NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

GRIN2A-Related Speech Disorders and Epilepsy

, MD, PhD, FRCPC and , FAA, FAHMS, FRACP, MBBS, PhD.

Author Information

Initial Posting: .

Estimated reading time: 21 minutes

Summary

Clinical characteristics.

GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals and a range of epilepsy syndromes present in about 90%. Severe speech disorders observed can include dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression; 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) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Seizure types include seizures associated with aura of perioral paresthesia, focal or focal motor seizures (often evolving to generalized tonic-clonic), and atypical absence seizures. Epilepsy syndromes can include: Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), childhood epilepsy with centrotemporal spikes (CECTS), atypical childhood epilepsy with centrotemporal spikes (ACECTS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), and infantile-onset epileptic encephalopathy.

Diagnosis/testing.

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

Management.

Treatment of manifestations: Significant speech/language deficits require therapy from a speech pathologist. Seizures should be treated with antiepileptic drugs (AEDs). Many different AEDs may be effective, and no one medication has been demonstrated to be effective specifically for these disorders.

Prevention of secondary complications: Monitoring for possible adverse effects of AEDs.

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

Agents/circumstances to avoid: In individuals with ECSWS, phenytoin, barbiturates and carbamazepine should be avoided as they are rarely effective, may worsen the EEG, and have negative effects on neuropsychological outcomes.

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 prompt evaluation for speech disorders and/or seizures and institution of treatment.

Genetic counseling.

GRIN2A-related speech disorders and epilepsy are inherited in an autosomal dominant manner. The proportion of GRIN2A-related speech disorders and epilepsy caused by a de novo pathogenic variant is unknown. Each child of an individual with a GRIN2A-related speech disorder and epilepsy has a 50% chance of inheriting the GRIN2A pathogenic variant. Once the GRIN2A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options.

Diagnosis

Suggestive Findings

In general, a GRIN2A pathogenic variant should be considered in an individual presenting with an otherwise unexplained combination of the following speech disorders and/or epilepsy features, seizure types, epilepsy syndromes [Tsai et al 2013].

Speech disorders

  • Acquired aphasia
  • Auditory agnosia (impaired recognition of sounds)
  • Dysarthria
  • Speech dyspraxia

Epilepsy features

  • Onset in early childhood (usually age 3-6 years)
  • Focal epilepsy with language and/or global developmental regression
  • Electroencephalogram (EEG) showing continuous spike-and-wave discharges in sleep or very active centrotemporal discharges

Seizure types

  • Most commonly, focal seizures
  • Sometimes occurring with an aura of perioral paresthesia, and often evolving to generalized tonic-clonic seizures

Epilepsy syndromes

  • Landau-Kleffner syndrome (LKS)
  • Epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS)
  • Childhood epilepsy with centrotemporal spikes (CECTS)
  • Atypical childhood epilepsy with centrotemporal spikes (ACECTS)
  • Autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD)
  • Infantile-onset epileptic encephalopathy

Note: Detailed descriptions of each epilepsy syndrome can be found in Clinical Description.

Establishing the Diagnosis

The diagnosis of GRIN2A-related speech disorder and epilepsy is established in a proband by identification of either a heterozygous pathogenic variant in GRIN2A or a heterozygous deletion involving GRIN2A using molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) or genomic testing (chromosomal microarray analysis or comprehensive genomic sequencing).

Gene-targeted testing requires that the clinician develop a hypothesis about which gene(s) are likely involved, whereas genomic testing may not. The phenotypes of many genetic epileptic encephalopathies overlap; thus, most children with a GRIN2A-related speech disorder and epilepsy are diagnosed by CMA or multigene panel (see Recommended Testing) or by comprehensive genomic sequencing (see Testing to Consider).

Recommended Testing

Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays is recommended first when developmental impairment/intellectual disability and/or dysmorphic features are present. The ability to determine the size of the deletion depends on the type of microarray used and the density of probes in the 16p13.2 region.

A multigene panel that incorporates both sequence analysis and deletion/duplication analysis and includes GRIN2A and other genes of interest (see Differential Diagnosis) is recommended when epilepsy associated with speech dyspraxia and dysarthria are the primary findings (see Table 1). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likley to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Testing to Consider

Comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if the phenotype alone is insufficient to support gene-targeted testing). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Single-gene testing (sequence analysis of GRIN2A, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found may be considered first in individuals with features that are highly suggestive of GRIN2A-related speech disorder and epilepsy. However, because many of these features overlap with those of other genetic epileptic encephalopathies, multigene panels or comprehensive genomic testing are often performed in lieu of single-gene testing.

Table 1.

Molecular Genetic Testing Used in GRIN2A-Related Speech Disorders and Epilepsy

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method 3
GRIN2ASequence analysis 458/71
Gene-targeted deletion/duplication analysis 513/71 6
CMASee footnote 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Based on the combined results of published reports of GRIN2A-related disorders [Endele et al 2010, Reutlinger et al 2010, Lesca et al 2012, Carvill et al 2013, DeVries & Patel 2013, Lemke et al 2013, Lesca et al 2013, Conroy et al 2014, Dimassi et al 2014, Venkateswaran et al 2014, Yuan et al 2014, Allen et al 2016, Fainberg et al 2016]. In one proband, GRIN2A was disrupted by an inherited translocation detectable by karyotype [Endele et al 2010]; this was categorized as "detectable by sequence analysis."

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications. These methods will detect from single-exon to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.

6.

Of these 13 probands: 9 had small losses of genetic material (<292 kb), resulting in partial deletion of GRIN2A; 3 had large deletions (>0.9 Mb) affecting multiple genes (in 2 of the 3 GRIN2A was entirely deleted); and 1 had a small intragenic duplication.

7.

CMA is appropriate to define breakpoints of large deletions.

Clinical Characteristics

Clinical Description

The clinical spectrum of GRIN2A-related speech disorders and epilepsy is broad and may vary within a family (e.g., from mild isolated speech impairment to rolandic epilepsy with speech dyspraxia) [Turner et al 2015b].

Disease progression is variable: some individuals have normal development and spontaneous remission of seizures, while others develop medically refractory epilepsy and severe developmental impairment. Language and/or global developmental regression often occurs in those with the more severe epilepsy-aphasia disorders.

Speech and language were impaired in 100% of individuals in a study of the speech manifestations of GRIN2A-related disorders [Turner et al 2015a]. Abnormalities included dysarthria and speech dyspraxia, and both receptive and expressive language delay/regression.

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

Intellectual disability, observed in 38%-67% of affected individuals, ranges from mild to severe [Carvill et al 2013, Lemke et al 2013].

Epilepsy occurs in approximately 90% of individuals [Lemke et al 2013, Lesca et al 2013].

Seizure onset is typically between ages three and six years (mean 4.6 years), although individuals may present from infancy to adolescence [Endele et al 2010, Lesca et al 2012, Carvill et al 2013, Lemke et al 2013, Venkateswaran et al 2014].

The most common seizure type overall is focal seizures. These are often associated with an aura of perioral paresthesia, and frequently evolve to generalized tonic-clonic convulsions. The predominant seizure type(s) in a given individual vary depending on which clinical syndrome is present.

The most common GRIN2A-related speech disorder and epilepsy is epilepsy-aphasia syndromes (EAS), a spectrum of disorders that includes: Landau-Kleffner syndrome (LKS); epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS); childhood epilepsy with centrotemporal spikes (CECTS); atypical childhood epilepsy with centrotemporal spikes (ACECTS); and autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD) [Tsai et al 2013]. Other epilepsy phenotypes can be broadly divided into infantile-onset epileptic encephalopathy and unclassified childhood epilepsy.

Landau-Kleffner syndrome (LKS) [Landau & Kleffner 1957, Wang et al 2006, Hughes 2011]

  • Onset in childhood (peak age range 5-8 years)
  • Acquired aphasia, with auditory agnosia (impaired recognition of sounds) frequently described as the earliest feature
  • Seizures in approximately 70% of cases, most commonly atypical absence, with focal motor, atonic, and focal seizures evolving to bilateral tonic-clonic seizures also described
  • Developmental regression limited to language domains
  • Normal development prior to onset of aphasia or isolated language impairment
  • EEG showing frequent, sleep-activated, bilateral sharp and slow wave discharges (centrotemporal or perisylvian field), eventually evolving to continuous spike-and-wave in sleep (CSWS)

Epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS) [Van Bogaert 2013]

  • Onset in childhood (peak age range 4-5 years)
  • Seizures in approximately 80% of cases, most commonly hemiclonic or generalized tonic-clonic in sleep and atypical absence while awake
  • Global developmental regression (as distinct from the pure language regression of LKS)
  • EEG showing near-continuous (>85% of recording), bilateral sharp and slow wave discharges in slow wave sleep (i.e., CSWS)

Childhood epilepsy with centrotemporal spikes (CECTS) [Guerrini & Pellacani 2012]

  • Onset is in childhood (peak age range 5-8 years; range 3-13 years).
  • Seizures have a characteristic aura of perioral paresthesia which may involve the tongue, cheeks, and mouth. There is often speech arrest and a motor component involving the oropharyngeal muscles, unilateral facial tonic or clonic activity, and (less commonly) an upper limb. The majority of events occur during sleep, and classically involve drooling. Bilateral tonic-clonic seizures are also commonly observed.
  • Seizure frequency is low: half of patients have fewer than six seizures in their lifetime.
  • Epilepsy follows a self-limited course with duration less than five years in the majority of individuals.
  • Development is essentially normal, though mild deficits in language, computation, and motor skills may be apparent when compared to healthy controls [Staden et al 1998, Lillywhite et al 2009, Garcia-Ramos et al 2015].
  • EEG background is normal and shows focal epileptiform discharges from the centrotemporal regions, potentiated in sleep. In 40% of affected individuals, the centrotemporal discharges are bilateral and independent.

Atypical childhood epilepsy with centrotemporal spikes (ACECTS) [Aicardi & Chevrie 1982]

  • Epilepsy course is similar to CECTS with onset and spontaneous remission occurring in childhood.
  • Seizures are different from those seen in CECTS, and include negative myoclonus and atypical absence seizures.
  • Developmental regression or slowing is coincident with seizure onset; however, long-term developmental outcome may be normal.
  • EEG is similar to CECTS in that focal centrotemporal discharges potentiated in sleep are seen; however, focal or diffuse background slowing is also often present.

Autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD) [Scheffer 2000, Turner et al 2015b]

  • Seizure characteristics and epilepsy course are identical to CECTS in most family members. One individual had an encephalopathic presentation associated with cognitive regression.
  • Affected individuals have oral and speech dyspraxia with dysarthria.
  • Individuals may have isolated speech dysfunction without seizures.
  • Cognitive function is usually within the normal range.

Infantile-onset epileptic encephalopathy [Endele et al 2010, Venkateswaran et al 2014, Yuan et al 2014, Allen et al 2016]

  • Multiple different seizure types may be present, including tonic seizures, focal impaired awareness with evolution to bilateral seizures, infantile spasms, and myoclonic seizures.
  • Severe intellectual disability was seen in the three individuals reported.
  • EEG findings vary in the few reported cases and include background slowing, hypsarrhythmia, and focal spikes.
  • Brain MRI may show bilateral parenchymal volume loss and thin corpus callosum.

Unclassified childhood-onset epilepsy [Reutlinger et al 2010, DeVries & Patel 2013]

  • Focal seizures are the most commonly seen; myoclonic, eyelid myoclonia, and atypical absence have also been reported.
  • Development ranges from normal to severely impaired.
  • Mild dysmorphic features may be present in individuals with a contiguous gene deletion.
  • EEG usually shows multifocal epileptiform discharges.

Contiguous gene deletions. Reutlinger et al [2010] described three individuals with 16p13 deletions involving multiple genes and complete or partial heterozygous deletion of GRIN2A. All had mild dysmorphic features, intellectual disability, and epilepsy involving the rolandic region.

EEG most commonly shows bilateral epileptiform discharges (usually spike or spike-wave) in the central-temporal or temporal-parietal regions which may be independent or bilaterally synchronous. These abnormalities become more frequent in sleep, often evolving to continuous spike-and-wave in sleep (CSWS). CSWS is defined as near-continuous (>85% of non-REM sleep recording) bilateral sharp and slow wave discharges in slow wave sleep. CECTS is classically associated with a horizontal dipole; tangential dipole across the Sylvian fissure has been reported in LKS [Morrell et al 1995, Dalla Bernardina et al 2005].

Brain imaging. Brain MRI is normal in the vast majority. Severely affected individuals may have enlargement of extra-axial spaces and a thin corpus callosum [Reutlinger et al 2010, Pierson et al 2014, Venkateswaran et al 2014, Yuan et al 2014]. One individual with focal cortical dysplasia was reported [Lesca et al 2013].

Positron emission tomography (PET) showing diffuse cortical hypometabolism was reported in one individual [DeVries & Patel 2013].

Genotype-Phenotype Correlations

Genotype-phenotype correlation is observed in a number of families in which all individuals heterozygous for the GRIN2A pathogenic variant have an epilepsy-aphasia syndrome (EAS) phenotype. However, the specific EAS phenotype may vary considerably within the family, including one individual with isolated speech dysfunction and another with epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS) [Carvill et al 2013, Lemke et al 2013, Lesca et al 2013, Turner et al 2015a].

For single-nucleotide variants (SNVs) and small intragenic copy number variants (CNVs), the genomic region in which the pathogenic variant occurs does not appear to have any relationship to the phenotype. Specifically, the pathogenic variants associated with infantile-onset epileptic encephalopathies do not cluster in a region distinct from the location of pathogenic variants associated with the epilepsy-aphasia syndromes (EAS).

Penetrance

GRIN2A-related speech disorders and epilepsy show incomplete but high penetrance and variable expressivity.

Penetrance is not clearly different for males and females.

Nomenclature

Landau-Kleffner syndrome (LKS) has also been referred to as epileptic acquired aphasia.

Epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS) has also been referred to as continuous spike-and-wave during slow-wave sleep (CSWS) and electrical status epilepticus during sleep (ESES).

Childhood epilepsy with centrotemporal spikes (CECTS) has been commonly referred to as benign epilepsy with centrotemporal spikes (BECTS) and benign rolandic epilepsy of childhood (BREC).

Atypical childhood epilepsy with centrotemporal spikes (ACECTS) has been known as atypical benign partial epilepsy (ABPE), pseudo-Lennox syndrome, and atonic-benign childhood epilepsy with centrotemporal spikes.

Prevalence

The prevalence of GRIN2A-related speech disorders and epilepsy in the general population is unknown; however, estimates can be made for some of the classic disorders.

GRIN2A pathogenic variants account for 9%-20% of epilepsy-aphasia syndrome (EAS), with pathogenic variants more likely to be present in persons with more severe phenotypes and a positive family history [Lesca et al 2012, Carvill et al 2013].

GRIN2A pathogenic variants are present in:

  • 4.8%-7.7% of Landau-Kleffner syndrome (LKS)
  • 17.6% of epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS)
  • 0%-4.9% of childhood epilepsy with centrotemporal spikes (CECTS)
  • 13.5% of atypical childhood epilepsy with centrotemporal spikes (ACECTS)
  • 2% of early-onset epileptic encephalopathy

[Lemke et al 2013, Conroy et al 2014, Allen et al 2016].

Differential Diagnosis

Non-GRIN2-related genetic epilepsy

  • Epilepsy-aphasia syndrome (EAS). While GRIN2A is the gene most commonly associated with EAS, the majority of individuals with this group of syndromes do not have an identified genetic cause. A number of CNVs have been associated with EAS in individual cases. Pathogenic variants in RBFOX1 and RBFOX3 may play a contributory role in some cases [Lal et al 2013, Turner et al 2015b]. At present, no clinical features differentiate GRIN2A-related EAS from EAS of other genetic causes.
  • Non-EAS childhood-onset focal epilepsy and infantile-onset epileptic encephalopathy. Each phenotype has only a small number of reported cases associated with a GRIN2A pathogenic variant. Clinical data currently available are insufficient to distinguish those with a GRIN2A pathogenic variant from those with other genetic causes.

Non-genetic causes of epilepsy. Focal epilepsy and epileptic encephalopathy may have many non-genetic causes, including autoimmune and infectious processes. A non-genetic cause should be more strongly considered when a history of any of the following is present:

  • Maternal substance abuse during pregnancy
  • Significant complications in the perinatal period
  • Significant cerebral insult (e.g., central nervous system infection, hypoxic-ischemic injury, major head trauma, toxic ingestion/exposure)

Non-GRIN2A-related genetic language impairment. A severe speech and language disorder that primarily involves developmental verbal dyspraxia is caused by pthogenic variants in FOXP2 (see FOXP2-Related Speech and Language Disorders) [Lai et al 2001]. FOXP2 regulates CNTNAP2, and CNTNAP2 missense variants and deletions have been associated with childhood apraxia of speech; however, evidence of a causative link is at present limited [Worthey et al 2013, Centanni et al 2015].

Hearing impairment is a common cause of language-specific developmental delay or regression, thus in children with delayed speech development or regression in speech, the auditory system should be assessed (see Hereditary Hearing Loss and Deafness Overview).

Structural brain abnormality. Brain malformations and acquired structural brain anomalies can present with a constellation of symptoms that can mimic the GRIN2A-related disorders. Worster-Drought syndrome (OMIM 185480) involves congenital bilateral perisylvian lesions, most commonly polymicrogyria [Christen et al 2000]. Affected children typically have seizures, expressive language delay, dysarthria, and oromotor apraxia.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a GRIN2A-related speech disorder and epilepsy, the following evaluations are recommended:

  • Consultation with a speech and language pathologist
  • Epilepsy consultation (if not done at the time of initial assessment)
  • Sleep-deprived or sleep EEG with monitoring to capture slow-wave sleep (if not done at the time of initial assessment), as this is essential to diagnosing or excluding continuous spike-and-wave in sleep (CSWS).
  • Neuropsychological assessment
  • Hearing testing
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Speech/language deficits. Individuals with significant speech/language deficits may benefit from therapy by a speech pathologist. The therapies, which are individualized to the specific speech disorder, often include linguistic approaches and augmentative and alternative communication [Murray et al 2014].

Seizures, if present, should be treated with antiepileptic drugs (AEDs). Many different AEDs may be effective, and no one medication has been demonstrated to be effective specifically for GRIN2A-related disorders.

In one individual a good response to refractory epilepsy was achieved with topiramate [Venkateswaran et al 2014].

In one individual seizure burden was reduced with the addition of memantine; however, cognitive function did not improve [Pierson et al 2014].

Ketogenic diet and vagal nerve stimulator may also be considered in patients with refractory epilepsy.

Treatment for epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS) and Landau-Kleffner syndrome (LKS) includes AEDs such as valproic acid, benzodiazepines, and corticosteroids. Sulthiame, ethosuximide, and levetiracetam may also be effective.

Of note, intravenous immunoglobulin has not been proven to be efficacious [Striano & Capovilla 2013, Van Bogaert 2013].

Caregivers. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Prevention of Secondary Complications

AEDs are associated with possible adverse reactions (e.g., sedation, gastrointestinal symptoms, changes in appetite [increase or decrease], weight gain or loss, and rash) which vary according to the specific medication. Patients on AEDs should be monitored closely for adverse reactions and, if they develop, a change to an alternate AED should be considered.

Corticosteroids are associated with a wide variety of possible adverse reactions, including weight gain with cushingoid appearance, skin thinning and purpura, alopecia, acne, posterior subscapular cataract, glaucoma, exophthalmos, cardiac arrhythmias, hypertension, gastrointestinal upset, pancreatitis, hypokalemia, osteoporosis, avascular necrosis, myopathy, behavioral/psychiatric disturbance, diabetes mellitus, adrenal insufficiency, and increased infection risk. If complications of corticosteroid therapy become of concern, gradual tapering and alternate therapy should be considered.

Surveillance

Routine monitoring of speech and language by a speech pathologist should be considered for all children, particularly those diagnosed before reaching school age.

Developmental surveillance should be conducted in all affected children.

Agents/Circumstances to Avoid

In individuals with epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), phenytoin, barbiturates and carbamazepine should be avoided as they are rarely effective, may worsen the EEG, and have negative effects on neuropsychological outcomes [Striano & Capovilla 2013, Van Bogaert 2013].

Evaluation of Relatives at Risk

Using molecular genetic testing for the GRIN2A pathogenic variant found in an affected family member, it is appropriate to evaluate apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from institution of treatment. Of note, some individuals heterozygous for a GRIN2A pathogenic variant who have only relatively mild speech dysfunction may benefit from early evaluation and intervention by a speech and language pathologist.

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with a GRIN2A-related speech disorder and epilepsy have an affected parent. There is considerable clinical variability within families.
  • A proband with a GRIN2A-related speech disorder and epilepsy may have a de novo GRIN2A pathogenic variant; however, the proportion of GRIN2A-related speech disorders and epilepsy caused by a de novo pathogenic variant is unknown because to date an insufficient number of parents of simplex cases (i.e., a single occurrence in a family) have been tested.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. (Although no instances of germline mosaicism have been reported, it remains a possibility.)
  • The family history of some individuals diagnosed with a GRIN2A-related speech disorder and epilepsy may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or variable clinical severity. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of 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 the parents have been tested for the GRIN2A pathogenic variant identified in the proband and:
    • A parent of the proband has the GRIN2A pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Some familial cases have demonstrated reduced penetrance and phenotypic variability.
    • The GRIN2A pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be low but greater than that of the general population because of the theoretic possibility of germline mosaicism.
  • If the parents have not been tested for the GRIN2A pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for a GRIN2A-related speech disorder and epilepsy because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with a GRIN2A-related speech disorder and epilepsy has a 50% chance of inheriting the GRIN2A pathogenic variant. Some familial cases have demonstrated reduced penetrance and phenotypic variability.

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, his or her 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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the GRIN2A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for a GRIN2A-related speech disorder and epilepsy are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Epilepsy Society (AES)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

GRIN2A-Related Speech Disorders and Epilepsy: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for GRIN2A-Related Speech Disorders and Epilepsy (View All in OMIM)

138253GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 2A; GRIN2A
245570EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION; FESD

Molecular Genetic Pathogenesis

N-methyl-D-aspartate (NMDA) receptors are glutamate-activated ion channels permeable to sodium, calcium, and potassium ions, thought to be primarily important in mediation of excitatory processes in the human brain. The NMDA receptor is a heterotetramer composed of two NMDA-receptor 1 subunits (NR1) and two different NMDA-receptor subunits (NR2A and NR2B). The NR2A subunit is encoded by GRIN2A [Matta et al 2011].

Gene structure. GRIN2A comprises 14 exons [Endele et al 2010]. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. Of probands with pathogenic variants, 41/71 (58%) had missense variants, 8/71 (11%) nonsense variants, 8/71 (11%) splice site variants, and 13/71 (18%) copy number variations; the remaining proband had a translocation affecting GRIN2A without loss of genetic material.

One recurrent splice site variant (c.1007+1G>A) located in intron 4 has been identified in six apparently unrelated probands [Carvill et al 2013, Lemke et al 2013]. Four missense variants (c.1553G>A, c.1845C>A, c.2146G>A, and c.2927A>G) have been reported in two probands each [Endele et al 2010, Lesca et al 2013, Conroy et al 2014, Allen et al 2016, Fainberg et al 2016].

In two nonfamilial cases, a recurrent pathogenic variant (c.1845C>A) has been associated with severe intellectual disability and refractory early-onset epileptic encephalopathy [Endele et al 2010, Allen et al 2016].

Table 2.

GRIN2A Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1007+1G>ASplice regionNM_000833​.4
NP_000824​.1
c.1553G>Ap.Arg518His
c.1845C>Ap.Asn615Lys
c.2146G>Ap.Ala716Thr
c.2927A>Gp.Asn976Ser

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The human GRIN2A gene product contains 1464 amino acids.

Abnormal gene product. In in vitro models, NMDA receptors with GRIN2A pathogenic variants demonstrate reduced inhibition by both Zn2+ and Mg2+, and have shorter closed-state and longer open-state durations, all of which suggests that GRIN2A pathogenic variants lead to increased neuronal excitability [Endele et al 2010, Lesca et al 2012, Lemke et al 2013].

References

Literature Cited

  • Aicardi J, Chevrie JJ. Atypical benign partial epilepsy of childhood. Dev Med Child Neurol. 1982;24:281–92. [PubMed: 6807733]
  • Allen NM, Conroy J, Shahwan A, Lynch B, Correa RG, Pena SD, McCreary D, Magalhaes TR, Ennis S, Lynch SA, King MD. Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. Epilepsia. 2016;57:e12–7. [PubMed: 26648591]
  • Carvill GL, Regan BM, Yendle SC, O'Roak BJ, Lozovaya N, Bruneau N, Burnashev N, Khan A, Cook J, Geraghty E, Sadleir LG, Turner SJ, Tsai MH, Webster R, Ouvrier R, Damiano JA, Berkovic SF, Shendure J, Hildebrand MS, Szepetowski P, Scheffer IE, Mefford HC. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet. 2013;45:1073–6. [PMC free article: PMC3868952] [PubMed: 23933818]
  • Centanni TM, Sanmann JN, Green JR, Iuzzini-Seigel J, Bartlett C, Sanger WG, Hogan TP. The role of candidate-gene CNTNAP2 in childhood apraxia of speech and specific language impairment. Am J Med Genet B Neuropsychiatr Genet. 2015;168:536–43. [PubMed: 26097074]
  • Christen HJ, Hanefeld F, Kruse E, Imhauser S, Ernst JP, Finkenstaedt M. Foix-Chavany-Marie (anterior operculum) syndrome in childhood: a reappraisal of Worster-Drought syndrome. Dev Med Child Neurol. 2000;42:122–32. [PubMed: 10698330]
  • Conroy J, McGettigan PA, McCreary D, Shah N, Collins K, Parry-Fielder B, Moran M, Hanrahan D, Deonna TW, Korff CM, Webb D, Ennis S, Lynch SA, King MD. Towards the identification of a genetic basis for Landau-Kleffner syndrome. Epilepsia. 2014;55:858–65. [PubMed: 24828792]
  • Dalla Bernardina B, Sgrò V, Fejerman N. Epilepsy with centro-temporal spikes and related syndromes. In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 4 ed. Montrouge, France, John Libbey Eurotext. 2005:203-26.
  • DeVries SP, Patel AD. Two patients with a GRIN2A mutation and childhood-onset epilepsy. Pediatr Neurol. 2013;49:482–5. [PubMed: 24125812]
  • Dimassi S, Labalme A, Lesca G, Rudolf G, Bruneau N, Hirsch E, Arzimanoglou A, Motte J, de Saint Martin A, Boutry-Kryza N, Cloarec R, Benitto A, Ameil A, Edery P, Ryvlin P, De Bellescize J, Szepetowski P, Sanlaville D. A subset of genomic alterations detected in rolandic epilepsies contains candidate or known epilepsy genes including GRIN2A and PRRT2. Epilepsia. 2014;55:370–8. [PubMed: 24372385]
  • Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, Milh M, Kortum F, Fritsch A, Pientka FK, Hellenbroich Y, Kalscheuer VM, Kohlhase J, Moog U, Rappold G, Rauch A, Ropers HH, von Spiczak S, Tonnies H, Villeneuve N, Villard L, Zabel B, Zenker M, Laube B, Reis A, Wieczorek D, Van Maldergem L, Kutsche K. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet. 2010;42:1021–6. [PubMed: 20890276]
  • Fainberg N, Harper A, Tchapyjnikov D, Mikati MA. Response to immunotherapy in a patient with Landau-Kleffner syndrome and GRIN2A mutation. Epileptic Disord. 2016;18:97–100. [PubMed: 26806548]
  • Garcia-Ramos C, Jackson DC, Lin JJ, Dabbs K, Jones JE, Hsu DA, Stafstrom CE, Zawadzki L, Seidenberg M, Prabhakaran V, Hermann BP. Cognition and brain development in children with benign epilepsy with centrotemporal spikes. Epilepsia. 2015;56:1615–22. [PMC free article: PMC4593750] [PubMed: 26337046]
  • Guerrini R, Pellacani S. Benign childhood focal epilepsies. Epilepsia. 2012;53 Suppl 4:9–18. [PubMed: 22946717]
  • Hughes JR. A review of the relationships between Landau-Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike-waves during sleep. Epilepsy Behav. 2011;20:247–53. [PubMed: 21242107]
  • Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature. 2001;413:519–23. [PubMed: 11586359]
  • Lal D, Reinthaler EM, Altmuller J, Toliat MR, Thiele H, Nurnberg P, Lerche H, Hahn A, Moller RS, Muhle H, Sander T, Zimprich F, Neubauer BA. RBFOX1 and RBFOX3 mutations in rolandic epilepsy. PLoS One. 2013;8:e73323. [PMC free article: PMC3765197] [PubMed: 24039908]
  • Landau WM, Kleffner FR. Syndrome of acquired aphasia with convulsive disorder in children. Neurology. 1957;7:523–30. [PubMed: 13451887]
  • Lemke JR, Lal D, Reinthaler EM, Steiner I, Nothnagel M, Alber M, Geider K, Laube B, Schwake M, Finsterwalder K, Franke A, Schilhabel M, Jahn JA, Muhle H, Boor R, Van Paesschen W, Caraballo R, Fejerman N, Weckhuysen S, De Jonghe P, Larsen J, Moller RS, Hjalgrim H, Addis L, Tang S, Hughes E, Pal DK, Veri K, Vaher U, Talvik T, Dimova P, Guerrero Lopez R, Serratosa JM, Linnankivi T, Lehesjoki AE, Ruf S, Wolff M, Buerki S, Wohlrab G, Kroell J, Datta AN, Fiedler B, Kurlemann G, Kluger G, Hahn A, Haberlandt DE, Kutzer C, Sperner J, Becker F, Weber YG, Feucht M, Steinbock H, Neophythou B, Ronen GM, Gruber-Sedlmayr U, Geldner J, Harvey RJ, Hoffmann P, Herms S, Altmuller J, Toliat MR, Thiele H, Nurnberg P, Wilhelm C, Stephani U, Helbig I, Lerche H, Zimprich F, Neubauer BA, Biskup S, von Spiczak S. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013;45:1067–72. [PubMed: 23933819]
  • Lesca G, Rudolf G, Bruneau N, Lozovaya N, Labalme A, Boutry-Kryza N, Salmi M, Tsintsadze T, Addis L, Motte J, Wright S, Tsintsadze V, Michel A, Doummar D, Lascelles K, Strug L, Waters P, de Bellescize J, Vrielynck P, de Saint Martin A, Ville D, Ryvlin P, Arzimanoglou A, Hirsch E, Vincent A, Pal D, Burnashev N, Sanlaville D, Szepetowski P. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet. 2013;45:1061–6. [PubMed: 23933820]
  • Lesca G, Rudolf G, Labalme A, Hirsch E, Arzimanoglou A, Genton P, Motte J, de Saint Martin A, Valenti MP, Boulay C, De Bellescize J, Keo-Kosal P, Boutry-Kryza N, Edery P, Sanlaville D, Szepetowski P. Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism. Epilepsia. 2012;53:1526–38. [PubMed: 22738016]
  • Lillywhite LM, Saling MM, Harvey AS, Abbott DF, Archer JS, Vears DF, Scheffer IE, Jackson GD. Neuropsychological and functional MRI studies provide converging evidence of anterior language dysfunction in BECTS. Epilepsia. 2009;50:2276–84. [PubMed: 19292755]
  • Matta JA, Ashby MC, Sanz-Clemente A, Roche KW, Isaac JT. mGluR5 and NMDA receptors drive the experience- and activity-dependent NMDA receptor NR2B to NR2A subunit switch. Neuron. 2011;70:339–51. [PMC free article: PMC3087383] [PubMed: 21521618]
  • Morrell F, Whisler WW, Smith MC, Hoeppner TJ, de Toledo-Morrell L, Pierre-Louis SJ, Kanner AM, Buelow JM, Ristanovic R, Bergen D, Chez M, Hasegawa H. Landau-Kleffner syndrome. Treatment with subpial intracortical transection. Brain. 1995;118:1529–46. [PubMed: 8595482]
  • Murray E, McCabe P, Ballard KJ. A systematic review of treatment outcomes for children with childhood apraxia of speech. Am J Speech Lang Pathol. 2014;23:486–504. [PubMed: 24686844]
  • Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T, Golas G, Simeonov DR, Holloman C, Tankovic A, Karamchandani MM, Schreiber JM, Mullikin JC, Tifft CJ, Toro C, Boerkoel CF, Traynelis SF, Gahl WA. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1:190–8. [PMC free article: PMC4019449] [PubMed: 24839611]
  • Reutlinger C, Helbig I, Gawelczyk B, Subero JI, Tonnies H, Muhle H, Finsterwalder K, Vermeer S, Pfundt R, Sperner J, Stefanova I, Gillessen-Kaesbach G, von Spiczak S, van Baalen A, Boor R, Siebert R, Stephani U, Caliebe A. Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region. Epilepsia. 2010;51:1870–3. [PubMed: 20384727]
  • Scheffer IE. Autosomal dominant rolandic epilepsy with speech dyspraxia. Epileptic Disord. 2000;2 Suppl 1:S19–22. [PubMed: 11231219]
  • Staden U, Isaacs E, Boyd SG, Brandl U, Neville BG. Language dysfunction in children with Rolandic epilepsy. Neuropediatrics. 1998;29:242–8. [PubMed: 9810559]
  • Striano P, Capovilla G. Epileptic encephalopathy with continuous spikes and waves during sleep. Curr Neurol Neurosci Rep. 2013;13:360. [PubMed: 23666433]
  • Tsai MH, Vears DF, Turner SJ, Smith RL, Berkovic SF, Sadleir LG, Scheffer IE. Clinical genetic study of the epilepsy-aphasia spectrum. Epilepsia. 2013;54:280–7. [PubMed: 23294109]
  • Turner SJ, Mayes AK, Verhoeven A, Mandelstam SA, Morgan AT, Scheffer IE. GRIN2A: an aptly named gene for speech dysfunction. Neurology. 2015a;84:586–93. [PMC free article: PMC4335991] [PubMed: 25596506]
  • Turner SJ, Morgan AT, Perez ER, Scheffer IE. New genes for focal epilepsies with speech and language disorders. Curr Neurol Neurosci Rep. 2015b;15:35. [PubMed: 25921602]
  • Van Bogaert P. Epileptic encephalopathy with continuous spike-waves during slow-wave sleep including Landau-Kleffner syndrome. Handb Clin Neurol. 2013;111:635–40. [PubMed: 23622211]
  • Venkateswaran S, Myers KA, Smith AC, Beaulieu CL, Schwartzentruber JA, Majewski J, Bulman D, Boycott KM, Dyment DA. Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novo GRIN2A mutation. Epilepsia. 2014;55:e75–9. [PubMed: 24903190]
  • Wang S, Zhang YH, Bao XH, Wu Y, Jiang YW, Liu XY, Qin J. Zhonghua Er Ke Za Zhi. 2006;44:105–9. [Clinical characteristics and long-term prognosis of Landau-Kleffner syndrome] [PubMed: 16624025]
  • Worthey EA, Raca G, Laffin JJ, Wilk BM, Harris JM, Jakielski KJ, Dimmock DP, Strand EA, Shriberg LD. Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech. J Neurodev Disord. 2013;5:29. [PMC free article: PMC3851280] [PubMed: 24083349]
  • Yuan H, Hansen KB, Zhang J, Pierson TM, Markello TC, Fajardo KV, Holloman CM, Golas G, Adams DR, Boerkoel CF, Gahl WA, Traynelis SF. Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. Nat Commun. 2014;5:3251. [PMC free article: PMC3934797] [PubMed: 24504326]

Chapter Notes

Revision History

  • 29 September 2016 (bp) Review posted live
  • 12 October 2015 (kam) Original submission
Copyright © 1993-2019, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2019 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK385627PMID: 27683935

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...