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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="GRIN2A-Related Disorders" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2024/07/04" /><meta name="citation_author" content="Vincent Strehlow" /><meta name="citation_author" content="Kenneth A Myers" /><meta name="citation_author" content="Angela T Morgan" /><meta name="citation_author" content="Ingrid E Scheffer" /><meta name="citation_author" content="Johannes R. Lemke" /><meta name="citation_pmid" content="27683935" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK385627/" /><meta name="citation_keywords" content="Glutamate receptor ionotropic, NMDA 2A" /><meta name="citation_keywords" content="GRIN2A" /><meta name="citation_keywords" content="GRIN2A-Related Disorders" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="GRIN2A-Related Disorders" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Vincent Strehlow" /><meta name="DC.Contributor" content="Kenneth A Myers" /><meta name="DC.Contributor" content="Angela T Morgan" /><meta name="DC.Contributor" content="Ingrid E Scheffer" /><meta name="DC.Contributor" content="Johannes R. Lemke" /><meta name="DC.Date" content="2024/07/04" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK385627/" /><meta name="description" content="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." /><meta name="og:title" content="GRIN2A-Related Disorders" /><meta name="og:type" content="book" /><meta name="og:description" content="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. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK385627_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK385627_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/grin1-ndd/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/grin2b/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK385627_"><span class="title" itemprop="name"><i>GRIN2A</i>-Related Disorders</span></h1><p class="contrib-group"><span itemprop="author">Vincent Strehlow</span>, MD, <span itemprop="author">Kenneth A Myers</span>, MD, PhD, FRCPC, <span itemprop="author">Angela T Morgan</span>, BSpPath(Aud Hons), PhD, CPSP, <span itemprop="author">Ingrid E Scheffer</span>, MBBS, PhD, FRACP, FAA, FAHMS, FRS, and <span itemprop="author">Johannes R. Lemke</span>, MD.</p><a data-jig="ncbitoggler" href="#__NBK385627_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK385627_ai__"><div class="contrib half_rhythm"><span itemprop="author">Vincent Strehlow</span>, MD<div class="affiliation small">Institute of Human Genetics<br />University of Leipzig Medical Center<br />Leipzig, Germany<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ed.gizpiel-inu.nizidem@wolherts.tnecniv" class="oemail">ed.gizpiel-inu.nizidem@wolherts.tnecniv</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Kenneth A Myers</span>, MD, PhD, FRCPC<div class="affiliation small">Research Institute of the McGill University Health Centre<br />Montreal, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.liamg@1nek.ufs" class="oemail">moc.liamg@1nek.ufs</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Angela T Morgan</span>, BSpPath(Aud Hons), PhD, CPSP<div class="affiliation small">Murdoch Children’s Research Institute<br />Melbourne, Australia</div><div class="affiliation small">University of Melbourne<br />Melbourne, Australia<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ua.ude.bleminu@roma" class="oemail">ua.ude.bleminu@roma</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Ingrid E Scheffer</span>, MBBS, PhD, FRACP, FAA, FAHMS, FRS<div class="affiliation small">University of Melbourne<br />Melbourne, Australia<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ua.ude.bleminu@reffehcs.i" class="oemail">ua.ude.bleminu@reffehcs.i</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Johannes R. Lemke</span>, MD<div class="affiliation small">Institute of Human Genetics<br />University of Leipzig Medical Center<br />Leipzig, Germany<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ed.gizpiel-inu.nizidem@ekmel.sennahoj" class="oemail">ed.gizpiel-inu.nizidem@ekmel.sennahoj</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">September 29, 2016</span>; Last Update: <span itemprop="dateModified">July 4, 2024</span>.</p><p><em>Estimated reading time: 28 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="grin2a-dis.Summary" itemprop="description"><h2 id="_grin2a-dis_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>GRIN2A</i>-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.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of a <i>GRIN2A</i>-related disorder is established in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> by the identification of a <i>GRIN2A</i> <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</p></div><div><h4 class="inline">Management.</h4><p><i>Targeted therapy:</i> In some individuals with pathogenic <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> and <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> <i>GRIN2A</i> 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.</p><p><i>Supportive care:</i> 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 <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a>.</p><p><i>Surveillance:</i> 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.</p><p><i>Agents/circumstances to avoid:</i> In individuals with <i>GRIN2A</i>-related disorders due to pathogenic <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants activating the NMDAR (i.e., <a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a> 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 <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> variants, NMDA receptor blockers should be used with caution (e.g., memantine, dextromethorphan, ketamine).</p><p><i>Evaluation of relatives at risk:</i> 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.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>GRIN2A</i>-related disorders are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. Some individuals diagnosed with a <i>GRIN2A</i>-related disorder have the disorder as the result of a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> inherited from an affected parent. Approximately 50% of individuals diagnosed with a <i>GRIN2A</i>-related disorder have the disorder as the result of a <i>GRIN2A</i> pathogenic variant that occurred as a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> event in the affected individual or, rarely, as a <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a> <i>de novo</i> event in a mosaic, apparently unaffected parent. Each child of an individual with a <i>GRIN2A</i>-related disorder has a 50% chance of inheriting the <i>GRIN2A</i> pathogenic variant. Once the <i>GRIN2A</i> pathogenic variant has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p></div></div><div id="grin2a-dis.Diagnosis"><h2 id="_grin2a-dis_Diagnosis_">Diagnosis</h2><div id="grin2a-dis.Suggestive_Findings"><h3>Suggestive Findings</h3><p>A <i>GRIN2A</i>-related disorder <b>should be considered</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with the following suggestive clinical findings and family history.</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Mild-to-profound developmental delay / intellectual disability; some affected individuals may be of normal intellect.</div></li><li class="half_rhythm"><div>Focal epilepsy</div><ul><li class="half_rhythm"><div>Self-limited epilepsy with centrotemporal spikes</div></li><li class="half_rhythm"><div>Developmental and/or epileptic encephalopathy (DEE/EE) with spike-wave activation in sleep (DEE/EE-SWAS)</div></li><li class="half_rhythm"><div>Infantile-onset DEE, sometimes with epileptic spasms</div></li></ul></li><li class="half_rhythm"><div>Speech and language disorders including dysarthria, speech dyspraxia, aphasia, and nonverbal phenotypes</div></li><li class="half_rhythm"><div>Movement disorders including ataxia, dystonia, or choreiform movements</div></li><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>Neuropsychiatric features including behavioral issues, attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, anxiety disorders, and mood disorders</div></li></ul><p><b>Family history</b> may be consistent with <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> inheritance (e.g., affected males and females in multiple generations) or the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> may have a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> and therefore be <a class="def" href="/books/n/gene/glossary/def-item/sporadic/">sporadic</a>, with no other family members affected.</p></div><div id="grin2a-dis.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of a <i>GRIN2A</i>-related disorder <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with <a href="#grin2a-dis.Suggestive_Findings">suggestive findings</a> and a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic (or <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>) variant in <i>GRIN2A</i> identified by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK385627/table/grin2a-dis.T.molecular_genetic_testing_u/?report=objectonly" target="object" rid-ob="figobgrin2adisTmoleculargenetictestingu">Table 1</a>).</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "<a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>" and "<a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a> variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bk_pop" href="#grin2a-dis.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>GRIN2A</i> variant of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches should include <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>).</p><p>Note: Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing (<a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> of <i>GRIN2A</i>, followed by gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>) is rarely useful and typically NOT recommended.</p><p><b>Comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> does not require the clinician to identify which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is likely involved. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible. To date, all reported <i>GRIN2A</i> pathogenic variants are within the <a class="def" href="/books/n/gene/glossary/def-item/coding-region/">coding region</a> or canonical splice sites and are likely to be identified on <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="grin2a-dis.T.molecular_genetic_testing_u" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>GRIN2A</i>-Related Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385627/table/grin2a-dis.T.molecular_genetic_testing_u/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__grin2a-dis.T.molecular_genetic_testing_u_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_grin2a-dis.T.molecular_genetic_testing_u_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1, 2</sup></th><th id="hd_h_grin2a-dis.T.molecular_genetic_testing_u_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_grin2a-dis.T.molecular_genetic_testing_u_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_grin2a-dis.T.molecular_genetic_testing_u_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GRIN2A</i>
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</td><td headers="hd_h_grin2a-dis.T.molecular_genetic_testing_u_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_grin2a-dis.T.molecular_genetic_testing_u_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">85% (206/243) <sup>4</sup></td></tr><tr><td headers="hd_h_grin2a-dis.T.molecular_genetic_testing_u_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>5</sup></td><td headers="hd_h_grin2a-dis.T.molecular_genetic_testing_u_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15% (37/243) <sup>4</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="grin2a-dis.TF.1.1"><p class="no_margin">See <a href="/books/NBK385627/#grin2a-dis.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="grin2a-dis.TF.1.2"><p class="no_margin">See <a href="#grin2a-dis.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>. Several additional individuals with complex chromosomal rearrangements disrupting <i>GRIN2A</i> (not included in these calculations) have been reported [<a class="bk_pop" href="#grin2a-dis.REF.endele.2010.1021">Endele et al 2010</a>].</p></div></dd><dt>3. </dt><dd><div id="grin2a-dis.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants and small intragenic deletions/insertions; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>4. </dt><dd><div id="grin2a-dis.TF.1.4"><p class="no_margin">
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<a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al [2019]</a>
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</p></div></dd><dt>5. </dt><dd><div id="grin2a-dis.TF.1.5"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 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. Exome and <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a> may be able to detect deletions/duplications using breakpoint detection or read depth; however, <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> can be lower than gene-targeted deletion/duplication analysis.</p></div></dd></dl></div></div></div></div></div><div id="grin2a-dis.Clinical_Characteristics"><h2 id="_grin2a-dis_Clinical_Characteristics_">Clinical Characteristics</h2><div id="grin2a-dis.Clinical_Description"><h3>Clinical Description</h3><p>The clinical spectrum of <i>GRIN2A</i>-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. <i>GRIN2A</i>-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).</p><p>To date, about 400 individuals have been identified with a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>GRIN2A</i> [<a class="bk_pop" href="#grin2a-dis.REF.lemke.2013.1067">Lemke et al 2013</a>, <a class="bk_pop" href="#grin2a-dis.REF.lesca.2013.1061">Lesca et al 2013</a>, <a class="bk_pop" href="#grin2a-dis.REF.carvill.2013.1073">Carvill et al 2013</a>, <a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al 2019</a>] (see also <a href="https://grin-portal.broadinstitute.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">grin-portal.broadinstitute.org</a>). The following description of the phenotypic features associated with this condition is based on reports of these individuals.</p><div id="grin2a-dis.T.select_features_of_grin2are" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Select Features of <i>GRIN2A</i>-Related Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385627/table/grin2a-dis.T.select_features_of_grin2are/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__grin2a-dis.T.select_features_of_grin2are_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons<br />w/Feature <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Developmental delay /</b>
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<br />
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<b>intellectual disability</b>
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</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Any severity</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">63% (111/177)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Mild</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">45% (33/74)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Moderate</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">23% (17/74)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Severe</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">11% (8/74)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Profound</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">22% (16/74)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" rowspan="4" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Epilepsy</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Any type</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">88% (192/219)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Focal</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">83% (121/146)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Generalized</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">14% (21/146)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Epileptic spasms</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3% (4/146)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Speech & language disorders</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Any type/severity</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">92% (129/140)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Moderate <sup>2</sup></td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">48% (55/115)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Nonverbal</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">16% (18/115)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Speech delays</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">23% (26/115)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Temporary speech regression / acquired aphasia</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">14% (16/115)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Movement disorders <sup>3</sup></b>
|
||
</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">26% (19/72)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurobehavioral/psychiatric manifestations</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">24% (17/70)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Muscular hypotonia</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">29% (40/139)</td></tr><tr><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_1" colspan="2" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Brain MRI abnormalities <sup>4</sup></b>
|
||
</td><td headers="hd_h_grin2a-dis.T.select_features_of_grin2are_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">14% (12/85)</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="grin2a-dis.TF.2.1"><p class="no_margin">
|
||
<a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al [2019]</a>
|
||
</p></div></dd><dt>2. </dt><dd><div id="grin2a-dis.TF.2.2"><p class="no_margin">Moderate speech and language impairment includes dysarthria, speech dyspraxia, dysphasia, speech regression with residual impairments, sometimes with additional impairments such as impaired pitch, hypernasality, or imprecise articulation [<a class="bk_pop" href="#grin2a-dis.REF.turner.2015.586">Turner et al 2015</a>].</p></div></dd><dt>3. </dt><dd><div id="grin2a-dis.TF.2.3"><p class="no_margin">Movement disorders include ataxia, dystonia, chorea, and complex movement disorders.</p></div></dd><dt>4. </dt><dd><div id="grin2a-dis.TF.2.4"><p class="no_margin">Several brain abnormalities have been reported including focal cortical dysplasia, dysplastic corpus callosum, hypoplasia of corpus callosum with midline lipoma, hippocampal hyperintensity, hippocampal sclerosis, heterotopia, subcortical lesion, hypoplastic olfactory bulb, cerebellar glioma, enlarged Virchow-Robin spaces, and delayed myelination; 11% of individuals (9/85) also had generalized cortical atrophy.</p></div></dd></dl></div></div></div><p><b>Developmental delay (DD) and intellectual disability (ID)</b> 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 [<a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al 2019</a>].</p><p><b>Epilepsy</b> occurs in approximately 90% of individuals [<a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al 2019</a>].</p><p>Seizure onset depends on the type of underlying <i>GRIN2A</i> variant [<a class="bk_pop" href="#grin2a-dis.REF.camp.2023.952">Camp et al 2023</a>] (see <a href="#grin2a-dis.GenotypePhenotype_Correlation">Genotype-Phenotype Correlation</a>). The most common seizure type is focal seizures (121/146, 83%), which frequently evolve to bilateral tonic-clonic seizures.</p><p>The predominant seizure type(s) in a given individual depends on the epilepsy syndrome. Broadly, <i>GRIN2A</i>-related disorders fall into the epilepsy-aphasia syndromes group, which includes DEE/EE-SWAS, of which Landau-Kleffner syndrome (LKS) is a subtype [<a class="bk_pop" href="#grin2a-dis.REF.carvill.2013.1073">Carvill et al 2013</a>, <a class="bk_pop" href="#grin2a-dis.REF.lesca.2013.1061">Lesca et al 2013</a>]. Related self-limited focal epilepsies such as SeLECTS and related disorders are also included, as well as unclassified phenotypes [<a class="bk_pop" href="#grin2a-dis.REF.carvill.2013.1073">Carvill et al 2013</a>, <a class="bk_pop" href="#grin2a-dis.REF.lemke.2013.1067">Lemke et al 2013</a>, <a class="bk_pop" href="#grin2a-dis.REF.lesca.2013.1061">Lesca et al 2013</a>].</p><p>Specific epilepsy syndromes associated with <i>GRIN2A</i> pathogenic variants include:</p><ul><li class="half_rhythm"><div>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 [<a class="bk_pop" href="#grin2a-dis.REF.specchio.2022.1398">Specchio et al 2022</a>].</div></li><li class="half_rhythm"><div>In LKS, a subtype of DEE/EE-SWAS, 30% of individuals do not have seizures.</div></li><li class="half_rhythm"><div>Self-limited epilepsy with centrotemporal spikes (SeLECTS) with onset in childhood (usually age 3-6 years) with EEG showing centrotemporal discharges [<a class="bk_pop" href="#grin2a-dis.REF.specchio.2022.1398">Specchio et al 2022</a>].</div></li><li class="half_rhythm"><div>Infantile-onset DEE, with severe-to-profound impairment and sometimes epileptic spasms</div></li></ul><p><b>EEG</b> 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 [<a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al 2019</a>].</p><p><b>Speech and language</b>
|
||
<b>disorders</b> are among the most common features of <i>GRIN2A</i>-related disorders [<a class="bk_pop" href="#grin2a-dis.REF.turner.2015.586">Turner et al 2015</a>, <a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al 2019</a>]. Abnormalities include dysarthria, speech dyspraxia, dysphasia (55/115; 48%), and speech regression with acquired aphasia (16/115; 14%), which is typically seen in LKS.</p><p>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 [<a class="bk_pop" href="#grin2a-dis.REF.turner.2015.586">Turner et al 2015</a>].</p><p><b>Neuroimaging.</b> 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 [<a class="bk_pop" href="#grin2a-dis.REF.reutlinger.2010.1870">Reutlinger et al 2010</a>, <a class="bk_pop" href="#grin2a-dis.REF.pierson.2014.190">Pierson et al 2014</a>, <a class="bk_pop" href="#grin2a-dis.REF.venkateswaran.2014.e75">Venkateswaran et al 2014</a>, <a class="bk_pop" href="#grin2a-dis.REF.yuan.2014.3251">Yuan et al 2014</a>, <a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al 2019</a>].</p><p>
|
||
<b>Other neurodevelopmental features</b>
|
||
</p><ul><li class="half_rhythm"><div>Hypotonia (40/139; 29%)</div></li><li class="half_rhythm"><div>Movement disorders, including dystonia, chorea, and ataxia (19/72; 26%)</div></li></ul><p><b>Neurobehavioral/psychiatric manifestations.</b> Seventeen of 70 individuals (24%) had behavioral or psychiatric disorders, such as ADHD (n=6), ASD (n=6), schizophrenia, or anxiety disorders [<a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al 2019</a>, <a class="bk_pop" href="#grin2a-dis.REF.shepard.2024.2798">Shepard et al 2024</a>].</p><p>Mental health disorders are relatively frequent in individuals with pathogenic <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> variants in <i>GRIN2A</i>. 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].</p><p><b>Facial features.</b> No obvious <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> features; some individuals may have nonspecific features.</p><p><b>Interfamilial and <a class="def" href="/books/n/gene/glossary/def-item/intrafamilial-variability/">intrafamilial variability</a>.</b> Individuals who have the same pathogenic <i>GRIN2A</i> variant show similar severity of DD/ID, both within and across families [<a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al 2019</a>].</p><p><b>Prognosis.</b> It is unknown whether life span in <i>GRIN2A</i>-related disorders is abnormal. The oldest known individual is 80 years old [J Lemke et al, unpublished data]. Since many adults with mild <i>GRIN2A</i> phenotypes have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.</p></div><div id="grin2a-dis.GenotypePhenotype_Correlation"><h3>Genotype-Phenotype Correlations</h3><p>Several <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> have been observed.</p><p>Pathogenic <i>GRIN2A</i> <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants in transmembrane domains (TMD) and linker regions (linker) are associated with severe infantile-onset DEE, whereas missense variants in the amino terminal <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a> (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 <i>GRIN2A</i> 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 <a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a> effect by, for example, disrupted channel inhibition [<a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al 2019</a>].</p><p>Individuals with pathogenic <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> variants have later mean seizure onset (age 4.5 ± 0.2 years) compared to those with pathogenic <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants (age 3.1 ± 0.4 years), and individuals with pathogenic missense variants usually have drug-resistant seizures persisting throughout childhood and adolescence [<a class="bk_pop" href="#grin2a-dis.REF.camp.2023.952">Camp et al 2023</a>].</p><p>Mental health disorders are relatively frequent in individuals with pathogenic <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> variants in <i>GRIN2A</i>, including mood disorders, anxiety disorders, and psychotic disorders such as schizophrenia and, rarely, personality disorders [J Lemke et al, unpublished data].</p></div><div id="grin2a-dis.Penetrance"><h3>Penetrance</h3><p><i>GRIN2A</i>-related disorders show high <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> and <a class="def" href="/books/n/gene/glossary/def-item/variable-expressivity/">variable expressivity</a>.</p><p>In families of mildly affected individuals, carriers of the <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> pathogenic <i>GRIN2A</i> variant have been observed who were less severely or very rarely not known to be affected [<a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al 2019</a>].</p></div><div id="grin2a-dis.Nomenclature"><h3>Nomenclature</h3><div id="grin2a-dis.T.epilepsy_syndrome_terminolo" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Epilepsy Syndrome Terminology Used in <i>GRIN2A</i>-Related Disorders</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385627/table/grin2a-dis.T.epilepsy_syndrome_terminolo/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__grin2a-dis.T.epilepsy_syndrome_terminolo_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_grin2a-dis.T.epilepsy_syndrome_terminolo_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2022 ILAE Classification <sup>1</sup></th><th id="hd_h_grin2a-dis.T.epilepsy_syndrome_terminolo_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Other Terms</th></tr></thead><tbody><tr><td headers="hd_h_grin2a-dis.T.epilepsy_syndrome_terminolo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental and/or epileptic encephalopathy with spike-wave activation in sleep (DEE/EE-SWAS)<br />(Note: Landau-Kleffner syndrome [LKS] is a subtype of DEE-SWAS.)</td><td headers="hd_h_grin2a-dis.T.epilepsy_syndrome_terminolo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Epileptic acquired aphasia</div></li><li class="half_rhythm"><div>Continuous spike-wave during slow-wave sleep (CSWS)</div></li><li class="half_rhythm"><div>Electrical status epilepticus in sleep (ESES)</div></li><li class="half_rhythm"><div>Epilepsy aphasia spectrum disorders</div></li><li class="half_rhythm"><div>Atypical childhood epilepsy with centrotemporal spikes (ACECTS)</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_grin2a-dis.T.epilepsy_syndrome_terminolo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Self-limited epilepsy with centrotemporal spikes (SeLECTS)</td><td headers="hd_h_grin2a-dis.T.epilepsy_syndrome_terminolo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Childhood epilepsy with centrotemporal spikes (CECTS)</div></li><li class="half_rhythm"><div>Benign epilepsy with centrotemporal spikes (BECTS)</div></li><li class="half_rhythm"><div>Benign rolandic epilepsy of childhood (BREC)</div></li><li class="half_rhythm"><div>Benign focal epilepsy of childhood (BFEC)</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ILAE = International League Against Epilepsy</p></div></dd><dt>1. </dt><dd><div id="grin2a-dis.TF.3.1"><p class="no_margin">See <a href="https://www.ilae.org/guidelines/definition-and-classification/classification-and-definition-of-epilepsy-syndromes" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ILAE Classification and Definition of Epilepsy Syndromes</a>.</p></div></dd></dl></div></div></div></div><div id="grin2a-dis.Prevalence"><h3>Prevalence</h3><p>The prevalence of <i>GRIN2A</i>-related disorders in the general population is unknown. Among 3,038 individuals with neurodevelopmental disorders with epilepsy screened by epilepsy <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a> sequencing (including <i>GRIN2A</i>), seven had (likely) pathogenic variants, suggesting <i>GRIN2A</i> accounts for 0.23% of neurodevelopmental disorders [<a class="bk_pop" href="#grin2a-dis.REF.lemke.2020.1046">Lemke 2020</a>].</p></div></div><div id="grin2a-dis.Genetically_Related_Allelic_D"><h2 id="_grin2a-dis_Genetically_Related_Allelic_D_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with <a class="def" href="/books/n/gene/glossary/def-item/germline/">germline</a> pathogenic variants in <i>GRIN2A</i>.</p><p><b>Contiguous <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions.</b>
|
||
<a class="bk_pop" href="#grin2a-dis.REF.reutlinger.2010.1870">Reutlinger et al [2010]</a> described three individuals with 16p13 deletions involving multiple genes and complete or partial <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> of <i>GRIN2A</i>. All had mild <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> features, intellectual disability, and epilepsy involving the rolandic region.</p></div><div id="grin2a-dis.Differential_Diagnosis"><h2 id="_grin2a-dis_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>Genetic epilepsy syndromes.</b>
|
||
<i>GRIN2A</i>-related epilepsy phenotypes cannot be distinguished from other epilepsy-aphasia syndromes (EAS), apart from the ongoing subtle speech abnormalities that persist into adult life in those with <i>GRIN2A</i> pathogenic variants. <i>GRIN2A</i>-related infantile-onset developmental and epileptic encephalopathy (DEE) has no distinguishing features from other genetic causes.</p><p>Note: While <i>GRIN2A</i> pathogenic variants can be associated with EAS, the majority of individuals with EAS do not have an identified genetic cause. A number of copy number variants (CNVs) have been associated with EAS in individual cases.</p><p>While no other monogenic causes are known for self-limited epilepsy with centrotemporal spikes (SeLECTS) and Landau-Kleffner syndrome (LKS), pathogenic variants in the genes <i>SCN2A</i>, <i>NHE6/SLC9A6</i>, <i>DRPLA/ATN1</i>, <i>Neuroserpin/SRPX2</i>, <i>OPA3</i>, <i>KCNQ2</i>, <i>KCNA2</i>, <i>CNKSR2</i>, <i>SLC6A1</i>, and <i>KCNB1</i> have been found in individuals with spike-wave activation in sleep (SWAS) [<a class="bk_pop" href="#grin2a-dis.REF.kessi.2018.40">Kessi et al 2018</a>]. Many genetic causes have been found for DEEs [<a class="bk_pop" href="#grin2a-dis.REF.heyne.2018.1048">Heyne et al 2018</a>].</p><p><b>Genetic language impairment.</b> A severe speech and language disorder that primarily involves childhood apraxia of speech (CAS) is caused by pathogenic variants in <i>FOXP2</i> (see <a href="/books/n/gene/foxp2-sl-dis/"><i>FOXP2</i>-Related Speech and Language Disorder</a>). CAS is a disorder of speech motor programming or planning that affects the production, sequencing, timing, and stress of sounds, and the accurate sequencing of speech sounds into syllables and syllables into words. CAS also interferes nonselectively with multiple other aspects of language, including phonology, grammar, and literacy. For other chromosomal and single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> disorders associated with CAS, see <i>FOXP2</i>-Related Speech and Language Disorder, <a href="/books/n/gene/foxp2-sl-dis/#foxp2-sl-dis.Differential_Diagnosis">Differential Diagnosis</a> [<a class="bk_pop" href="#grin2a-dis.REF.morgan.2024.1281">Morgan et al 2024</a>].</p></div><div id="grin2a-dis.Management"><h2 id="_grin2a-dis_Management_">Management</h2><p>No clinical practice guidelines for <i>GRIN2A</i>-related disorders have been published.</p><div id="grin2a-dis.Evaluations_Following_Initial"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>GRIN2A</i>-related disorders, the evaluations summarized in <a href="/books/NBK385627/table/grin2a-dis.T.grin2arelated_disorders_rec/?report=objectonly" target="object" rid-ob="figobgrin2adisTgrin2arelateddisordersrec">Table 4</a> (if not performed as part of the evaluation that led to diagnosis) are recommended.</p><div id="grin2a-dis.T.grin2arelated_disorders_rec" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p><i>GRIN2A</i>-Related Disorders: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385627/table/grin2a-dis.T.grin2arelated_disorders_rec/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__grin2a-dis.T.grin2arelated_disorders_rec_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Constitutional</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment of overall growth incl weight, height, & head circumference</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Development</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl motor, adaptive, cognitive, & speech-language eval</div></li><li class="half_rhythm"><div>Evaluate for early intervention & need for special education.</div></li><li class="half_rhythm"><div>Assess for developmental regression across all areas.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Epilepsy</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>EEG</div></li><li class="half_rhythm"><div>Careful clinical history to identify seizures</div></li><li class="half_rhythm"><div>In infancy & childhood, sleep-deprived or sleep EEG w/monitoring to capture sleep, as this is essential to identify DEE-SWAS</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Speech & language disorders</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/speech-language pathologist</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for dyspraxia, dysarthria, & language impairment</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Movement disorders /</b>
|
||
<br />
|
||
<b>Musculoskeletal /</b>
|
||
<br />
|
||
<b>Activities of daily living</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT & OT eval</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In severe DEE cases, consider eval for:
|
||
<ul><li class="half_rhythm"><div>Gross motor & fine motor skills;</div></li><li class="half_rhythm"><div>Mobility, ADL, & need for adaptive devices;</div></li><li class="half_rhythm"><div>Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurobehavioral/</b>
|
||
<br />
|
||
<b>Psychiatric</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropsychiatric eval</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Screening for behavior concerns incl sleep disturbances, ADHD, &/or ASD</div></li><li class="half_rhythm"><div>In persons w/<a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> variants, consider eval for psychiatric disorders (e.g., anxiety, mood, psychotic disorders).</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gastrointestinal/</b>
|
||
<br />
|
||
<b>Feeding</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gastroenterology / nutrition / feeding team eval</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Eval of aspiration risk & nutritional status</div></li><li class="half_rhythm"><div>Consider need for gastrostomy tube in persons w/dysphagia &/or aspiration risk.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Genetic counseling</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a <a class="def" href="/books/n/gene/glossary/def-item/pedigree/">pedigree</a> & inform affected persons & their families re nature, MOI, & implications of <i>GRIN2A</i>-related disorders to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family support</b>
|
||
<br />
|
||
<b>& resources</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By clinicians, wider care team, & family support organizations</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment of family & social structure to determine need for:
|
||
<ul><li class="half_rhythm"><div>Community or <a href="#grin2a-dis.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a></div></li><li class="half_rhythm"><div>Social work involvement for parental support</div></li><li class="half_rhythm"><div>Home nursing referral</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; DEE-SWAS = developmental and epileptic encephalopathy with spike-wave activation in sleep; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; OT = occupational therapy; PT = physical therapy</p></div></dd><dt>1. </dt><dd><div id="grin2a-dis.TF.4.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="grin2a-dis.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>There is no cure for <i>GRIN2A</i>-related disorders.</p><div id="grin2a-dis.Targeted_Therapy"><h4>Targeted Therapy</h4><p>
|
||
<i>In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure</i>. —ED</p><div id="grin2a-dis.T.grin2arelated_disorders_tar" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p><i>GRIN2A</i>-Related Disorders: Targeted Therapy</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385627/table/grin2a-dis.T.grin2arelated_disorders_tar/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__grin2a-dis.T.grin2arelated_disorders_tar_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_tar_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment Class</th><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_tar_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mechanism of Action</th><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_tar_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Specific Drug</th><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_tar_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comments</th></tr></thead><tbody><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NMDAR coagonists</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Mediates coagonistic effects on NMDAR in neurons via its enantiomer, D-serine</div></li><li class="half_rhythm"><div>NMDAR coagonists are specifically effective in persons w/<i>GRIN2A</i> pathogenic <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> & <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> variants. <sup>1</sup></div></li></ul>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">L-serine</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tar_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Orally available non-essential amino acid</div></li><li class="half_rhythm"><div>Has been demonstrated to cause improvements in behavior, development, EEG pattern, & sometimes also seizure frequency. After description of 1st treated case in 2019, <sup>2</sup> findings were confirmed in a case series in 2022. <sup>3</sup> The results of the 1st Phase IIa clinical trial have been published. <sup>4</sup></div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">NMDAR = N-methyl-D-aspartate receptor</p></div></dd><dt>1. </dt><dd><div id="grin2a-dis.TF.5.1"><p class="no_margin">In individuals with <i>GRIN2A</i>-related disorders due to pathogenic <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants activating the NMDAR, receptor-specific agonists and other activators (e.g., L-serine) should be avoided, as this could result in worsening of symptoms [<a class="bk_pop" href="#grin2a-dis.REF.krey.2022.334">Krey et al 2022</a>].</p></div></dd><dt>2. </dt><dd><div id="grin2a-dis.TF.5.2"><p class="no_margin">
|
||
<a class="bk_pop" href="#grin2a-dis.REF.soto.2019.eaaw0936">Soto et al [2019]</a>
|
||
</p></div></dd><dt>3. </dt><dd><div id="grin2a-dis.TF.5.3"><p class="no_margin">
|
||
<a class="bk_pop" href="#grin2a-dis.REF.krey.2022.334">Krey et al [2022]</a>
|
||
</p></div></dd><dt>4. </dt><dd><div id="grin2a-dis.TF.5.4"><p class="no_margin">
|
||
<a class="bk_pop" href="#grin2a-dis.REF.juli_palacios.2024.1653">Juliá-Palacios et al [2024]</a>
|
||
</p></div></dd></dl></div></div></div></div><div id="grin2a-dis.Supportive_Care"><h4>Supportive Care</h4><p>Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK385627/table/grin2a-dis.T.grin2arelated_disorders_tar/?report=objectonly" target="object" rid-ob="figobgrin2adisTgrin2arelateddisorderstar">Table 5</a>).</p><div id="grin2a-dis.T.grin2arelated_disorders_tre" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p><i>GRIN2A</i>-Related Disorders: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385627/table/grin2a-dis.T.grin2arelated_disorders_tre/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__grin2a-dis.T.grin2arelated_disorders_tre_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Developmental delay /</b>
|
||
<br />
|
||
<b>Intellectual disability</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#grin2a-dis.Developmental_Delay__Intellec">Developmental Delay / Intellectual Disability Management Issues</a>.</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Epilepsy</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standardized treatment w/ASM by experienced neurologist</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.</div></li><li class="half_rhythm"><div>Education of parents/caregivers <sup>1</sup></div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">L-serine treatment (<i>GRIN2A</i> pathogenic <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> & <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> variants)</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#grin2a-dis.Targeted_Therapy">Targeted Therapy</a>.</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Speech & language deficits</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Therapy by speech-language pathologist</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Therapies, which are individualized to the specific speech disorder, incl linguistic approaches & AAC [<a class="bk_pop" href="#grin2a-dis.REF.morgan.2018.cd006278">Morgan et al 2018</a>].</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neuromuscular / Activities of daily living</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In persons w/severe DEE, consider need for positioning & mobility devices & disability parking certificate.</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurobehavioral/</b>
|
||
<br />
|
||
<b>Psychiatric</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standardized treatment by experienced psychiatrist</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Many medications may be effective; none has been demonstrated effective specifically for this disorder.</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">L-serine treatment (<i>GRIN2A</i> pathogenic <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> & <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> variants)</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#grin2a-dis.Targeted_Therapy">Targeted Therapy</a>.</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Poor weight gain /</b>
|
||
<br />
|
||
<b>Failure to thrive</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Feeding therapy</div></li><li class="half_rhythm"><div>Gastrostomy tube placement may be required for severe, persistent feeding issues.</div></li></ul>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In persons w/DEE, low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family/Community</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ensure appropriate social work involvement to connect families w/local resources, respite, & support.</div></li><li class="half_rhythm"><div>Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.</div></li></ul>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ongoing assessment of need for palliative care &/or home nursing</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AAC = augmentative and alternative communication; ASM = anti-seizure medication; DEE = developmental and/or epileptic encephalopathy; OT = occupational therapy; PT = physical therapy</p></div></dd><dt>1. </dt><dd><div id="grin2a-dis.TF.6.1"><p class="no_margin">Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see <a href="https://www.epilepsy.com/tools-resources/forms-resources#Epilepsy-Foundation-Toolbox" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Epilepsy Foundation Toolbox</a>.</p></div></dd></dl></div></div></div><div id="grin2a-dis.Developmental_Delay__Intellec"><h5>
|
||
<b>Developmental Delay / Intellectual Disability Management Issues</b>
|
||
</h5><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.</p><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.</p><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:</p><ul><li class="half_rhythm"><div>IEP services:</div><ul><li class="half_rhythm"><div>An IEP provides specially designed instruction and related services to children who qualify.</div></li><li class="half_rhythm"><div>IEP services will be reviewed annually to determine whether any changes are needed.</div></li><li class="half_rhythm"><div>Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.</div></li><li class="half_rhythm"><div>PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</div></li><li class="half_rhythm"><div>As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.</div></li></ul></li><li class="half_rhythm"><div>A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.</div></li><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul><p><b>Communication issues.</b> In individuals with DEEs, consider evaluation for alternative means of communication (e.g., <a href="https://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">augmentative and alternative communication</a> [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.</p></div><div id="grin2a-dis.NeurobehavioralPsychiatric_Co"><h5>
|
||
<b>Neurobehavioral/Psychiatric Concerns</b>
|
||
</h5><p>Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.</p><p>Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.</p><p>Consultation with a pediatric psychiatrist may be helpful in evaluation and treatment of psychiatric disorders.</p></div></div></div><div id="grin2a-dis.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK385627/table/grin2a-dis.T.grin2arelated_disorders_rec_1/?report=objectonly" target="object" rid-ob="figobgrin2adisTgrin2arelateddisordersrec1">Table 7</a> are recommended.</p><div id="grin2a-dis.T.grin2arelated_disorders_rec_1" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p><i>GRIN2A</i>-Related Disorders: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385627/table/grin2a-dis.T.grin2arelated_disorders_rec_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__grin2a-dis.T.grin2arelated_disorders_rec_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Development</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress & educational needs.</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_3" rowspan="6" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurologic</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assess for new manifestations such as seizures, changes in tone, movement disorders, & regression</div></li><li class="half_rhythm"><div>Assess for more subtle seizure types that many not have been recognized.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Speech & language disorders</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Routine monitoring of speech & language by speech-language pathologist should be considered, particularly in childhood. Parents should be asked by all clinicians about loss of understanding or regression in spoken language skills.</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Neurobehavioral/</b>
|
||
<br />
|
||
<b>Psychiatric</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for behavioral disorders (particularly ADHD & ASD) & mental health issues (particularly anxiety, mood, & psychotic disorders).</td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal /</b>
|
||
<br />
|
||
<b>Activities of daily living</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical medicine (particularly in childhood), OT/PT assessment of mobility, & self-help skills depending on child’s <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a></td></tr><tr><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Family/Community</b>
|
||
</td><td headers="hd_h_grin2a-dis.T.grin2arelated_disorders_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> if new questions arise (e.g., family planning).</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy</p></div></dd></dl></div></div></div></div><div id="grin2a-dis.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>In individuals with <i>GRIN2A</i>-related disorders due to pathogenic <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> 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 [<a class="bk_pop" href="#grin2a-dis.REF.krey.2022.334">Krey et al 2022</a>].</p><p>In individuals with <i>GRIN2A</i>-related disorders due to pathogenic <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants inhibiting the NMDAR as well as <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> variants, receptor-specific blockers should be used with caution (e.g., memantine, dextromethorphan, ketamine).</p></div><div id="grin2a-dis.Evaluation_of_Relatives_at_Ri"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to clarify the genetic status of apparently asymptomatic relatives of an affected individual by <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> for the <i>GRIN2A</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> 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.</p><p>See <a href="#grin2a-dis.Related_Genetic_Counseling_Is">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="grin2a-dis.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Several treatments are now under investigation in individuals with <i>GRIN2A</i> pathogenic <a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a> (GOF) variants:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>NMDAR blocker (memantine).</b> In one individual with a GOF <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variant in <i>GRIN2A</i>, seizure burden was reduced with the NMDAR blocker memantine. However, cognitive function did not improve [<a class="bk_pop" href="#grin2a-dis.REF.pierson.2014.190">Pierson et al 2014</a>]. 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 <i>GRIN1</i> variants [<a class="bk_pop" href="#grin2a-dis.REF.xu.2021.1480">Xu et al 2021</a>].</div></li><li class="half_rhythm"><div class="half_rhythm"><b>GluN2B negative allosteric modulator (radiprodil).</b> 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 [<a class="bk_pop" href="#grin2a-dis.REF.auvin.2020.343">Auvin et al 2020</a>].</div><div class="half_rhythm">A clinical trial on the evaluation of radiprodil in children with <i>GRIN</i>-related disorders is currently being performed with a focus on children with pathogenic <a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a> <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants (<a href="https://clinicaltrials.gov/study/NCT05818943" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT05818943</a>).</div></li></ul><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="grin2a-dis.Genetic_Counseling"><h2 id="_grin2a-dis_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="grin2a-dis.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>GRIN2A</i>-related disorders are inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p><p>Note: Compound <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>GRIN2A</i> pathogenic <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> variants were reported in a child with a severe developmental and epileptic encephalopathy [<a class="bk_pop" href="#grin2a-dis.REF.strehlow.2022.e132">Strehlow et al 2022</a>]. Her heterozygous parents had milder manifestations largely consistent with a <i>GRIN2A</i>-related disorder.</p></div><div id="grin2a-dis.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>Some individuals diagnosed with a <i>GRIN2A</i>-related disorder have the disorder as the result of a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> inherited from an affected parent. Because considerable clinical variability can be observed among <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> family members, an affected parent may have different manifestations of a <i>GRIN2A</i>-related disorder than the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li><li class="half_rhythm"><div>Approximately 50% of individuals diagnosed with a <i>GRIN2A</i>-related disorder have the disorder as the result of a <i>GRIN2A</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that occurred as a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> event in the affected individual [<a class="bk_pop" href="#grin2a-dis.REF.strehlow.2019.80">Strehlow et al 2019</a>] or, rarely, as a <a class="def" href="/books/n/gene/glossary/def-item/postzygotic/">postzygotic</a> <i>de novo</i> event in a mosaic, apparently unaffected parent [<a class="bk_pop" href="#grin2a-dis.REF.fern_ndezmarmiesse.2018.992">Fernández-Marmiesse et al 2018</a>].</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> appears to be the only affected family member (i.e., a <a class="def" href="/books/n/gene/glossary/def-item/simplex/">simplex</a> case), <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> is recommended for the parents of the proband to evaluate their genetic status and inform <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> assessment.</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</div></li><li class="half_rhythm"><div>The <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> inherited a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> from a parent with gonadal (or somatic and gonadal) <a class="def" href="/books/n/gene/glossary/def-item/mosaicism/">mosaicism</a> [<a class="bk_pop" href="#grin2a-dis.REF.fern_ndezmarmiesse.2018.992">Fernández-Marmiesse et al 2018</a>]. Testing of parental leukocyte DNA may not detect all instances of <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.</div></li></ul></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with a <i>GRIN2A</i>-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 <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> has demonstrated that neither parent is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li></ul><p><b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The risk to the sibs of the proband depends on the genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected and/or is known to have the <i>GRIN2A</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The specific <i>GRIN2A</i>-related <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> may vary considerably among <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> family members, ranging from <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> speech dysfunction to epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) [<a class="bk_pop" href="#grin2a-dis.REF.carvill.2013.1073">Carvill et al 2013</a>, <a class="bk_pop" href="#grin2a-dis.REF.lemke.2013.1067">Lemke et al 2013</a>, <a class="bk_pop" href="#grin2a-dis.REF.lesca.2013.1061">Lesca et al 2013</a>, <a class="bk_pop" href="#grin2a-dis.REF.turner.2015.586">Turner et al 2015</a>].</div></li><li class="half_rhythm"><div>If the <i>GRIN2A</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> cannot be detected in the leukocyte DNA of either parent, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to sibs is slightly greater than that of the general population because of the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/gonadal-mosaicism/">gonadal mosaicism</a> [<a class="bk_pop" href="#grin2a-dis.REF.fern_ndezmarmiesse.2018.992">Fernández-Marmiesse et al 2018</a>].</div></li><li class="half_rhythm"><div>If the parents have not been tested for the <i>GRIN2A</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> but are clinically unaffected, sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> are still presumed to be at increased risk for a <i>GRIN2A</i>-related disorder because of the possibility of variable clinical expressivity / mild or subclinical <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> in a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> parent and the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/gonadal-mosaicism/">gonadal mosaicism</a>.</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Each child of an individual with a <i>GRIN2A</i>-related disorder has a 50% chance of inheriting the <i>GRIN2A</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents: if a parent has the <i>GRIN2A</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the parent's family members may be at risk.</p></div><div id="grin2a-dis.Related_Genetic_Counseling_Is"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#grin2a-dis.Evaluation_of_Relatives_at_Ri">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.</div></li></ul></div><div id="grin2a-dis.Prenatal_Testing_and_Preimpla"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>GRIN2A</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> for <i>GRIN2A</i>-related disorders is possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a>. While most heath care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="grin2a-dis.Resources"><h2 id="_grin2a-dis_Resources_">Resources</h2><p>
|
||
<i>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 <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>Asociación Española De Grinpatías</b>
|
||
</div><div>Spain</div><div><b>Phone:</b> +34 660 339 770</div><div><b>Email:</b> info@grinpatias.org</div><div>
|
||
<a href="https://www.grinpatias.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">grinpatias.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Associazione MGrin2a Italia</b>
|
||
</div><div>Italy</div><div>
|
||
<a href="https://assmgrin2aitalia.it/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">assmgrin2aitalia.it</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>CureGRIN Foundation</b>
|
||
</div><div><b>Phone:</b> 303-881-3425</div><div>
|
||
<a href="https://curegrin.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">curegrin.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Simons Searchlight</b>
|
||
</div><div>
|
||
<a href="https://www.simonssearchlight.org/research/what-we-study/grin2a/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GRIN2A</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>American Epilepsy Society</b>
|
||
</div><div>
|
||
<a href="https://www.aesnet.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">aesnet.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Dyspraxia Foundation</b>
|
||
</div><div>United Kingdom</div><div><b>Phone:</b> 01462 454986; 01462 454986</div><div>
|
||
<a href="https://dyspraxiafoundation.org.uk/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">dyspraxiafoundation.org.uk</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Epilepsy Foundation</b>
|
||
</div><div><b>Phone:</b> 800-332-1000; 866-748-8008</div><div>
|
||
<a href="https://www.epilepsy.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">epilepsy.com</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>National Institute of Neurological Disorders and Stroke (NINDS)</b>
|
||
</div><div><b>Phone:</b> 800-352-9424</div><div>
|
||
<a href="https://www.ninds.nih.gov/Disorders/All-Disorders/Epilepsy-Information-Page" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Epilepsy and Seizures</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>GRIN Registry</b>
|
||
</div><div>
|
||
<a href="https://grin-portal.broadinstitute.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">grin-portal.broadinstitute.org</a>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>GRIN Variant Patient Registry</b>
|
||
</div><div>
|
||
<a href="http://grin2b.com/grin-registry/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">grin2b.com/grin-registry/</a>
|
||
</div></li></ul>
|
||
</div><div id="grin2a-dis.Molecular_Genetics"><h2 id="_grin2a-dis_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div id="grin2a-dis.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>GRIN2A-Related Disorders: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385627/table/grin2a-dis.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__grin2a-dis.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_grin2a-dis.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_grin2a-dis.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_grin2a-dis.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_grin2a-dis.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_grin2a-dis.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_grin2a-dis.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_grin2a-dis.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="/gene/2903" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
|
||
<i>GRIN2A</i>
|
||
</a>
|
||
</td><td headers="hd_b_grin2a-dis.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=2903" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">16p13<wbr style="display:inline-block"></wbr>.2</a>
|
||
</td><td headers="hd_b_grin2a-dis.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.uniprot.org/uniprot/Q12879" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Glutamate receptor ionotropic, NMDA 2A</a>
|
||
</td><td headers="hd_b_grin2a-dis.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://grin-portal.broadinstitute.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GRIN Portal - GRIN2A</a>
|
||
</td><td headers="hd_b_grin2a-dis.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GRIN2A" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GRIN2A</a>
|
||
</td><td headers="hd_b_grin2a-dis.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=GRIN2A[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">GRIN2A</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="grin2a-dis.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
|
||
<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="grin2a-dis.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for GRIN2A-Related Disorders (<a href="/omim/138253,245570" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK385627/table/grin2a-dis.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__grin2a-dis.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/138253" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">138253</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE, SUBUNIT 2A; GRIN2A</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/245570" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">245570</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT IMPAIRED INTELLECTUAL DEVELOPMENT; FESD</td></tr></tbody></table></div></div><div id="grin2a-dis.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>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 <i>GRIN2A</i> [<a class="bk_pop" href="#grin2a-dis.REF.matta.2011.339">Matta et al 2011</a>].</p><p>In vitro tests on <i>Xenopus laevis</i> oocytes and transfected mammalian fibroblasts show that pathogenic variants in <i>GRIN2A</i> can lead to a gain or loss of function of the NMDAR [<a class="bk_pop" href="#grin2a-dis.REF.myers.2023.2857">Myers et al 2023</a>].</p><p><b>Mechanism of disease causation.</b>
|
||
<i>GRIN2A</i>-related disorders can be caused by two functional mechanisms:</p><ul><li class="half_rhythm"><div>Loss of function (usually associated with milder phenotypes, such as speech abnormalities and/or seizures with mild intellectual disability or normal intellect)</div></li><li class="half_rhythm"><div>Gain of function (usually associated with more severe phenotypes, such as severe developmental and epileptic encephalopathies)</div></li></ul></div></div><div id="grin2a-dis.Chapter_Notes"><h2 id="_grin2a-dis_Chapter_Notes_">Chapter Notes</h2><div id="grin2a-dis.Author_Notes"><h3>Author Notes</h3><p>Dr Vincent Strehlow (<a href="mailto:dev@null" data-email="ed.gizpiel-inu.nizidem@wolherts.tnecniv" class="oemail">ed.gizpiel-inu.nizidem@wolherts.tnecniv</a>) and Dr Johannes R Lemke (<a href="mailto:dev@null" data-email="ed.gizpiel-inu.nizidem@ekmel.sennahoj" class="oemail">ed.gizpiel-inu.nizidem@ekmel.sennahoj</a>) are actively involved in clinical research regarding individuals with <i>GRIN2A</i>-related disorders. They would be happy to communicate with persons who have any questions regarding diagnosis of <i>GRIN2A</i>-related disorders or other considerations. They further encourage families and caregivers to enroll affected individuals in the global GRIN registry (<a href="https://grin-portal.broadinstitute.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">grin-portal.broadinstitute.org</a>).</p><p>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.</p><p>Contact Dr Vincent Strehlow and Dr Johannes R Lemke to inquire about review of <i>GRIN2A</i> variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>.</p></div><div id="grin2a-dis.Acknowledgments"><h3>Acknowledgments</h3><p>The authors thank all the families and individuals who have contributed to <i>GRIN2A</i> research studies as well as patient organizations such as CureGRIN for their kind collaboration.</p><p>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.</p></div><div id="grin2a-dis.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>4 July 2024 (gm) Comprehensive update posted live</div></li><li class="half_rhythm"><div>29 September 2016 (bp) Review posted live</div></li><li class="half_rhythm"><div>12 October 2015 (kam) Original submission</div></li></ul></div></div><div id="grin2a-dis.References"><h2 id="_grin2a-dis_References_">References</h2><div id="grin2a-dis.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="grin2a-dis.REF.auvin.2020.343">Auvin
|
||
S, Dozières-Puyravel
|
||
B, Avbersek
|
||
A, Sciberras
|
||
D, Collier
|
||
J, Leclercq
|
||
K, Mares
|
||
P, Kaminski
|
||
RM, Muglia
|
||
P. Radiprodil, a NR2B negative allosteric modulator, from bench to bedside in infantile spasm syndrome.
|
||
Ann Clin Transl Neurol.
|
||
2020;7:343-52.
|
||
[<a href="/pmc/articles/PMC7085998/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7085998</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32106360" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32106360</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="grin2a-dis.REF.camp.2023.952">Camp
|
||
CR, Vlachos
|
||
A, Klöckner
|
||
C, Krey
|
||
I, Banke
|
||
TG, Shariatzadeh
|
||
N, Ruggiero
|
||
SM, Galer
|
||
P, Park
|
||
KL, Caccavano
|
||
A, Kimmel
|
||
S, Yuan
|
||
X, Yuan
|
||
H, Helbig
|
||
I, Benke
|
||
TA, Lemke
|
||
JR, Pelkey
|
||
KA, McBain
|
||
CJ, Traynelis
|
||
SF. Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons.
|
||
Commun Biol.
|
||
2023;6:952.
|
||
[<a href="/pmc/articles/PMC10507040/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10507040</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/37723282" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 37723282</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="grin2a-dis.REF.carvill.2013.1073">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.
|
||
[<a href="/pmc/articles/PMC3868952/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3868952</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23933818" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23933818</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="grin2a-dis.REF.endele.2010.1021">Endele
|
||
S, Rosenberger
|
||
G, Geider
|
||
K, Popp
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E, Moshé
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SL, Tinuper
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P, Auvin
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S. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions.
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Epilepsia.
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2022;63:1398-442.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/35503717" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35503717</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="grin2a-dis.REF.strehlow.2019.80">Strehlow
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V, Heyne
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HO, Vlaskamp
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DRM, Marwick
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KFM, Rudolf
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G, de Bellescize
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J, Biskup
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S, Brilstra
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EH, Brouwer
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OF, Callenbach
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J, Hirsch
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E, Kind
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PC, Mignot
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C, Platzer
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K, Rump
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P, Skehel
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PA, Wyllie
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DJA, Hardingham
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GE, van Ravenswaaij-Arts
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CMA, Lesca
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G, Lemke
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JR; GRIN2A study group. GRIN2A-related disorders: genotype and functional consequence predict phenotype.
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Brain.
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2019;142:80-92.
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[<a href="/pmc/articles/PMC6308310/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6308310</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30544257" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30544257</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="grin2a-dis.REF.strehlow.2022.e132">Strehlow
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V, Rieubland
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C, Gallati
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S, Kim
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S, Myers
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SJ, Peterson
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V, Ramsey
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AJ, Teuscher
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DD, Traynelis
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SF, Lemke
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JR. Compound-heterozygous GRIN2A null variants associated with severe developmental and epileptic encephalopathy.
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Epilepsia.
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2022;63:e132-e137.
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[<a href="/pmc/articles/PMC10681797/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10681797</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35983985" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35983985</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="grin2a-dis.REF.turner.2015.586">Turner
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SJ, Mayes
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AK, Verhoeven
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A, Mandelstam
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SA, Morgan
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AT, Scheffer
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IE. GRIN2A: an aptly named gene for speech dysfunction.
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Neurology.
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2015;84:586-93.
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[<a href="/pmc/articles/PMC4335991/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4335991</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25596506" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25596506</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="grin2a-dis.REF.venkateswaran.2014.e75">Venkateswaran
|
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S, Myers
|
||
KA, Smith
|
||
AC, Beaulieu
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||
CL, Schwartzentruber
|
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JA, Majewski
|
||
J, Bulman
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D, Boycott
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KM, Dyment
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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.
|
||
[<a href="https://pubmed.ncbi.nlm.nih.gov/24903190" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24903190</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="grin2a-dis.REF.xu.2021.1480">Xu
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Y, Song
|
||
R, Chen
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W, Strong
|
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K, Shrey
|
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D, Gedela
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S, Traynelis
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SF, Zhang
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G, Yuan
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H. Recurrent seizure-related GRIN1 variant: molecular mechanism and targeted therapy.
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||
Ann Clin Transl Neurol.
|
||
2021;8:1480-94.
|
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[<a href="/pmc/articles/PMC8283169/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8283169</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/34227748" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34227748</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="grin2a-dis.REF.yuan.2014.3251">Yuan
|
||
H, Hansen
|
||
KB, Zhang
|
||
J, Pierson
|
||
TM, Markello
|
||
TC, Fajardo
|
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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.
|
||
[<a href="/pmc/articles/PMC3934797/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3934797</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24504326" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24504326</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK385627/?report=reader">PubReader</a></li><li><a href="/books/NBK385627/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK385627" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK385627" style="display:none" title="Cite this Page"><div class="bk_tt">Strehlow V, Myers KA, Morgan AT, et al. GRIN2A-Related Disorders. 2016 Sep 29 [Updated 2024 Jul 4]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK385627/pdf/Bookshelf_NBK385627.pdf">PDF version of this page</a> (526K)</li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#grin2a-dis.Summary" ref="log$=inpage&link_id=inpage">Summary</a></li><li><a href="#grin2a-dis.Diagnosis" ref="log$=inpage&link_id=inpage">Diagnosis</a></li><li><a href="#grin2a-dis.Clinical_Characteristics" ref="log$=inpage&link_id=inpage">Clinical Characteristics</a></li><li><a href="#grin2a-dis.Genetically_Related_Allelic_D" ref="log$=inpage&link_id=inpage">Genetically Related (Allelic) Disorders</a></li><li><a href="#grin2a-dis.Differential_Diagnosis" ref="log$=inpage&link_id=inpage">Differential Diagnosis</a></li><li><a href="#grin2a-dis.Management" ref="log$=inpage&link_id=inpage">Management</a></li><li><a href="#grin2a-dis.Genetic_Counseling" ref="log$=inpage&link_id=inpage">Genetic Counseling</a></li><li><a href="#grin2a-dis.Resources" ref="log$=inpage&link_id=inpage">Resources</a></li><li><a href="#grin2a-dis.Molecular_Genetics" ref="log$=inpage&link_id=inpage">Molecular Genetics</a></li><li><a href="#grin2a-dis.Chapter_Notes" ref="log$=inpage&link_id=inpage">Chapter Notes</a></li><li><a href="#grin2a-dis.References" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Bulk Download</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://ftp.ncbi.nlm.nih.gov/pub/litarch/ca/84/" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">Bulk download GeneReviews data from FTP</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>GeneReviews Links</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/n/gene/advanced/"><i>GeneReviews</i> Advanced Search</a></li><li><a href="/books/n/gene/glossary/"><i>GeneReviews</i> Glossary</a></li><li><a href="/books/n/gene/resource_mats/">Resource Materials</a> <span class="bk_hlight1">NEW FEATURE</span></li><li><a href="/books/n/gene/updates/">New in <i>GeneReviews</i></a></li><li><a href="/books/n/gene/authors/">Author List</a></li><li><a href="/books/n/gene/prospective_authors/">For Current/Prospective Authors</a></li><li><a href="/books/n/gene/GRpersonnel/"><i>GeneReviews</i> Personnel</a></li><li><a href="/books/n/gene/howto_linkin/">Download/Link to <i>GeneReviews</i></a></li><li><a href="/books/n/gene/contact_us/">Contact Us</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Key Sections in This GeneReview</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li>
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<a class="text-white" href="//www.nlm.nih.gov/">NLM</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.nih.gov/">NIH</a>
|
||
</li>
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||
<li>
|
||
<a class="text-white" href="https://www.hhs.gov/">HHS</a>
|
||
</li>
|
||
<li>
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||
<a class="text-white" href="https://www.usa.gov/">USA.gov</a>
|
||
</li>
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</ul>
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</nav>
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</div>
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</div>
|
||
</section>
|
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<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentOmnitureBaseJS/InstrumentNCBIConfigJS/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js?v=1"> </script>
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<script type="text/javascript" src="/portal/portal3rc.fcgi/static/js/hfjs2.js"> </script>
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<noscript><img alt="statistics" src="/stat?jsdisabled=true&ncbi_db=books&ncbi_pdid=book-part&ncbi_acc=NBK385627&ncbi_domain=gene&ncbi_report=record&ncbi_type=fulltext&ncbi_objectid=&ncbi_pcid=/NBK385627/&ncbi_pagename=GRIN2A-Related Disorders - GeneReviews® - NCBI Bookshelf&ncbi_bookparttype=chapter&ncbi_app=bookshelf" /></noscript>
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<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3879255/4121861/3501987/4008961/3893018/3821238/4062932/4209313/4212053/4076480/3921943/3400083/3426610.js" snapshot="books"></script></body>
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