRIN1 pathogenic missense variant; inheritance is autosomal dominant and probands are typically simplex cases.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:31219694 SUPPORT Human Clinical

"All probands with a heterozygous GRIN1 pathogenic variant reported to date whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GRIN1 pathogenic missense variant."

GeneReviews documents the de novo, autosomal dominant origin of the heterozygous form.

PMID:27164704 SUPPORT Human Clinical

"We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients."

The founding cohort established heterozygous de novo GRIN1 variants as the predominant cause.

Autosomal recessive HP:0000007

A minority of individuals have biallelic (homozygous) GRIN1 pathogenic missense or truncating variants, inherited in an autosomal recessive manner from unaffected heterozygous carrier parents; because two GluN1 subunits are obligatory, biallelic null variants abolish the receptor.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:31219694 SUPPORT Human Clinical

"each sib of an individual with biallelic GRIN1 pathogenic variants has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."

GeneReviews genetic-counseling recurrence-risk statement for the autosomal recessive (biallelic) form.

PMID:28051072 SUPPORT Human Clinical

"support the existence of hypomorphic variants causing severe neurodevelopmental impairment with autosomal recessive inheritance."

A consanguineous family with a homozygous hypomorphic GRIN1 variant demonstrates autosomal recessive inheritance.

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Discussions and Knowledge Gaps

1

Can GRIN1 variants be reliably partitioned into gain-of-function and loss-of-function classes, and does that functional classification predict the correct genotype-directed precision therapy (NMDA-receptor channel blockers such as memantine for gain-of-function versus NMDA-receptor co-agonist strategies such as L-serine for loss-of-function)?

KNOWLEDGE GAP OPEN gap_grin1_gof_vs_lof_precision_therapy

Attached to

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

GRIN1 variants converge on the same disorder through opposite changes in receptor activity, so the gain-of-function versus loss-of-function distinction is potentially the key determinant of rational, opposite-direction treatment (channel blockade to damp excess activity versus co-agonist supplementation to boost deficient activity). However, functional classification requires electrophysiological characterization unavailable for most variants, many variants have mixed or indeterminate effects, and the founding cohort noted that the extent of measured loss of function correlated only marginally with the uniformly severe clinical phenotype, suggesting secondary compensatory mechanisms. Whether functional class prospectively predicts treatment response is central to precision therapy for GRIN1-NDD.

Proposed experiments

Functional-class to genotype-directed treatment-response mapping

exp_grin1_functional_class_to_treatment_map

Characterize a large panel of patient GRIN1 variants with standardized electrophysiology (agonist potency, open probability, calcium permeability, magnesium block, surface expression) to assign gain- or loss-of-function class, then prospectively correlate class with responses to genotype-matched therapy (memantine for gain-of-function; L-serine or other co-agonist strategies for loss-of-function).

Show evidence (2 references)

PMID:41489401 SUPPORT Human Clinical

"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."

Correct gain-/loss-of-function classification is emphasized as a prerequisite for precision therapy, framing the open question.

PMID:38380699 SUPPORT Human Clinical

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

The L-serine loss-of-function trial included GRIN1 patients, the opposite therapeutic arm to memantine for gain-of-function.

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Pathophysiology

6

GRIN1 Variant and Altered GluN1/NMDA Receptor Function

De novo heterozygous missense variants (clustered in the transmembrane, pore, and ligand-binding domains) or biallelic missense/truncating variants in GRIN1 alter GluN1, the obligatory subunit of the NMDA receptor. Because every NMDA receptor contains two GluN1 subunits, these variants perturb the glutamate-gated, calcium-permeable channel that mediates excitatory neurotransmission across the developing brain.

glutamatergic neuron CL:0000679

glutamate receptor signaling GO:0007215 ⚠ ABNORMAL

NMDA glutamate receptor activity GO:0004972 ⚠ ABNORMAL

Downstream

NMDA Receptor Gain-of-Function A subset of missense variants (especially in the M3 helix and pore) increases receptor activity.

NMDA Receptor Loss-of-Function Other missense variants, and biallelic missense/truncating variants, reduce receptor function.

Show evidence (2 references)

PMID:29365063 SUPPORT Human Clinical

"GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor."

GRIN1 encodes the essential (obligatory) GluN1 subunit of the NMDA receptor, so variants perturb the receptor directly.

PMID:27164704 SUPPORT Human Clinical

"Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect."

De novo GRIN1 missense variants cluster in transmembrane segments and alter channel function.

NMDA Receptor Gain-of-Function

A subset of GRIN1 missense variants increases NMDA receptor activity by enhancing agonist potency, increasing channel open probability and calcium permeability, or reducing voltage-dependent magnesium and proton inhibition, producing excessive NMDA-receptor-mediated current and calcium influx.

glutamatergic neuron CL:0000679

calcium ion transmembrane transport GO:0070588 ↑ INCREASED glutamate receptor signaling GO:0007215 ↑ INCREASED

calcium channel activity GO:0005262 ↑ INCREASED

Downstream

Disrupted Excitatory Neurotransmission and E/I Imbalance Excessive receptor current and calcium influx dysregulate excitatory signaling and network excitability.

Gain-of-Function Cortical Maldevelopment S2/M3-region gain-of-function variants perturb cortical neurodevelopment, producing extensive bilateral polymicrogyria.

Show evidence (2 references)

PMID:29365063 SUPPORT In Vitro

"Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor."

Polymicrogyria-associated GRIN1 variants increased agonist potency, a gain-of-function change in receptor activity.

PMID:38538865 SUPPORT In Vitro

"All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype."

GRIN1/GRIN2 M3-helix variants predominantly enhance channel gating, a gain-of-function mechanism.

Gain-of-Function Cortical Maldevelopment

A distinct subset of gain-of-function GRIN1 missense variants clustered in the S2 and M3 regions perturbs NMDA-receptor-dependent cortical neurodevelopment, producing a malformation of cortical development (extensive bilateral polymicrogyria); this is the opposite mechanistic direction from the classic loss-of-function route to the disorder.

glutamatergic neuron CL:0000679

cerebral cortex development GO:0021987 ⚠ ABNORMAL

Downstream

Impaired Neurodevelopment The cortical malformation is part of the impaired-neurodevelopment phenotype in the gain-of-function subset.

Show evidence (2 references)

PMID:29365063 SUPPORT Human Clinical

"Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy."

Gain-of-function GRIN1 variants cause a distinct cortical malformation (extensive bilateral polymicrogyria).

PMID:29365063 SUPPORT In Vitro

"Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor."

The polymicrogyria-associated variants are gain-of-function with increased agonist potency or reduced proton inhibition.

NMDA Receptor Loss-of-Function

Other GRIN1 variants reduce NMDA receptor function: de novo missense variants lower agonist potency and maximal current (frequently with a dominant-negative effect on hetero-oligomeric receptors), while biallelic truncating variants abolish receptor assembly. Because two GluN1 subunits are obligatory, loss of both alleles produces a functional NMDA-receptor knockout.

glutamatergic neuron CL:0000679

glutamate receptor signaling GO:0007215 ↓ DECREASED

Downstream

Disrupted Excitatory Neurotransmission and E/I Imbalance Reduced NMDA-receptor-mediated current diminishes excitatory drive and destabilizes network excitability.

Impaired Neurodevelopment Reduced NMDA-receptor signaling impairs activity-dependent synaptic and cortical development.

Show evidence (2 references)

PMID:27164704 SUPPORT In Vitro

"Our analyses of de novo mutations are consistent with a dominant-negative effect resulting in a significant loss of receptor function."

Functional analysis of de novo GRIN1 variants demonstrated loss of receptor function with a dominant-negative effect.

PMID:27164704 SUPPORT In Vitro

"As the NMDAR obligatorily contains 2 GluN1 subunits, truncation or lack of both GRIN1 alleles would result in a knock-out and complete deprivation of the NMDAR."

Biallelic loss of GluN1 abolishes the obligatory subunit and therefore the NMDA receptor.

Disrupted Excitatory Neurotransmission and E/I Imbalance

Whether from excessive or deficient receptor activity, GRIN1 variants disrupt the tightly regulated NMDA-receptor-mediated glutamatergic transmission that developing cortical networks depend on, shifting the balance between excitation and inhibition and producing neuronal hyperexcitability that generates seizures. Seizures occur in roughly two-thirds of individuals with de novo variants.

neuron CL:0000540

regulation of glutamatergic synaptic transmission GO:0051966 ↕ DYSREGULATED regulation of membrane potential GO:0042391 ⚠ ABNORMAL

Downstream

Impaired Neurodevelopment Frequent seizures and epileptiform activity further impair neurodevelopment at the developmental-and-epileptic-encephalopathy end of the spectrum.

Show evidence (1 reference)

PMID:27164704 SUPPORT Human Clinical

"Seizures occurred in about two-thirds of cases."

Epilepsy affects about two-thirds of individuals, reflecting the cortical excitation-inhibition imbalance produced by disrupted NMDAR signaling.

Impaired Neurodevelopment

Dysregulated NMDA-receptor signaling impairs activity-dependent synaptic maturation, plasticity, and cortical development, producing the disorder's core neurodevelopmental phenotype: profound developmental delay / intellectual disability with absent speech, muscular hypotonia, hyperkinetic and stereotypic movement disorders, cortical visual impairment, and, in a subset, a malformation of cortical development (polymicrogyria).

neuron CL:0000540

nervous system development GO:0007399 ⚠ ABNORMAL long-term synaptic potentiation GO:0060291 ⚠ ABNORMAL synapse organization GO:0050808 ⚠ ABNORMAL

Show evidence (2 references)

PMID:31219694 SUPPORT Human Clinical

"GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals."

Developmental delay / intellectual disability occurs in all affected individuals, the core neurodevelopmental outcome.

PMID:27164704 SUPPORT Human Clinical

"These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy."

The characteristic constellation of severe neurodevelopmental features defines the disorder.

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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

19

Digestive 1

Feeding Difficulties FREQUENT Feeding difficulties HP:0011968

Show evidence (2 references)

PMID:27164704 SUPPORT Human Clinical

"Several patients had feeding difficulties (9/23; 39%), likely due to their underlying hypotonia and spasticity, requiring tube feeding in some patients."

Feeding difficulties occurred in 9 of 23 (39%) of the founding cohort.

PMID:31219694 SUPPORT Human Clinical

"Other common manifestations are epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior issues."

Feeding difficulties are among the common manifestations.

Head and Neck 1

Postnatal Microcephaly Secondary microcephaly HP:0005484

Show evidence (1 reference)

PMID:29365063 SUPPORT Human Clinical

"Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy."

Postnatal microcephaly is a shared feature of the polymicrogyria subset.

Musculoskeletal 2

Hypotonia FREQUENT Hypotonia HP:0001252

Show evidence (1 reference)

PMID:27164704 SUPPORT Human Clinical

"Of the 21 patients in whom information regarding muscular tone could be retrieved, 15 (71%) had severe truncal and initial appendicular hypotonia."

Severe hypotonia was documented in 15 of 21 (71%) of the founding cohort, supporting a FREQUENT band.

Spasticity OCCASIONAL Spasticity HP:0001257

Show evidence (2 references)

PMID:27164704 SUPPORT Human Clinical

"Many patients developed corticospinal signs, such as hyperreflexia (6/21; 29%) or spasticity (6/21; 29%), consistent with a diagnosis of spastic quadriparesis."

Spasticity occurred in 6 of 21 (29%) of the founding cohort.

PMID:31219694 SUPPORT Human Clinical

"Other common manifestations are epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior issues."

Spasticity is listed among the common manifestations.

Nervous System 10

Global Developmental Delay OBLIGATE Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:31219694 SUPPORT Human Clinical

"GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals."

Developmental delay occurs in all affected individuals.

Intellectual Disability OBLIGATE Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:31219694 SUPPORT Human Clinical

"mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals."

Intellectual disability occurs in all affected individuals.

Absent Speech Absent speech HP:0001344

Show evidence (1 reference)

PMID:27164704 SUPPORT Human Clinical

"severe intellectual disability with absent speech"

Severe intellectual disability with absent speech is a defining feature.

Seizures FREQUENT Seizure HP:0001250

Show evidence (1 reference)

PMID:27164704 SUPPORT Human Clinical

"Seizures occurred in about two-thirds of cases."

Seizures affect approximately two-thirds of affected individuals.

Autistic Behavior FREQUENT Autistic behavior HP:0000729

Show evidence (2 references)

PMID:27164704 SUPPORT Human Clinical

"At least 8 GRIN1 patients were diagnosed with ASD or ASD-like features (8/23; 35%)"

About a third of the founding cohort (8/23; 35%) had ASD or ASD-like features, supporting a FREQUENT band.

PMID:28051072 SUPPORT Human Clinical

"We report on two consanguineous sibs affected with severe intellectual disability and autistic features due to a homozygous missense variant of GRIN1."

Autistic features are part of the phenotype, prominent in the biallelic hypomorphic form.

Polymicrogyria Polymicrogyria HP:0002126

Show evidence (1 reference)

PMID:29365063 SUPPORT Human Clinical

"Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy."

A distinct subset presents with extensive bilateral polymicrogyria.

Cerebral Atrophy FREQUENT Cerebral atrophy HP:0002059

Show evidence (2 references)

PMID:27164704 SUPPORT Human Clinical

"generalized cerebral atrophy"

Generalized cerebral atrophy is part of the distinct GRIN1 phenotype.

PMID:27164704 SUPPORT Human Clinical

"nonspecific volume loss or atrophy was seen in 11/19 (58%) patients."

Nonspecific volume loss or atrophy was seen in 11 of 19 (58%) on MRI, supporting a FREQUENT band.

Hyperreflexia OCCASIONAL Hyperreflexia HP:0001347

Show evidence (1 reference)

PMID:27164704 SUPPORT Human Clinical

"Many patients developed corticospinal signs, such as hyperreflexia (6/21; 29%) or spasticity (6/21; 29%), consistent with a diagnosis of spastic quadriparesis."

Hyperreflexia occurred in 6 of 21 (29%) of the founding cohort.

Sleep Disturbance FREQUENT Sleep disturbance HP:0002360

Show evidence (1 reference)

PMID:27164704 SUPPORT Human Clinical

"Eight patients (8/23; 35%) had nonspecified sleep disorders."

Sleep disorders were documented in 8 of 23 (35%).

Self-Injurious Behavior OCCASIONAL Self-injurious behavior HP:0100716

Show evidence (1 reference)

PMID:27164704 SUPPORT Human Clinical

"4 individuals presented with aggression and self-injurious behavior or disturbed pain perception (4/23; 17%)."

Self-injurious behavior occurred in 4 of 23 (17%) of the founding cohort.

Other 5

Epileptic Encephalopathy Epileptic encephalopathy HP:0200134

Show evidence (1 reference)

PMID:28051072 SUPPORT Human Clinical

"Heterozygous variants of GRIN1, encoding the GluN1 subunit of the NMDA receptor, have been reported in patients with neurodevelopmental disorders including epileptic encephalopathy, severe intellectual disability, and movement disorders."

Epileptic encephalopathy is part of the reported GRIN1 phenotypic spectrum.

Hyperkinetic Movement Disorder FREQUENT Hyperkinetic movements HP:0002487

Show evidence (1 reference)

PMID:27164704 SUPPORT Human Clinical

"The majority of patients showed choreatic, dystonic, or dyskinetic movement disorders (14/23; 61%)"

A hyperkinetic (choreatic/dystonic/dyskinetic) movement disorder affects the majority.

Motor Stereotypy Motor stereotypy HP:0000733

Show evidence (1 reference)

PMID:27164704 SUPPORT Human Clinical

"Nonspecific stereotypic movements were noted in 7/21 patients (33%)."

Stereotypic movements were documented in about a third of patients.

Cortical Visual Impairment Cerebral visual impairment HP:0100704

Show evidence (1 reference)

PMID:27164704 SUPPORT Human Clinical

"Several patients presented with cortical visual impairment or delayed visual maturation (5/23; 22%)."

Cortical visual impairment is a recurrent, discriminating feature.

Oculogyric Crisis OCCASIONAL Oculogyric crisis HP:0010553

Show evidence (1 reference)

PMID:27164704 SUPPORT Human Clinical

"including oculomotor abnormalities such as oculogyric crises (5/23; 22%)."

Oculogyric crises occurred in 5 of 23 (22%) and are highlighted as a discriminating feature of the disorder.

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Genetic Associations

1

GRIN1 (Causative)

Gene: GRIN1 hgnc:4584 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:27164704 SUPPORT Human Clinical

"Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect."

De novo GRIN1 variants cluster in transmembrane segments and alter channel function.

PMID:31219694 SUPPORT Human Clinical

"The diagnosis of GRIN1-NDD is established in a proband who has either a heterozygous de novo GRIN1 pathogenic missense variant (64 individuals reported) or biallelic GRIN1 pathogenic missense or truncating variants (8 individuals from 4 families reported)."

Establishes the two genetic mechanisms (heterozygous de novo and biallelic).

💊

Medical Actions

4

Antiseizure Medication

Action: Pharmacotherapy NCIT:C15986

Seizures are managed with antiseizure medications per standard practice; there is no single characteristic epilepsy pattern and response is variable.

Show evidence (1 reference)

PMID:31219694 SUPPORT Human Clinical

"Standard treatment of DD/ID, seizures, feeding problems, and behavioral issues."

Seizures and other manifestations are treated with standard symptomatic management.

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

Action: Pharmacotherapy NCIT:C15986

Agent: memantine CHEBI:64312

For gain-of-function variants, the use-dependent NMDA-receptor channel blocker memantine has been used off-label as mechanism-directed therapy; a retrospective series reported behavioral, developmental, and seizure benefit in individuals with GRIN gain-of-function variants.

Mechanism Target:

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

Show evidence (1 reference)

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 retrospective series reports memantine benefit in GRIN gain-of-function variants, motivating genotype-directed use.

L-Serine Supplementation for Loss-of-Function Variants

Action: Pharmacotherapy NCIT:C15986

Agent: L-serine CHEBI:17115

For loss-of-function variants, oral L-serine (a precursor of the NMDA-receptor co-agonists glycine and D-serine) has been trialed to potentiate hypofunctional receptors; a phase 2A trial that included GRIN1 patients reported motor, adaptive-behavior, and quality-of-life improvement.

Mechanism Target:

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

Show evidence (1 reference)

PMID:38380699 SUPPORT Human Clinical

"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."

L-serine is a mechanism-directed therapy for GRIN loss-of-function variants, a cohort that included GRIN1 patients.

Developmental and Supportive Therapy

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

Multidisciplinary developmental support (physical, occupational, and speech therapy), feeding and nutritional management, and surveillance of developmental, educational, and behavioral needs address the neurodevelopmental manifestations.

Show evidence (1 reference)

PMID:31219694 SUPPORT Human Clinical

"regular assessment of swallowing, feeding, and nutritional status to determine safety of oral vs gastrostomy feeding."

Supportive management, including feeding and developmental surveillance, is the mainstay of care.

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Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from GRIN1-Related Neurodevelopmental Disorder:

GRIN2B-related developmental and epileptic encephalopathy MONDO:0014505

Overlapping Features GRIN2B disorder shares the NMDA-receptor mechanism (GluN2B subunit) and a similar developmental-delay/epilepsy/movement-disorder spectrum with the same gain-/loss-of-function functional dichotomy.

Distinguishing Features

Both are NMDA-receptor-subunit disorders; the causal gene distinguishes them (GRIN1/GluN1 obligatory subunit vs GRIN2B/GluN2B).
GRIN1-NDD more characteristically shows cortical visual impairment, oculogyric crises, and (in a subset) extensive bilateral polymicrogyria.
GRIN1-NDD occurs in both de novo autosomal dominant and biallelic autosomal recessive forms, whereas GRIN2B disorder is de novo autosomal dominant.

GRIN2A-related complex neurodevelopmental disorder

Overlapping Features GRIN2A disorder is the other core NMDA-receptor-subunit (GluN2A) disorder but typically presents with an epilepsy-aphasia spectrum rather than the profound, early, non-epilepsy-dominant phenotype of GRIN1-NDD.

Distinguishing Features

GRIN2A disorder classically causes epilepsy-aphasia spectrum disorders (including epileptic encephalopathy with spike-wave activation in sleep).
GRIN1-NDD is dominated by profound global developmental delay with absent speech and hyperkinetic movements from early life.

STXBP1 encephalopathy MONDO:0012812

Overlapping Features STXBP1-related developmental and epileptic encephalopathy overlaps through early-onset epilepsy, profound developmental delay, and movement disorder.

Distinguishing Features

STXBP1 disorder is caused by heterozygous STXBP1 variants affecting synaptic vesicle release rather than NMDA-receptor function.
Identification of a GRIN1 variant, and the discriminating cortical visual impairment, favor GRIN1-NDD.

SCN2A-related developmental and epileptic encephalopathy MONDO:0013388

Overlapping Features SCN2A encephalopathy is a sodium-channelopathy that can mimic GRIN1-NDD with early-onset epilepsy, developmental delay, and movement abnormalities.

Distinguishing Features

SCN2A disorder arises from a voltage-gated sodium channel defect, not NMDA-receptor dysfunction, and has distinct sodium-channel-blocker treatment implications.
The GRIN1-NDD constellation of cortical visual impairment and hyperkinetic movements helps distinguish it.

🔬

Clinical Trials

1

NCT04646447 PHASE_II COMPLETED

A phase 2A, non-randomized, open-label, single-arm trial of oral L-serine in children with GRIN loss-of-function variants; the enrolled cohort included 6 GRIN1 patients (of 24 participants).

Target Phenotypes: Intellectual disability HP:0001249 Hypotonia HP:0001252

Show evidence (1 reference)

clinicaltrials:NCT04646447 SUPPORT Human Clinical

"the investigators will include about 20 spanish patients older than 2 years of age, harbouring GRIN variants functionally anotated as loss-of-function pathogenic variants."

The L-serine phase 2A trial enrolled children with GRIN loss-of-function variants, a cohort that included GRIN1 patients.

{ }

Source YAML

click to show

name: GRIN1-Related Neurodevelopmental Disorder
creation_date: "2026-07-25T00:00:00Z"
category: Mendelian
synonyms:
- GRIN1-NDD
- GRIN1-related neurodevelopmental disorder
- GRIN1-related developmental and epileptic encephalopathy
- NMDA receptor (GluN1) encephalopathy
- Developmental and epileptic encephalopathy 101
description: >-
  GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is a complex
  neurodevelopmental disorder caused by variants in GRIN1, which encodes GluN1,
  the obligatory subunit of the N-methyl-D-aspartate (NMDA)-type glutamate
  receptor, a glutamate-gated, calcium-permeable cation channel. Because two
  GluN1 subunits are present in every NMDA receptor, GRIN1 variants perturb
  NMDA-receptor signaling throughout the developing brain. Two inheritance modes
  and two functional directions converge on the same disorder: de novo
  heterozygous missense variants clustered in the transmembrane, pore, and
  ligand-binding domains act as a channelopathy, producing either
  gain-of-function (increased agonist potency, reduced voltage-dependent
  magnesium block, increased calcium permeability and current) or
  loss-of-function (reduced current, impaired surface expression, often with a
  dominant-negative effect), while biallelic (homozygous) missense or truncating
  variants cause loss of function. In both directions, disrupted excitatory
  neurotransmission impairs activity-dependent synaptic and cortical development
  and shifts the cortical excitation-inhibition balance, producing profound
  developmental delay / intellectual disability with absent speech, muscular
  hypotonia, hyperkinetic and stereotypic movement disorders, cortical visual
  impairment, and epilepsy; a subset of individuals show extensive bilateral
  polymicrogyria. GRIN1-NDD is the GluN1 counterpart of the GRIN2B and GRIN2A
  NMDA-receptor-subunit disorders.
disease_term:
  preferred_term: GRIN1-related complex neurodevelopmental disorder
  term:
    id: MONDO:1060123
    label: GRIN1-related complex neurodevelopmental disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:1060123
      label: GRIN1-related complex neurodevelopmental disorder
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      This entry is deliberately anchored on the gene-level MONDO umbrella
      MONDO:1060123 (GRIN1-related complex neurodevelopmental disorder), whose
      MONDO definition names GRIN1 (HGNC:4584) as the causal gene, rather than on
      a single clinical subtype. The umbrella subsumes the phenotypic and
      inheritance breadth of the disorder (de novo autosomal dominant and
      biallelic autosomal recessive; gain- and loss-of-function), matching the
      unified mechanism-based scope of this dismech entry.
  - term:
      id: MONDO:0030727
      label: developmental and epileptic encephalopathy 101
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      DEE101 (MONDO:0030727) is a GRIN1 child of the umbrella, representing the
      developmental-and-epileptic-encephalopathy end of the spectrum.
  - term:
      id: MONDO:0013655
      label: neurodevelopmental disorder with or without hyperkinetic movements
        and seizures, autosomal dominant
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      The autosomal dominant (de novo) GRIN1 child of the umbrella, capturing the
      heterozygous-variant, hyperkinetic-movement presentation.
  - term:
      id: MONDO:0060629
      label: neurodevelopmental disorder with or without hyperkinetic movements
        and seizures, autosomal recessive
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      The autosomal recessive GRIN1 child of the umbrella, capturing the biallelic
      (homozygous) loss-of-function presentation.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      GRIN1-NDD is a disorder of the central nervous system with developmental
      delay, movement disorder, and epilepsy.
  channelopathy_category:
    classification_value: neurological channelopathy
    notes: >-
      GRIN1 encodes the obligatory GluN1 subunit of the NMDA-receptor cation
      channel; pathogenic variants act as a neurological channelopathy.
parents:
- Neurodevelopmental Disorder
- Genetic Disease
references:
- reference: PMID:31219694
  title: "GRIN1-Related Neurodevelopmental Disorder."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant
  description: >-
    Most affected individuals have a heterozygous de novo GRIN1 pathogenic
    missense variant; inheritance is autosomal dominant and probands are
    typically simplex cases.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:31219694
    reference_title: "GRIN1-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All probands with a heterozygous GRIN1 pathogenic variant reported to date whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GRIN1 pathogenic missense variant."
    explanation: >-
      GeneReviews documents the de novo, autosomal dominant origin of the
      heterozygous form.
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients."
    explanation: >-
      The founding cohort established heterozygous de novo GRIN1 variants as the
      predominant cause.
- name: Autosomal recessive
  description: >-
    A minority of individuals have biallelic (homozygous) GRIN1 pathogenic
    missense or truncating variants, inherited in an autosomal recessive manner
    from unaffected heterozygous carrier parents; because two GluN1 subunits are
    obligatory, biallelic null variants abolish the receptor.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31219694
    reference_title: "GRIN1-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "each sib of an individual with biallelic GRIN1 pathogenic variants has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
    explanation: >-
      GeneReviews genetic-counseling recurrence-risk statement for the autosomal
      recessive (biallelic) form.
  - reference: PMID:28051072
    reference_title: "Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "support the existence of hypomorphic variants causing severe neurodevelopmental impairment with autosomal recessive inheritance."
    explanation: >-
      A consanguineous family with a homozygous hypomorphic GRIN1 variant
      demonstrates autosomal recessive inheritance.
pathophysiology:
- name: GRIN1 Variant and Altered GluN1/NMDA Receptor Function
  description: >-
    De novo heterozygous missense variants (clustered in the transmembrane,
    pore, and ligand-binding domains) or biallelic missense/truncating variants
    in GRIN1 alter GluN1, the obligatory subunit of the NMDA receptor. Because
    every NMDA receptor contains two GluN1 subunits, these variants perturb the
    glutamate-gated, calcium-permeable channel that mediates excitatory
    neurotransmission across the developing brain.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: 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
  biological_processes:
  - preferred_term: glutamate receptor signaling
    term:
      id: GO:0007215
      label: glutamate receptor signaling pathway
    modifier: ABNORMAL
  evidence:
  - reference: PMID:29365063
    reference_title: "De novo mutations in GRIN1 cause extensive bilateral polymicrogyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor."
    explanation: >-
      GRIN1 encodes the essential (obligatory) GluN1 subunit of the NMDA
      receptor, so variants perturb the receptor directly.
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect."
    explanation: >-
      De novo GRIN1 missense variants cluster in transmembrane segments and alter
      channel function.
  downstream:
  - target: NMDA Receptor Gain-of-Function
    causal_link_type: DIRECT
    description: >-
      A subset of missense variants (especially in the M3 helix and pore)
      increases receptor activity.
  - target: NMDA Receptor Loss-of-Function
    causal_link_type: DIRECT
    description: >-
      Other missense variants, and biallelic missense/truncating variants, reduce
      receptor function.
- name: NMDA Receptor Gain-of-Function
  description: >-
    A subset of GRIN1 missense variants increases NMDA receptor activity by
    enhancing agonist potency, increasing channel open probability and calcium
    permeability, or reducing voltage-dependent magnesium and proton inhibition,
    producing excessive NMDA-receptor-mediated current and calcium influx.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  molecular_functions:
  - preferred_term: calcium channel activity
    term:
      id: GO:0005262
      label: calcium channel activity
    modifier: INCREASED
  biological_processes:
  - preferred_term: calcium ion transmembrane transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
    modifier: INCREASED
  - preferred_term: glutamate receptor signaling
    term:
      id: GO:0007215
      label: glutamate receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:29365063
    reference_title: "De novo mutations in GRIN1 cause extensive bilateral polymicrogyria."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor."
    explanation: >-
      Polymicrogyria-associated GRIN1 variants increased agonist potency, a
      gain-of-function change in receptor activity.
  - reference: PMID:38538865
    reference_title: "De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype."
    explanation: >-
      GRIN1/GRIN2 M3-helix variants predominantly enhance channel gating,
      a gain-of-function mechanism.
  downstream:
  - target: Disrupted Excitatory Neurotransmission and E/I Imbalance
    causal_link_type: DIRECT
    description: >-
      Excessive receptor current and calcium influx dysregulate excitatory
      signaling and network excitability.
  - target: Gain-of-Function Cortical Maldevelopment
    causal_link_type: DIRECT
    description: >-
      S2/M3-region gain-of-function variants perturb cortical neurodevelopment,
      producing extensive bilateral polymicrogyria.
- name: Gain-of-Function Cortical Maldevelopment
  description: >-
    A distinct subset of gain-of-function GRIN1 missense variants clustered in
    the S2 and M3 regions perturbs NMDA-receptor-dependent cortical
    neurodevelopment, producing a malformation of cortical development
    (extensive bilateral polymicrogyria); this is the opposite mechanistic
    direction from the classic loss-of-function route to the disorder.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: cerebral cortex development
    term:
      id: GO:0021987
      label: cerebral cortex development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:29365063
    reference_title: "De novo mutations in GRIN1 cause extensive bilateral polymicrogyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy."
    explanation: >-
      Gain-of-function GRIN1 variants cause a distinct cortical malformation
      (extensive bilateral polymicrogyria).
  - reference: PMID:29365063
    reference_title: "De novo mutations in GRIN1 cause extensive bilateral polymicrogyria."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor."
    explanation: >-
      The polymicrogyria-associated variants are gain-of-function with increased
      agonist potency or reduced proton inhibition.
  downstream:
  - target: Impaired Neurodevelopment
    causal_link_type: DIRECT
    description: >-
      The cortical malformation is part of the impaired-neurodevelopment
      phenotype in the gain-of-function subset.
- name: NMDA Receptor Loss-of-Function
  description: >-
    Other GRIN1 variants reduce NMDA receptor function: de novo missense variants
    lower agonist potency and maximal current (frequently with a
    dominant-negative effect on hetero-oligomeric receptors), while biallelic
    truncating variants abolish receptor assembly. Because two GluN1 subunits are
    obligatory, loss of both alleles produces a functional NMDA-receptor
    knockout.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: glutamate receptor signaling
    term:
      id: GO:0007215
      label: glutamate receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our analyses of de novo mutations are consistent with a dominant-negative effect resulting in a significant loss of receptor function."
    explanation: >-
      Functional analysis of de novo GRIN1 variants demonstrated loss of receptor
      function with a dominant-negative effect.
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "As the NMDAR obligatorily contains 2 GluN1 subunits, truncation or lack of both GRIN1 alleles would result in a knock-out and complete deprivation of the NMDAR."
    explanation: >-
      Biallelic loss of GluN1 abolishes the obligatory subunit and therefore the
      NMDA receptor.
  downstream:
  - target: Disrupted Excitatory Neurotransmission and E/I Imbalance
    causal_link_type: DIRECT
    description: >-
      Reduced NMDA-receptor-mediated current diminishes excitatory drive and
      destabilizes network excitability.
  - target: Impaired Neurodevelopment
    causal_link_type: DIRECT
    description: >-
      Reduced NMDA-receptor signaling impairs activity-dependent synaptic and
      cortical development.
- name: Disrupted Excitatory Neurotransmission and E/I Imbalance
  description: >-
    Whether from excessive or deficient receptor activity, GRIN1 variants disrupt
    the tightly regulated NMDA-receptor-mediated glutamatergic transmission that
    developing cortical networks depend on, shifting the balance between
    excitation and inhibition and producing neuronal hyperexcitability that
    generates seizures. Seizures occur in roughly two-thirds of individuals with
    de novo variants.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: regulation of glutamatergic synaptic transmission
    term:
      id: GO:0051966
      label: regulation of synaptic transmission, glutamatergic
    modifier: DYSREGULATED
  - preferred_term: regulation of membrane potential
    term:
      id: GO:0042391
      label: regulation of membrane potential
    modifier: ABNORMAL
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance"
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures occurred in about two-thirds of cases."
    explanation: >-
      Epilepsy affects about two-thirds of individuals, reflecting the cortical
      excitation-inhibition imbalance produced by disrupted NMDAR signaling.
  downstream:
  - target: Impaired Neurodevelopment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Frequent seizures and epileptiform activity further impair
      neurodevelopment at the developmental-and-epileptic-encephalopathy end of
      the spectrum.
- name: Impaired Neurodevelopment
  description: >-
    Dysregulated NMDA-receptor signaling impairs activity-dependent synaptic
    maturation, plasticity, and cortical development, producing the disorder's
    core neurodevelopmental phenotype: profound developmental delay / intellectual
    disability with absent speech, muscular hypotonia, hyperkinetic and
    stereotypic movement disorders, cortical visual impairment, and, in a subset,
    a malformation of cortical development (polymicrogyria).
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  - 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
  evidence:
  - reference: PMID:31219694
    reference_title: "GRIN1-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals."
    explanation: >-
      Developmental delay / intellectual disability occurs in all affected
      individuals, the core neurodevelopmental outcome.
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy."
    explanation: >-
      The characteristic constellation of severe neurodevelopmental features
      defines the disorder.
phenotypes:
- category: Neurodevelopmental
  name: Global Developmental Delay
  description: >-
    Profound global developmental delay, usually apparent in the neonatal period,
    is a near-constant feature.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:31219694
    reference_title: "GRIN1-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals."
    explanation: >-
      Developmental delay occurs in all affected individuals.
- category: Neurodevelopmental
  name: Intellectual Disability
  description: >-
    Intellectual disability, ranging from mild to profound (most often severe to
    profound), is characteristic.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:31219694
    reference_title: "GRIN1-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals."
    explanation: >-
      Intellectual disability occurs in all affected individuals.
- category: Neurodevelopmental
  name: Absent Speech
  description: >-
    Verbal communication is typically absent or extremely limited.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe intellectual disability with absent speech"
    explanation: >-
      Severe intellectual disability with absent speech is a defining feature.
- category: Neurologic
  name: Seizures
  description: >-
    Seizures of varied type and onset occur in about two-thirds of individuals
    with de novo variants, ranging to severe developmental and epileptic
    encephalopathy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures occurred in about two-thirds of cases."
    explanation: >-
      Seizures affect approximately two-thirds of affected individuals.
- category: Neurologic
  name: Epileptic Encephalopathy
  description: >-
    A subset present at the developmental-and-epileptic-encephalopathy end of the
    spectrum, including severe neonatal epileptic encephalopathy with biallelic
    truncating variants.
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:28051072
    reference_title: "Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous variants of GRIN1, encoding the GluN1 subunit of the NMDA receptor, have been reported in patients with neurodevelopmental disorders including epileptic encephalopathy, severe intellectual disability, and movement disorders."
    explanation: >-
      Epileptic encephalopathy is part of the reported GRIN1 phenotypic spectrum.
- category: Neurologic
  name: Hypotonia
  description: >-
    Severe truncal and appendicular muscular hypotonia is common, often evolving
    to spastic quadriparesis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 21 patients in whom information regarding muscular tone could be retrieved, 15 (71%) had severe truncal and initial appendicular hypotonia."
    explanation: >-
      Severe hypotonia was documented in 15 of 21 (71%) of the founding cohort,
      supporting a FREQUENT band.
- category: Neurologic
  name: Spasticity
  description: >-
    Corticospinal signs including spasticity develop in a substantial subset,
    consistent with spastic quadriparesis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many patients developed corticospinal signs, such as hyperreflexia (6/21; 29%) or spasticity (6/21; 29%), consistent with a diagnosis of spastic quadriparesis."
    explanation: >-
      Spasticity occurred in 6 of 21 (29%) of the founding cohort.
  - reference: PMID:31219694
    reference_title: "GRIN1-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other common manifestations are epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior issues."
    explanation: >-
      Spasticity is listed among the common manifestations.
- category: Neurologic
  name: Hyperkinetic Movement Disorder
  description: >-
    A hyperkinetic movement disorder including choreatic, dystonic, or dyskinetic
    movements occurs in the majority of individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hyperkinetic movements
    term:
      id: HP:0002487
      label: Hyperkinetic movements
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients showed choreatic, dystonic, or dyskinetic movement disorders (14/23; 61%)"
    explanation: >-
      A hyperkinetic (choreatic/dystonic/dyskinetic) movement disorder affects
      the majority.
- category: Neurologic
  name: Motor Stereotypy
  description: >-
    Nonspecific stereotypic movements are noted in a subset of individuals.
  phenotype_term:
    preferred_term: Motor stereotypy
    term:
      id: HP:0000733
      label: Motor stereotypy
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nonspecific stereotypic movements were noted in 7/21 patients (33%)."
    explanation: >-
      Stereotypic movements were documented in about a third of patients.
- category: Ophthalmologic
  name: Cortical Visual Impairment
  description: >-
    Cortical (cerebral) visual impairment or blindness is a discriminating
    feature of the disorder.
  phenotype_term:
    preferred_term: Cerebral visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several patients presented with cortical visual impairment or delayed visual maturation (5/23; 22%)."
    explanation: >-
      Cortical visual impairment is a recurrent, discriminating feature.
- category: Neurodevelopmental
  name: Autistic Behavior
  description: >-
    Autism spectrum disorder or autistic features occur in a subset; the biallelic
    hypomorphic form can present as severe intellectual disability with autistic
    features without epilepsy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At least 8 GRIN1 patients were diagnosed with ASD or ASD-like features (8/23; 35%)"
    explanation: >-
      About a third of the founding cohort (8/23; 35%) had ASD or ASD-like
      features, supporting a FREQUENT band.
  - reference: PMID:28051072
    reference_title: "Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on two consanguineous sibs affected with severe intellectual disability and autistic features due to a homozygous missense variant of GRIN1."
    explanation: >-
      Autistic features are part of the phenotype, prominent in the biallelic
      hypomorphic form.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Feeding difficulties, likely secondary to hypotonia and spasticity, occur and
    can require tube feeding.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several patients had feeding difficulties (9/23; 39%), likely due to their underlying hypotonia and spasticity, requiring tube feeding in some patients."
    explanation: >-
      Feeding difficulties occurred in 9 of 23 (39%) of the founding cohort.
  - reference: PMID:31219694
    reference_title: "GRIN1-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other common manifestations are epilepsy, muscular hypotonia, movement disorders, spasticity, feeding difficulties, and behavior issues."
    explanation: >-
      Feeding difficulties are among the common manifestations.
- category: Neurologic
  name: Polymicrogyria
  description: >-
    A subset of individuals (particularly with gain-of-function variants in the
    S2/M3 region) show a malformation of cortical development consisting of
    extensive and diffuse bilateral polymicrogyria.
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  evidence:
  - reference: PMID:29365063
    reference_title: "De novo mutations in GRIN1 cause extensive bilateral polymicrogyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy."
    explanation: >-
      A distinct subset presents with extensive bilateral polymicrogyria.
- category: Neurologic
  name: Oculogyric Crisis
  description: >-
    Oculomotor abnormalities including oculogyric crises are a discriminating
    phenotypic feature of GRIN1-NDD.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Oculogyric crisis
    term:
      id: HP:0010553
      label: Oculogyric crisis
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including oculomotor abnormalities such as oculogyric crises (5/23; 22%)."
    explanation: >-
      Oculogyric crises occurred in 5 of 23 (22%) and are highlighted as a
      discriminating feature of the disorder.
- category: Neurologic
  name: Cerebral Atrophy
  description: >-
    Generalized cerebral atrophy / nonspecific volume loss is seen on
    neuroimaging in a majority of individuals, apparent already at young ages.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "generalized cerebral atrophy"
    explanation: >-
      Generalized cerebral atrophy is part of the distinct GRIN1 phenotype.
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nonspecific volume loss or atrophy was seen in 11/19 (58%) patients."
    explanation: >-
      Nonspecific volume loss or atrophy was seen in 11 of 19 (58%) on MRI,
      supporting a FREQUENT band.
- category: Neurologic
  name: Hyperreflexia
  description: >-
    Corticospinal signs including hyperreflexia develop in a subset, consistent
    with evolving spastic quadriparesis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many patients developed corticospinal signs, such as hyperreflexia (6/21; 29%) or spasticity (6/21; 29%), consistent with a diagnosis of spastic quadriparesis."
    explanation: >-
      Hyperreflexia occurred in 6 of 21 (29%) of the founding cohort.
- category: Neurodevelopmental
  name: Sleep Disturbance
  description: >-
    Nonspecified sleep disorders occur in about a third of individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight patients (8/23; 35%) had nonspecified sleep disorders."
    explanation: >-
      Sleep disorders were documented in 8 of 23 (35%).
- category: Neurodevelopmental
  name: Self-Injurious Behavior
  description: >-
    A subset present with aggression and self-injurious behavior or disturbed
    pain perception.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "4 individuals presented with aggression and self-injurious behavior or disturbed pain perception (4/23; 17%)."
    explanation: >-
      Self-injurious behavior occurred in 4 of 23 (17%) of the founding cohort.
- category: Neurologic
  name: Postnatal Microcephaly
  description: >-
    Postnatal (secondary) microcephaly is a shared feature of individuals with
    the polymicrogyria-associated gain-of-function variants.
  phenotype_term:
    preferred_term: Postnatal microcephaly
    term:
      id: HP:0005484
      label: Secondary microcephaly
  evidence:
  - reference: PMID:29365063
    reference_title: "De novo mutations in GRIN1 cause extensive bilateral polymicrogyria."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy."
    explanation: >-
      Postnatal microcephaly is a shared feature of the polymicrogyria subset.
genetic:
- name: GRIN1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: GRIN1
    term:
      id: hgnc:4584
      label: GRIN1
  notes: >-
    GRIN1 encodes GluN1, the obligatory subunit of the NMDA receptor. De novo
    heterozygous missense variants cluster in the transmembrane, pore, and
    ligand-binding domains and confer gain- or loss-of-function; biallelic
    (homozygous) missense or truncating variants cause loss of function.
    Heterozygous GRIN1 truncation/haploinsufficiency, in contrast, is tolerated
    and does not by itself cause the disorder.
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect."
    explanation: >-
      De novo GRIN1 variants cluster in transmembrane segments and alter channel
      function.
  - reference: PMID:31219694
    reference_title: "GRIN1-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of GRIN1-NDD is established in a proband who has either a heterozygous de novo GRIN1 pathogenic missense variant (64 individuals reported) or biallelic GRIN1 pathogenic missense or truncating variants (8 individuals from 4 families reported)."
    explanation: >-
      Establishes the two genetic mechanisms (heterozygous de novo and biallelic).
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A rare disorder; 72 individuals with GRIN1-NDD had been reported at the time
    of the GeneReviews summary.
  evidence:
  - reference: PMID:31219694
    reference_title: "GRIN1-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, 72 individuals with GRIN1-NDD have been reported."
    explanation: >-
      Fewer than 100 reported individuals indicates an ultra-rare disorder.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Diagnosis is established by identifying either a heterozygous de novo GRIN1
    pathogenic missense variant or biallelic GRIN1 pathogenic variants on
    molecular genetic testing.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:31219694
    reference_title: "GRIN1-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of GRIN1-NDD is established in a proband who has either a heterozygous de novo GRIN1 pathogenic missense variant (64 individuals reported) or biallelic GRIN1 pathogenic missense or truncating variants (8 individuals from 4 families reported)."
    explanation: >-
      Defines the molecular diagnostic criteria.
differential_diagnoses:
- name: GRIN2B-related developmental and epileptic encephalopathy
  description: >-
    GRIN2B disorder shares the NMDA-receptor mechanism (GluN2B subunit) and a
    similar developmental-delay/epilepsy/movement-disorder spectrum with the same
    gain-/loss-of-function functional dichotomy.
  distinguishing_features:
  - Both are NMDA-receptor-subunit disorders; the causal gene distinguishes them
    (GRIN1/GluN1 obligatory subunit vs GRIN2B/GluN2B).
  - GRIN1-NDD more characteristically shows cortical visual impairment,
    oculogyric crises, and (in a subset) extensive bilateral polymicrogyria.
  - GRIN1-NDD occurs in both de novo autosomal dominant and biallelic autosomal
    recessive forms, whereas GRIN2B disorder is de novo autosomal dominant.
  disease_term:
    preferred_term: developmental and epileptic encephalopathy, 27
    term:
      id: MONDO:0014505
      label: developmental and epileptic encephalopathy, 27
- name: GRIN2A-related complex neurodevelopmental disorder
  description: >-
    GRIN2A disorder is the other core NMDA-receptor-subunit (GluN2A) disorder but
    typically presents with an epilepsy-aphasia spectrum rather than the profound,
    early, non-epilepsy-dominant phenotype of GRIN1-NDD.
  distinguishing_features:
  - GRIN2A disorder classically causes epilepsy-aphasia spectrum disorders
    (including epileptic encephalopathy with spike-wave activation in sleep).
  - GRIN1-NDD is dominated by profound global developmental delay with absent
    speech and hyperkinetic movements from early life.
- name: STXBP1 encephalopathy
  description: >-
    STXBP1-related developmental and epileptic encephalopathy overlaps through
    early-onset epilepsy, profound developmental delay, and movement disorder.
  distinguishing_features:
  - STXBP1 disorder is caused by heterozygous STXBP1 variants affecting synaptic
    vesicle release rather than NMDA-receptor function.
  - Identification of a GRIN1 variant, and the discriminating cortical visual
    impairment, favor GRIN1-NDD.
  disease_term:
    preferred_term: STXBP1 encephalopathy
    term:
      id: MONDO:0012812
      label: developmental and epileptic encephalopathy, 4
- name: SCN2A-related developmental and epileptic encephalopathy
  description: >-
    SCN2A encephalopathy is a sodium-channelopathy that can mimic GRIN1-NDD with
    early-onset epilepsy, developmental delay, and movement abnormalities.
  distinguishing_features:
  - SCN2A disorder arises from a voltage-gated sodium channel defect, not
    NMDA-receptor dysfunction, and has distinct sodium-channel-blocker treatment
    implications.
  - The GRIN1-NDD constellation of cortical visual impairment and hyperkinetic
    movements helps distinguish it.
  disease_term:
    preferred_term: developmental and epileptic encephalopathy, 11
    term:
      id: MONDO:0013388
      label: developmental and epileptic encephalopathy, 11
progression:
- phase: Neonatal to Early Childhood
  notes: >-
    Profound global developmental delay is usually apparent already in the
    neonatal period; affected individuals typically never acquire the ability to
    walk and have absent or extremely limited verbal communication, with
    hypotonia, movement disorders, cortical visual impairment, and (in most) an
    epilepsy that emerges without a single characteristic onset age or semiology.
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy."
    explanation: >-
      Describes the characteristic early, severe, and persistent phenotype.
- phase: Severe Neonatal Encephalopathy in Biallelic Null Variants
  notes: >-
    The most severe end of the spectrum, seen with biallelic truncating variants
    that abolish the obligatory GluN1 subunit, presents as intractable neonatal
    epileptic encephalopathy that can be fatal in infancy.
  evidence:
  - reference: PMID:27164704
    reference_title: "Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As the NMDAR obligatorily contains 2 GluN1 subunits, truncation or lack of both GRIN1 alleles would result in a knock-out and complete deprivation of the NMDAR."
    explanation: >-
      Biallelic null variants abolish the receptor, producing the most severe,
      often fatal, neonatal presentation.
treatments:
- name: Antiseizure Medication
  description: >-
    Seizures are managed with antiseizure medications per standard practice;
    there is no single characteristic epilepsy pattern and response is variable.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:31219694
    reference_title: "GRIN1-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Standard treatment of DD/ID, seizures, feeding problems, and behavioral issues."
    explanation: >-
      Seizures and other manifestations are treated with standard symptomatic
      management.
- name: Memantine (NMDA Receptor Channel Blocker) for Gain-of-Function Variants
  description: >-
    For gain-of-function variants, the use-dependent NMDA-receptor channel
    blocker memantine has been used off-label as mechanism-directed therapy; a
    retrospective series reported behavioral, developmental, and seizure benefit
    in individuals with GRIN gain-of-function 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 NMDA-receptor channel blockade counteracts the excessive
      receptor activity of gain-of-function variants.
  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: "Fourteen of 19 individuals (74%) benefited from memantine, comprising improvements in behavior (71%), development (50%), and seizure frequency (39%)."
    explanation: >-
      A retrospective series reports memantine benefit in GRIN gain-of-function
      variants, motivating genotype-directed use.
- name: L-Serine Supplementation for Loss-of-Function Variants
  description: >-
    For loss-of-function variants, oral L-serine (a precursor of the NMDA-receptor
    co-agonists glycine and D-serine) has been trialed to potentiate hypofunctional
    receptors; a phase 2A trial that included GRIN1 patients reported motor,
    adaptive-behavior, and quality-of-life improvement.
  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 in loss-of-function variants.
  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: "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: >-
      L-serine is a mechanism-directed therapy for GRIN loss-of-function
      variants, a cohort that included GRIN1 patients.
- name: Developmental and Supportive Therapy
  description: >-
    Multidisciplinary developmental support (physical, occupational, and speech
    therapy), feeding and nutritional management, and surveillance of
    developmental, educational, and behavioral needs address the
    neurodevelopmental manifestations.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31219694
    reference_title: "GRIN1-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "regular assessment of swallowing, feeding, and nutritional status to determine safety of oral vs gastrostomy feeding."
    explanation: >-
      Supportive management, including feeding and developmental surveillance, is
      the mainstay of care.
discussions:
- discussion_id: gap_grin1_gof_vs_lof_precision_therapy
  prompt: >-
    Can GRIN1 variants be reliably partitioned into gain-of-function and
    loss-of-function classes, and does that functional classification predict the
    correct genotype-directed precision therapy (NMDA-receptor channel blockers
    such as memantine for gain-of-function versus NMDA-receptor co-agonist
    strategies such as L-serine for loss-of-function)?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#NMDA Receptor Gain-of-Function
  - pathophysiology#NMDA Receptor Loss-of-Function
  rationale: >-
    GRIN1 variants converge on the same disorder through opposite changes in
    receptor activity, so the gain-of-function versus loss-of-function distinction
    is potentially the key determinant of rational, opposite-direction treatment
    (channel blockade to damp excess activity versus co-agonist supplementation to
    boost deficient activity). However, functional classification requires
    electrophysiological characterization unavailable for most variants, many
    variants have mixed or indeterminate effects, and the founding cohort noted
    that the extent of measured loss of function correlated only marginally with
    the uniformly severe clinical phenotype, suggesting secondary compensatory
    mechanisms. Whether functional class prospectively predicts treatment response
    is central to precision therapy for GRIN1-NDD.
  proposed_experiments:
  - experiment_id: exp_grin1_functional_class_to_treatment_map
    name: Functional-class to genotype-directed treatment-response mapping
    description: >-
      Characterize a large panel of patient GRIN1 variants with standardized
      electrophysiology (agonist potency, open probability, calcium permeability,
      magnesium block, surface expression) to assign gain- or loss-of-function
      class, then prospectively correlate class with responses to
      genotype-matched therapy (memantine for gain-of-function; L-serine or other
      co-agonist strategies for loss-of-function).
  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: "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: >-
      Correct gain-/loss-of-function classification is emphasized as a
      prerequisite for precision therapy, framing the open question.
  - 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: >-
      The L-serine loss-of-function trial included GRIN1 patients, the opposite
      therapeutic arm to memantine for gain-of-function.
clinical_trials:
- name: NCT04646447
  phase: PHASE_II
  status: COMPLETED
  description: >-
    A phase 2A, non-randomized, open-label, single-arm trial of oral L-serine in
    children with GRIN loss-of-function variants; the enrolled cohort included 6
    GRIN1 patients (of 24 participants).
  target_phenotypes:
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: clinicaltrials:NCT04646447
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the investigators will include about 20 spanish patients older than 2 years of age, harbouring GRIN variants functionally anotated as loss-of-function pathogenic variants."
    explanation: >-
      The L-serine phase 2A trial enrolled children with GRIN loss-of-function
      variants, a cohort that included GRIN1 patients.
datasets: []

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PMID:31219694

GRIN1-Related Neurodevelopmental Disorder.

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GRIN1-Related Neurodevelopmental Disorder

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