Clinical characteristics.

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. Intellect ranges from normal to profoundly impaired. Observed speech disorders include dysarthria and speech dyspraxia, and both receptive and expressive language delays; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) abnormalities, including continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Epilepsy is typically focal and ranges from self-limited epilepsy with centrotemporal spikes to developmental and/or epileptic encephalopathies (DEE/EE), including the syndromes of DEE/EE with spike-wave activation in sleep (DEE/EE-SWAS), which include Landau-Kleffner syndrome. Movement disorders occur less frequently and include ataxia, dystonia, and chorea.

Diagnosis/testing.

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.

Management.

Targeted therapy: 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.

Supportive care: Significant speech and language deficits require therapy from a speech-language pathologist. Seizures should be treated with anti-seizure medication (ASM). 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.

Surveillance: Developmental surveillance in all affected children; routine monitoring of speech and language by a speech-language pathologist should be considered for all children, particularly those diagnosed before reaching school age.

Agents/circumstances to avoid: 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. 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).

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from evaluation for speech disorders and/or seizures and institution of treatment.

Genetic counseling.

GRIN2A-related disorders are inherited in an autosomal dominant manner. Some individuals diagnosed with a GRIN2A-related disorder have the disorder as the result of a pathogenic variant inherited from an affected parent. 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 or, rarely, as a postzygotic de novo event in a mosaic, apparently unaffected parent. Each child of an individual with a GRIN2A-related disorder has a 50% chance of inheriting the GRIN2A pathogenic variant. Once the GRIN2A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

A GRIN2A-related disorder should be considered in a proband with the following suggestive clinical findings and family history.

Clinical findings

• Mild-to-profound developmental delay / intellectual disability; some affected individuals may be of normal intellect.
• Focal epilepsy
  • Self-limited epilepsy with centrotemporal spikes
  • Developmental and/or epileptic encephalopathy (DEE/EE) with spike-wave activation in sleep (DEE/EE-SWAS)
  • Infantile-onset DEE, sometimes with epileptic spasms
• Speech and language disorders including dysarthria, speech dyspraxia, aphasia, and nonverbal phenotypes
• Movement disorders including ataxia, dystonia, or choreiform movements
• Hypotonia
• Neuropsychiatric features including behavioral issues, attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, anxiety disorders, and mood disorders

Family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) or the proband may have a de novo pathogenic variant and therefore be sporadic, with no other family members affected.

Establishing the Diagnosis

The diagnosis of a GRIN2A-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in GRIN2A identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous GRIN2A variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches should include comprehensive genomic testing (exome sequencing, genome sequencing).

Note: Single-gene testing (sequence analysis of GRIN2A, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Comprehensive genomic testing does not require the clinician to identify which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, all reported GRIN2A pathogenic variants are within the coding region or canonical splice sites and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

The clinical spectrum of GRIN2A-related disorders is broad and includes developmental delay / intellectual disability (DD/ID), epilepsy, speech and language disorders, movement disorders, and neuropsychiatric disorders. Cognitive function can be normal or show mild-to-profound impairment. The spectrum of epilepsy phenotypes ranges from self-limited epilepsy with centrotemporal spikes (SeLECTS) to developmental and/or epileptic encephalopathies (DEE/EE) with spike-wave activation in sleep (DEE/EE-SWAS) – including Landau-Kleffner syndrome (LKS) – to infantile-onset DEE. Speech and language disorders range from mild speech impairment to aphasia to nonverbal phenotypes. Movement disorders occur less frequently and include ataxia, dystonia, and chorea. GRIN2A-related disorders also carry an increased risk for early-onset neuropsychiatric disorders such as anxiety disorders, mood disorders, and schizophrenia as well as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).

To date, about 400 individuals have been identified with a pathogenic variant in GRIN2A [Lemke et al 2013, Lesca et al 2013, Carvill et al 2013, Strehlow et al 2019] (see also grin-portal.broadinstitute.org). The following description of the phenotypic features associated with this condition is based on reports of these individuals.

Developmental delay (DD) and intellectual disability (ID) is observed in 63% (111/177) of affected individuals and ranges from mild to profound. Intellect of the 37% (66/177) of individuals without ID ranges from normal to learning disabled [Strehlow et al 2019].

Epilepsy occurs in approximately 90% of individuals [Strehlow et al 2019].

Seizure onset depends on the type of underlying GRIN2A variant [Camp et al 2023] (see Genotype-Phenotype Correlation). The most common seizure type is focal seizures (121/146, 83%), which frequently evolve to bilateral tonic-clonic seizures.

The predominant seizure type(s) in a given individual depends on the epilepsy syndrome. Broadly, GRIN2A-related disorders fall into the epilepsy-aphasia syndromes group, which includes DEE/EE-SWAS, of which Landau-Kleffner syndrome (LKS) is a subtype [Carvill et al 2013, Lesca et al 2013]. Related self-limited focal epilepsies such as SeLECTS and related disorders are also included, as well as unclassified phenotypes [Carvill et al 2013, Lemke et al 2013, Lesca et al 2013].

Specific epilepsy syndromes associated with GRIN2A pathogenic variants include:

• DEE/EE-SWAS with focal seizures, which may be drug-resistant. The electroencephalogram (EEG) shows marked activation in non-REM sleep of bilateral slow spike-and-wave discharges [Specchio et al 2022].
• In LKS, a subtype of DEE/EE-SWAS, 30% of individuals do not have seizures.
• Self-limited epilepsy with centrotemporal spikes (SeLECTS) with onset in childhood (usually age 3-6 years) with EEG showing centrotemporal discharges [Specchio et al 2022].
• Infantile-onset DEE, with severe-to-profound impairment and sometimes epileptic spasms

EEG most commonly shows focal discharges (86/152; 57%), with centrotemporal spikes (34/152; 22%) or multifocal discharges (28/152; 18%). One third of individuals had SWAS (51/152; 34%). SWAS is defined as marked activation of bilateral slow spike-and-wave discharges in non-REM sleep (previously known as continuous spike-wave in slow-wave sleep [CSWS] or electrical status epilepticus in sleep [ESES]). Generalized discharges (6/152; 4%) or individuals with normal EEG (9/152; 6%) are rare [Strehlow et al 2019].

Speech and language disorders are among the most common features of GRIN2A-related disorders [Turner et al 2015, Strehlow et al 2019]. Abnormalities include dysarthria, speech dyspraxia, dysphasia (55/115; 48%), and speech regression with acquired aphasia (16/115; 14%), which is typically seen in LKS.

Mildly affected individuals may display subtly impaired intelligibility of conversational speech, most characterized by dysarthric and dyspraxic features of hypernasality, imprecise consonant production, and impaired pitch and prosody [Turner et al 2015].

Neuroimaging. Brain MRI is normal in the majority of affected individuals (64/85; 75%). Severely affected individuals may show nonspecific abnormalities, such as cerebral atrophy (9/85; 11%) and a thin corpus callosum. A variety of other abnormalities have rarely been reported, including focal cortical dysplasia, dysplastic corpus callosum with delayed myelination, hypoplasia of corpus callosum with midline lipoma, hippocampal sclerosis, heterotopia, hypoplastic olfactory bulb, cerebellar glioma, enlarged Virchow-Robin spaces, and delayed myelination [Reutlinger et al 2010, Pierson et al 2014, Venkateswaran et al 2014, Yuan et al 2014, Strehlow et al 2019].

Other neurodevelopmental features

• Hypotonia (40/139; 29%)
• Movement disorders, including dystonia, chorea, and ataxia (19/72; 26%)

Neurobehavioral/psychiatric manifestations. Seventeen of 70 individuals (24%) had behavioral or psychiatric disorders, such as ADHD (n=6), ASD (n=6), schizophrenia, or anxiety disorders [Strehlow et al 2019, Shepard et al 2024].

Mental health disorders are relatively frequent in individuals with pathogenic null variants in GRIN2A. At least 27% of individuals develop early-onset mental health disorders including mood disorders (16%), anxiety disorders (14%), and psychotic disorders including schizophrenia (10%) and, rarely, personality disorders (4%) and eating disorders (1%) [J Lemke et al, unpublished data].

Facial features. No obvious dysmorphic features; some individuals may have nonspecific features.

Interfamilial and intrafamilial variability. Individuals who have the same pathogenic GRIN2A variant show similar severity of DD/ID, both within and across families [Strehlow et al 2019].

Prognosis. It is unknown whether life span in GRIN2A-related disorders is abnormal. The oldest known individual is 80 years old [J Lemke et al, unpublished data]. Since many adults with mild GRIN2A phenotypes have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

Several genotype-phenotype correlations have been observed.

Pathogenic GRIN2A missense variants in transmembrane domains (TMD) and linker regions (linker) are associated with severe infantile-onset DEE, whereas missense variants in the amino terminal domain (ATD) and ligand-binding domains (LBD) are associated with speech abnormalities and/or seizures with mild to no ID. Strikingly, both phenotypic groups are significantly correlated with opposing electrophysiologic consequences of the N-methyl-D-aspartate receptor (NMDAR), even though the complex functional alterations caused by a GRIN2A variant cannot always easily be reduced to a binary description such as loss or gain of function. Pathogenic missense variants in the LBD may impede agonist binding and thus reduce channel activity, whereas a TMD or linker missense variant may affect formation of the ion channel pore, mediating a gain-of-function effect by, for example, disrupted channel inhibition [Strehlow et al 2019].

Individuals with pathogenic null variants have later mean seizure onset (age 4.5 ± 0.2 years) compared to those with pathogenic missense variants (age 3.1 ± 0.4 years), and individuals with pathogenic missense variants usually have drug-resistant seizures persisting throughout childhood and adolescence [Camp et al 2023].

Mental health disorders are relatively frequent in individuals with pathogenic null variants in GRIN2A, including mood disorders, anxiety disorders, and psychotic disorders such as schizophrenia and, rarely, personality disorders [J Lemke et al, unpublished data].

Penetrance

GRIN2A-related disorders show high penetrance and variable expressivity.

In families of mildly affected individuals, carriers of the familial pathogenic GRIN2A variant have been observed who were less severely or very rarely not known to be affected [Strehlow et al 2019].

Nomenclature

Prevalence

The prevalence of GRIN2A-related disorders in the general population is unknown. Among 3,038 individuals with neurodevelopmental disorders with epilepsy screened by epilepsy multigene panel sequencing (including GRIN2A), seven had (likely) pathogenic variants, suggesting GRIN2A accounts for 0.23% of neurodevelopmental disorders [Lemke 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GRIN2A-related disorders, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for GRIN2A-related disorders.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Agents/Circumstances to Avoid

In individuals with GRIN2A-related disorders due to pathogenic missense variants activating the N-methyl-D-aspartate receptor (NMDAR), receptor-specific agonists and other activators (e.g., L-serine) should be avoided, as this could result in worsening of symptoms [Krey et al 2022].

In individuals with GRIN2A-related disorders due to pathogenic missense variants inhibiting the NMDAR as well as null variants, receptor-specific blockers should be used with caution (e.g., memantine, dextromethorphan, ketamine).

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic relatives of an affected individual by molecular genetic testing for the GRIN2A pathogenic variant in the family to identify as early as possible those who would benefit from monitoring for developmental disorders, epilepsy, speech-language disorders, behavioral and psychiatric disorders, and EEG abnormalities.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Several treatments are now under investigation in individuals with GRIN2A pathogenic gain-of-function (GOF) variants:

• NMDAR blocker (memantine). In one individual with a GOF missense variant in GRIN2A, seizure burden was reduced with the NMDAR blocker memantine. However, cognitive function did not improve [Pierson et al 2014]. Thereafter, multiple studies reporting the use of memantine have been published. However, these studies are inconclusive due to either lack of confirmation of the pathogenicity of the reported variants (including lack of confirmation that the variant causes GOF), or the observed treatment outcomes were subjective and poorly quantified. Of note, one study reported benefit with memantine in individuals with pathogenic GRIN1 variants [Xu et al 2021].
• GluN2B negative allosteric modulator (radiprodil). Three individuals with infantile epileptic spasms syndrome were treated with the GluN2B negative allosteric modulator radiprodil. One infant became spasm-free and two showed clinical improvement without being spasm-free. After radiprodil withdrawal, one infant continued to be spasm-free, while the two others experienced seizure worsening requiring the use of the ketogenic diet and other anti-seizure medications [Auvin et al 2020].
  A clinical trial on the evaluation of radiprodil in children with GRIN-related disorders is currently being performed with a focus on children with pathogenic gain-of-function missense variants (NCT05818943).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

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

Note: Compound heterozygous GRIN2A pathogenic null variants were reported in a child with a severe developmental and epileptic encephalopathy [Strehlow et al 2022]. Her heterozygous parents had milder manifestations largely consistent with a GRIN2A-related disorder.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with a GRIN2A-related disorder have the disorder as the result of a pathogenic variant inherited from an affected parent. Because considerable clinical variability can be observed among heterozygous family members, an affected parent may have different manifestations of a GRIN2A-related disorder than the proband.
• 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 [Strehlow et al 2019] or, rarely, as a postzygotic de novo event in a mosaic, apparently unaffected parent [Fernández-Marmiesse et al 2018].
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [Fernández-Marmiesse et al 2018]. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with a GRIN2A-related disorder may appear to be negative because of failure to recognize the disorder in family members, or variable clinical expressivity (e.g., subtle speech abnormality or learning difficulties). Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the GRIN2A pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The specific GRIN2A-related phenotype may vary considerably among heterozygous family members, ranging from isolated speech dysfunction to epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) [Carvill et al 2013, Lemke et al 2013, Lesca et al 2013, Turner et al 2015].
• If the GRIN2A pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [Fernández-Marmiesse et al 2018].
• If the parents have not been tested for the GRIN2A pathogenic variant but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for a GRIN2A-related disorder because of the possibility of variable clinical expressivity / mild or subclinical phenotype in a heterozygous parent and the possibility of parental gonadal mosaicism.

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

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the GRIN2A pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the GRIN2A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for GRIN2A-related disorders is possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-activated ion channel permeable to sodium, calcium, and potassium ions that is highly expressed throughout the brain and plays important roles in mediating excitatory neurotransmission critical for development, learning, memory, and other higher cognitive functions. The NMDAR is a heterotetrametric molecule composed of two NMDA receptor 1 subunits (GluN1) and two different NMDA receptor 2 subunits (GluN2A and GluN2B). The GluN2A subunit is encoded by GRIN2A [Matta et al 2011].

In vitro tests on Xenopus laevis oocytes and transfected mammalian fibroblasts show that pathogenic variants in GRIN2A can lead to a gain or loss of function of the NMDAR [Myers et al 2023].

Mechanism of disease causation. GRIN2A-related disorders can be caused by two functional mechanisms:

• Loss of function (usually associated with milder phenotypes, such as speech abnormalities and/or seizures with mild intellectual disability or normal intellect)
• Gain of function (usually associated with more severe phenotypes, such as severe developmental and epileptic encephalopathies)

Author Notes

Dr Vincent Strehlow ([email protected]) and Dr Johannes R Lemke ([email protected]) are actively involved in clinical research regarding individuals with GRIN2A-related disorders. They would be happy to communicate with persons who have any questions regarding diagnosis of GRIN2A-related disorders or other considerations. They further encourage families and caregivers to enroll affected individuals in the global GRIN registry (grin-portal.broadinstitute.org).

Professor Ingrid Scheffer and Dr Ken Myers are happy to assist with enquiries related to patient management. Professor Angela Morgan is happy to assist with enquiries related to speech and language management.

Contact Dr Vincent Strehlow and Dr Johannes R Lemke to inquire about review of GRIN2A variants of uncertain significance.

Acknowledgments

The authors thank all the families and individuals who have contributed to GRIN2A research studies as well as patient organizations such as CureGRIN for their kind collaboration.

Most of the pathophysiologic findings and understanding of mechanisms have been through the comprehensive functional investigations at the Center for Functional Evaluation of Rare Variants at Emory University, Atlanta, United States, lead by Dr Stephen Traynelis.

Revision History

• 4 July 2024 (gm) Comprehensive update posted live
• 29 September 2016 (bp) Review posted live
• 12 October 2015 (kam) Original submission

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