{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T10:59:37Z","timestamp":1771671577604,"version":"3.50.1"},"reference-count":30,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurology International"],"abstract":"<jats:p>Glutamate, the major excitatory neurotransmitter, plays a ubiquitous role in most aspects of normal brain functioning. Its indispensable position is paradoxically doubled by a high excitotoxic potential following disruption of its dynamic equilibrium. Several lines of evidence have suggested the involvement of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) in learning, memory formation, and human cognition. Furthermore, NMDARs play a pivotal role in various neuropsychiatric disorders, recently being identified as an important locus for disease-associated genomic variation. The GRIN2A gene encodes the NMDAR\u2019s GluN2A subunit. Genetic alterations of GRIN2A result in phenotypic pleiotropy, predisposing to a broad range of epilepsy syndromes, with an elusive and unpredictable evolution and response to treatment. The archetypal GRIN2A-related phenotype comprises the idiopathic focal epilepsies (IFEs), with a higher incidence of GRIN2A mutants among entities at the more severe end of the spectrum. We report the case of a patient heterozygous for GRIN2A, c.1081C&gt;T, presenting with febrile convulsions and later superimposed atonic seizures, expressive language delay, and macrocephaly. As the number of reported GRIN2A variants is continuously increasing, the phenotypic boundaries gradually grow faint. Therefore, it is fundamental to maintain an acute critical awareness of the possible genetic etiology of different epilepsy syndromes. So far, therapeutic strategies rely on empirical observations relating genotypes to specific drugs, but the overall success of treatment remains unpredictable. Deciphering the functional consequences of individual GRIN2A variants could lead to the development of precision therapeutic approaches for patients carrying NMDAR mutations.<\/jats:p>","DOI":"10.3390\/neurolint13020018","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T22:29:07Z","timestamp":1619648947000},"page":"184-189","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["GRIN2A Variant in A 3-Year-Old\u2014An Expanding Spectrum?"],"prefix":"10.3390","volume":"13","author":[{"given":"Ioana","family":"Ghe\u021ba","sequence":"first","affiliation":[{"name":"Department of Pediatric Neurology, \u201cDr Victor Gomoiu\u201d Children\u2019s Hospital, 22102 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raluca Ioana","family":"Teleanu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, \u201cDr Victor Gomoiu\u201d Children\u2019s Hospital, 22102 Bucharest, Romania"},{"name":"\u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugenia","family":"Roza","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, \u201cDr Victor Gomoiu\u201d Children\u2019s Hospital, 22102 Bucharest, Romania"},{"name":"\u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"\u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evelina","family":"Carapancea","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, \u201cDr Victor Gomoiu\u201d Children\u2019s Hospital, 22102 Bucharest, Romania"},{"name":"\u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oana","family":"Vladacenco","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, \u201cDr Victor Gomoiu\u201d Children\u2019s Hospital, 22102 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel Mihai","family":"Teleanu","sequence":"additional","affiliation":[{"name":"\u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/S0896-6273(00)80488-2","article-title":"Experience-dependent plasticity and the maturation of glutamatergic synapses","volume":"20","author":"Feldman","year":"1998","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Franchini, L., Carrano, N., Di Luca, M., and Gardoni, F. (2020). Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041538"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1085\/jgp.201812032","article-title":"Structure, function, and allosteric modulation of NMDA receptors","volume":"150","author":"Hansen","year":"2018","journal-title":"J. Gen. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.braindev.2017.09.007","article-title":"GRIN2A mutations in epilepsy-aphasia spectrum disorders","volume":"40","author":"Yang","year":"2018","journal-title":"Brain Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s12264-017-0191-5","article-title":"Mutations of N-Methyl-D-Aspartate Receptor Subunits in Epilepsy","volume":"34","author":"Xu","year":"2017","journal-title":"Neurosci. Bull."},{"key":"ref_7","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Mirzaa, G., and Amemiya, A. (2016). GRIN2A-Related Speech Disorders and Epilepsy. GeneReviews\u00ae, University of Washington, Seattle."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1684\/epd.2019.1056","article-title":"Update on the genetics of the epilepsy-aphasia spectrum and role of GRIN2A mutations","volume":"21","author":"Lesca","year":"2019","journal-title":"Epileptic Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.eplepsyres.2015.05.010","article-title":"Investigation of GRIN2A in common epilepsy phenotypes","volume":"115","author":"Lal","year":"2015","journal-title":"Epilepsy Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3623","DOI":"10.1523\/JNEUROSCI.3639-07.2008","article-title":"NMDA Receptor Subunit NR2A Is Required for Rapidly Acquired Spatial Working Memory But Not Incremental Spatial Reference Memory","volume":"28","author":"Bannerman","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/cr.2015.75","article-title":"Activity-induced synaptic delivery of the GluN2A-containing NMDA receptor is dependent on endoplasmic reticulum chaperone Bip and involved in fear memory","volume":"25","author":"Zhang","year":"2015","journal-title":"Cell Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1093\/brain\/awy304","article-title":"GRIN2A-related disorders: Genotype and functional consequence predict phenotype","volume":"142","author":"Strehlow","year":"2019","journal-title":"Brain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S105","DOI":"10.1016\/S1090-3798(15)30353-6","article-title":"P40\u20132775: Unusual presentation in a child with a mutation in GRIN2A","volume":"19","author":"Hasaerts","year":"2015","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S607","DOI":"10.1016\/j.cca.2019.03.1272","article-title":"Epileptic encephalopathy with phenotype pseudo-Dravet and missense mutation in the GRIN2A gene","volume":"493","author":"Petersen","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1002\/mds.27315","article-title":"A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder","volume":"33","author":"Kusumoto","year":"2018","journal-title":"Mov. Disord."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/acn3.39","article-title":"GRIN2Amutation and early-onset epileptic encephalopathy: Personalized therapy with memantine","volume":"1","author":"Pierson","year":"2014","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.ajhg.2016.10.002","article-title":"Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains","volume":"99","author":"Swanger","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00495","DOI":"10.1002\/prp2.495","article-title":"The human NMDA receptor GluN2AN615K variant influences channel blocker potency","volume":"7","author":"Marwick","year":"2019","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/ng.2727","article-title":"GRIN2A mutations cause epilepsy-aphasia spectrum disorders","volume":"45","author":"Carvill","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gao, K., Tankovic, A., Zhang, Y., Kusumoto, H., Zhang, J., Chen, W., XiangWei, W., Shaulsky, G.H., Hu, C., and Traynelis, S.F. (2017). A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0170818"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/bph.13658","article-title":"Synaptic Zn2+ and febrile seizure susceptibility","volume":"174","author":"Reid","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.pediatrneurol.2009.02.014","article-title":"Epileptic Negative Myoclonus as the Presenting Seizure Type in Rolandic Epilepsy","volume":"41","author":"Watemberg","year":"2009","journal-title":"Pediatr. Neurol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"108104","DOI":"10.1016\/j.celrep.2020.108104","article-title":"An Epilepsy-Associated GRIN2A Rare Variant Disrupts CaMKII\u03b1 Phosphorylation of GluN2A and NMDA Receptor Trafficking","volume":"32","author":"Vieira","year":"2020","journal-title":"Cell Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.eplepsyres.2019.03.001","article-title":"Identifying mutations in epilepsy genes: Impact on treatment selection","volume":"152","author":"Perucca","year":"2019","journal-title":"Epilepsy Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1016\/j.ejpn.2017.01.001","article-title":"Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs","volume":"21","author":"Ensslen","year":"2017","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1093\/brain\/awaa147","article-title":"Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice","volume":"143","author":"Amador","year":"2020","journal-title":"Brain"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1055\/s-0039-3401028","article-title":"GRIN2A-Related Severe Epileptic Encephalopathy Treated with Memantine: An Example of Precision Medicine","volume":"9","author":"Mir","year":"2020","journal-title":"J. Pediatr. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"106325","DOI":"10.1016\/j.eplepsyres.2020.106325","article-title":"Immunotherapy for GRIN2A and GRIN2D-related epileptic encephalopathy","volume":"163","author":"Menascu","year":"2020","journal-title":"Epilepsy Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s00415-010-5674-5","article-title":"Afferent facilitation of corticomotor responses is increased by IgGs of patients with NMDA-receptor antibodies","volume":"258","author":"Manto","year":"2010","journal-title":"J. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S1474-4422(10)70253-2","article-title":"Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis","volume":"10","author":"Dalmau","year":"2011","journal-title":"Lancet Neurol."}],"container-title":["Neurology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2035-8377\/13\/2\/18\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:54:56Z","timestamp":1760162096000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2035-8377\/13\/2\/18"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,29]]},"references-count":30,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["neurolint13020018"],"URL":"https:\/\/doi.org\/10.3390\/neurolint13020018","relation":{},"ISSN":["2035-8377"],"issn-type":[{"value":"2035-8377","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,29]]}}}