{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:30:22Z","timestamp":1788323422865,"version":"build-2803163510"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["NO.82071462"],"award-info":[{"award-number":["NO.82071462"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Pathogenic variants in\n                      <jats:italic>GRIN2B<\/jats:italic>\n                      are predominantly associated with neurodevelopmental disorders (NDDs). However, our understanding of the genotype-phenotype correlations and the optimal treatment strategies is limited.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We collected clinical data of seven new patients from the Xiangya Hospital and conducted an extensive literature review. Subsequently, we carried out comparisons of clinical features between patients with gain-of-function (GOF) variants and patients with loss-of-function (LOF) variants, as well as patients with LOF missense variants and LOF truncating variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified seven patients, five of whom had novel variants (p.Phe554Ser, p.Val821Phe, p.Ile641Thr, p.Asn649Ser, and p.Gly1182Arg), and two of whom had known variants (p.Gly820Val and p.Met818Leu). Of the seven cases, 4 (57.14%) presented with epilepsy. Two of these individuals (carrying the p.Ile641Thr and p.Met818Leu variants, respectively) achieved seizure control after receiving memantine. The clinical manifestations included severe developmental delay \/intellectual disability (DD\/ID) and hypotonia in 100% of cases, as well as microcephaly in 28.57% of cases. Brain imaging results were available for six cases, five of which (83.33%) had abnormal results. Combining our patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20097) and those reported in the literature (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200998), a total of 105 patients were analyzed. These patients carried 84 pathogenic variants, ten of which were recurrent. The two most frequently occurring variants were p.Gly820Ala and p.Gly689Ser. The predominant phenotypes observed were DD\/ID (100%), hypotonia (87.27%), epilepsy (53.08%), and language impairment (45.71%). We further analyzed the clinical genotypes and phenotypes of 55 patients with LOF variants and 16 patients with GOF variants. Variants located in the transmembrane domain predominantly resulted in a GOF effect. GOF variants were more likely to cause epilepsy and microcephaly than LOF variants. Moreover, in comparison to LOF truncated variants, missense variants were associated with more severe clinical phenotypes, including severe DD\/ID, language delay, and movement disorders.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study reports five novel\n                      <jats:italic>GRIN2B<\/jats:italic>\n                      variants and seven additional patients. Notably, it is the first report to distinguish between GOF and LOF\n                      <jats:italic>GRIN2B<\/jats:italic>\n                      variants, which have distinct clinical phenotypes. Furthermore, memantine has been shown to be effective in controlling seizures and improving cognition.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-025-04055-x","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T12:29:39Z","timestamp":1761568179000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["GRIN2B-related neurodevelopmental disorders: genotype-phenotype correlations and therapeutic implications"],"prefix":"10.1186","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9356-2189","authenticated-orcid":false,"given":"Changning","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7932-9292","authenticated-orcid":false,"given":"Miriam","family":"Kessi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7627-0424","authenticated-orcid":false,"given":"Fang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7752-6962","authenticated-orcid":false,"given":"Jing","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"key":"4055_CR1","doi-asserted-by":"crossref","unstructured":"Myers SJ, Yuan H, Kang J-Q, Tan FCK, Traynelis SF, Low C-M. Distinct roles of GRIN2A and GRIN2B variants in neurological conditions. F1000Research. England. 2019;8:F1000 Faculty Rev-1940.","DOI":"10.12688\/f1000research.18949.1"},{"key":"4055_CR2","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1085\/jgp.201812032","volume":"150","author":"KB Hansen","year":"2018","unstructured":"Hansen KB, Yi F, Perszyk RE, Furukawa H, Wollmuth LP, Gibb AJ, et al. Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol United States. 2018;150:1081\u2013105.","journal-title":"J Gen Physiol United States"},{"key":"4055_CR3","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1038\/nrn3504","volume":"14","author":"P Paoletti","year":"2013","unstructured":"Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci Engl. 2013;14:383\u2013400.","journal-title":"Nat Rev Neurosci Engl"},{"key":"4055_CR4","first-page":"S413","volume":"73","author":"M Korinek","year":"2024","unstructured":"Korinek M, Candelas Serra M, Abdel Rahman F, Dobrovolski M, Kuchtiak V, Abramova V, et al. Disease-Associated variants in GRIN1, GRIN2A and GRIN2B genes: insights into NMDA receptor Structure, Function, and pathophysiology. Physiol Res Czech Repub. 2024;73:S413\u201334.","journal-title":"Physiol Res Czech Repub"},{"key":"4055_CR5","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1136\/jmedgenet-2021-107971","volume":"60","author":"S Brock","year":"2023","unstructured":"Brock S, Laquerriere A, Marguet F, Myers SJ, Hongjie Y, Baralle D, et al. Overlapping cortical malformations in patients with pathogenic variants in GRIN1 and GRIN2B. J Med Genet Engl. 2023;60:183\u201392.","journal-title":"J Med Genet Engl"},{"key":"4055_CR6","doi-asserted-by":"publisher","first-page":"3009","DOI":"10.1093\/brain\/awz232","volume":"142","author":"W XiangWei","year":"2019","unstructured":"XiangWei W, Kannan V, Xu Y, Kosobucki GJ, Schulien AJ, Kusumoto H, et al. Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy. Brain Engl. 2019;142:3009\u201327.","journal-title":"Brain Engl"},{"key":"4055_CR7","doi-asserted-by":"publisher","first-page":"106325","DOI":"10.1016\/j.eplepsyres.2020.106325","volume":"163","author":"M Hausman-Kedem","year":"2020","unstructured":"Hausman-Kedem M, Menascu S, Greenstein Y, Fattal-Valevski A. Immunotherapy for GRIN2A and GRIN2D-related epileptic encephalopathy. Epilepsy Res Neth. 2020;163:106325.","journal-title":"Epilepsy Res Neth"},{"key":"4055_CR8","first-page":"947","volume-title":"Rare copy number variations and predictors in children with intellectual disability and epilepsy","author":"M Kessi","year":"2018","unstructured":"Kessi M, Xiong J, Wu L, Yang L, He F, Chen C, et al. Rare copy number variations and predictors in children with intellectual disability and epilepsy. Volume 9. Switzerland: Front Neurol; 2018;9:947."},{"key":"4055_CR9","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s12920-023-01474-2","volume":"16","author":"M Kessi","year":"2023","unstructured":"Kessi M, Chen B, Shan L-D, Wang Y, Yang L, Yin F, et al. Genotype-phenotype correlations of STXBP1 pathogenic variants and the treatment choices for STXBP1-related disorders in China. BMC Med Genomics Engl. 2023;16:46.","journal-title":"BMC Med Genomics Engl"},{"key":"4055_CR10","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1016\/j.pcl.2008.07.010","volume":"55","author":"M Shevell","year":"2008","unstructured":"Shevell M. Global developmental delay and mental retardation or intellectual disability: conceptualization, evaluation, and etiology. Pediatr Clin North Am United States. 2008;55:1071\u201384.","journal-title":"Pediatr Clin North Am United States"},{"key":"4055_CR11","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1136\/jmedgenet-2016-104509","volume":"54","author":"K Platzer","year":"2017","unstructured":"Platzer K, Yuan H, Sch\u00fctz H, Winschel A, Chen W, Hu C, et al. GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet Engl. 2017;54:460\u201370.","journal-title":"J Med Genet Engl"},{"key":"4055_CR12","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1111\/epi.16906","volume":"62","author":"H He","year":"2021","unstructured":"He H, Guzman RE, Cao D, Sierra-Marquez J, Yin F, Fahlke C, et al. The molecular and phenotypic spectrum of CLCN4-related epilepsy. Epilepsia United States. 2021;62:1401\u201315.","journal-title":"Epilepsia United States"},{"key":"4055_CR13","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1111\/cns.12860","volume":"24","author":"J Peng","year":"2018","unstructured":"Peng J, Wang Y, He F, Chen C, Wu L-W, Yang L-F, et al. Novel West syndrome candidate genes in a Chinese cohort. CNS Neurosci Ther Engl. 2018;24:1196\u2013206.","journal-title":"CNS Neurosci Ther Engl"},{"key":"4055_CR14","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17:405\u201324.","journal-title":"Genet Med"},{"key":"4055_CR15","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1093\/brain\/awae041","volume":"147","author":"N Juli\u00e1-Palacios","year":"2024","unstructured":"Juli\u00e1-Palacios N, Olivella M, Sigatullina Bondarenko M, Ib\u00e1\u00f1ez-Mic\u00f3 S, Mu\u00f1oz-Cabello B, Alonso-Luengo O, et al. L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study. Brain Engl. 2024;147:1653\u201366.","journal-title":"Brain Engl"},{"key":"4055_CR16","first-page":"1619","volume":"338","author":"BJ O\u2019Roak","year":"2012","unstructured":"O\u2019Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Sci United States. 2012;338:1619\u201322.","journal-title":"Sci United States"},{"key":"4055_CR17","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1038\/ng.677","volume":"42","author":"S Endele","year":"2010","unstructured":"Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet United States. 2010;42:1021\u20136.","journal-title":"Nat Genet United States"},{"key":"4055_CR18","doi-asserted-by":"publisher","first-page":"e1004772","DOI":"10.1371\/journal.pgen.1004772","volume":"10","author":"FF Hamdan","year":"2014","unstructured":"Hamdan FF, Srour M, Capo-Chichi J-M, Daoud H, Nassif C, Patry L, et al. De Novo mutations in moderate or severe intellectual disability. PLoS Genet United States. 2014;10:e1004772.","journal-title":"PLoS Genet United States"},{"key":"4055_CR19","doi-asserted-by":"publisher","first-page":"e55","DOI":"10.1038\/tp.2011.52","volume":"1","author":"J Tarabeux","year":"2011","unstructured":"Tarabeux J, Kebir O, Gauthier J, Hamdan FF, Xiong L, Piton A, et al. Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia. Transl Psychiatry United States. 2011;1:e55.","journal-title":"Transl Psychiatry United States"},{"key":"4055_CR20","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1016\/j.ajhg.2009.03.010","volume":"84","author":"HV Firth","year":"2009","unstructured":"Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, et al. DECIPHER: database of chromosomal imbalance and phenotype in humans using ensembl resources. Am J Hum Genet United States. 2009;84:524\u201333.","journal-title":"Am J Hum Genet United States"},{"key":"4055_CR21","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.neuroscience.2023.06.018","volume":"526","author":"X Wang","year":"2023","unstructured":"Wang X, Mei D, Gou L, Zhao S, Gao C, Guo J, et al. Functional evaluation of a novel GRIN2B missense variant associated with epilepsy and intellectual disability. Neurosci United States. 2023;526:107\u201320.","journal-title":"Neurosci United States"},{"key":"4055_CR22","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1055\/s-0041-1739130","volume":"53","author":"S Chidambaram","year":"2022","unstructured":"Chidambaram S, Manokaran RK. Favorable response to memantine in a child with GRIN2B epileptic encephalopathy. Neuropediatrics Ger. 2022;53:287\u201390.","journal-title":"Neuropediatrics Ger"},{"key":"4055_CR23","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1002\/humu.22901","volume":"36","author":"D Grozeva","year":"2015","unstructured":"Grozeva D, Carss K, Spasic-Boskovic O, Tejada M-I, Gecz J, Shaw M, et al. Targeted Next-Generation sequencing analysis of 1,000 individuals with intellectual disability. Hum Mutat United States. 2015;36:1197\u2013204.","journal-title":"Hum Mutat United States"},{"key":"4055_CR24","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.ymgme.2014.04.001","volume":"113","author":"DR Adams","year":"2014","unstructured":"Adams DR, Yuan H, Holyoak T, Arajs KH, Hakimi P, Markello TC, et al. Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity. Mol Genet Metab United States. 2014;113:161\u201370.","journal-title":"Mol Genet Metab United States"},{"key":"4055_CR25","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/nature12439","volume":"501","author":"AS Allen","year":"2013","unstructured":"Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE, et al. De Novo mutations in epileptic encephalopathies. Nature. 2013;501:217\u201321.","journal-title":"Nature"},{"key":"4055_CR26","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1002\/epd2.20210","volume":"26","author":"T Kolosky","year":"2024","unstructured":"Kolosky T, Erdemir G. A novel GRIN2B variant (p.F1340V) causes a severe neurodevelopmental disorder with refractory epileptic spasms. Epileptic Disord United States. 2024;26:395\u20137.","journal-title":"Epileptic Disord United States"},{"key":"4055_CR27","first-page":"774","volume":"17","author":"X Zhu","year":"2015","unstructured":"Zhu X, Petrovski S, Xie P, Ruzzo EK, Lu Y-F, McSweeney KM, et al. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med Off J Am Coll Med Genet United States. 2015;17:774\u201381.","journal-title":"Genet Med Off J Am Coll Med Genet United States"},{"key":"4055_CR28","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/ana.24073","volume":"75","author":"JR Lemke","year":"2014","unstructured":"Lemke JR, Hendrickx R, Geider K, Laube B, Schwake M, Harvey RJ, et al. GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. Ann Neurol United States. 2014;75:147\u201354.","journal-title":"Ann Neurol United States"},{"key":"4055_CR29","doi-asserted-by":"publisher","first-page":"5595","DOI":"10.1038\/ncomms6595","volume":"5","author":"BJ O\u2019Roak","year":"2014","unstructured":"O\u2019Roak BJ, Stessman HA, Boyle EA, Witherspoon KT, Martin B, Lee C, et al. Recurrent de Novo mutations implicate novel genes underlying simplex autism risk. Nat Commun Engl. 2014;5:5595.","journal-title":"Nat Commun Engl"},{"key":"4055_CR30","first-page":"696","volume":"18","author":"K Retterer","year":"2016","unstructured":"Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F, et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med Off J Am Coll Med Genet United States. 2016;18:696\u2013704.","journal-title":"Genet Med Off J Am Coll Med Genet United States"},{"key":"4055_CR31","doi-asserted-by":"publisher","first-page":"1921","DOI":"10.1056\/NEJMoa1206524","volume":"367","author":"J de Ligt","year":"2012","unstructured":"de Ligt J, Willemsen MH, van Bon BWM, Kleefstra T, Yntema HG, Kroes T, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med United States. 2012;367:1921\u20139.","journal-title":"N Engl J Med United States"},{"key":"4055_CR32","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1007\/s00439-015-1575-0","volume":"134","author":"T Yavarna","year":"2015","unstructured":"Yavarna T, Al-Dewik N, Al-Mureikhi M, Ali R, Al-Mesaifri F, Mahmoud L, et al. High diagnostic yield of clinical exome sequencing in middle Eastern patients with Mendelian disorders. Hum Genet Ger. 2015;134:967\u201380.","journal-title":"Hum Genet Ger"},{"key":"4055_CR33","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/1744-9081-9-20","volume":"9","author":"I Freunscht","year":"2013","unstructured":"Freunscht I, Popp B, Blank R, Endele S, Moog U, Petri H, et al. Behavioral phenotype in five individuals with de Novo mutations within the GRIN2B gene. Behav Brain Funct Engl. 2013;9:20.","journal-title":"Behav Brain Funct Engl"},{"key":"4055_CR34","doi-asserted-by":"publisher","first-page":"e0141782","DOI":"10.1371\/journal.pone.0141782","volume":"10","author":"Y Zhang","year":"2015","unstructured":"Zhang Y, Kong W, Gao Y, Liu X, Gao K, Xie H, et al. Gene mutation analysis in 253 Chinese children with unexplained epilepsy and Intellectual\/Developmental disabilities. PLoS One United States. 2015;10:e0141782.","journal-title":"PLoS One United States"},{"key":"4055_CR35","doi-asserted-by":"publisher","first-page":"3265","DOI":"10.1002\/ajmg.a.37887","volume":"170","author":"R Smigiel","year":"2016","unstructured":"Smigiel R, Kostrzewa G, Kosinska J, Pollak A, Stawinski P, Szmida E, et al. Further evidence for GRIN2B mutation as the cause of severe epileptic encephalopathy. Am J Med Genet United States. 2016;170:3265\u201370.","journal-title":"Am J Med Genet United States"},{"key":"4055_CR36","doi-asserted-by":"crossref","unstructured":"Kellner S, Abbasi A, Carmi I, Heinrich R, Garin-Shkolnik T, Hershkovitz T et al. Two de Novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy. Elife. England. 2021;10:e67555.","DOI":"10.7554\/eLife.67555"},{"key":"4055_CR37","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1038\/mp.2013.127","volume":"19","author":"EM Kenny","year":"2014","unstructured":"Kenny EM, Cormican P, Furlong S, Heron E, Kenny G, Fahey C, et al. Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders. Mol Psychiatry Engl. 2014;19:872\u20139.","journal-title":"Mol Psychiatry Engl"},{"key":"4055_CR38","doi-asserted-by":"publisher","first-page":"1588","DOI":"10.1007\/s11064-022-03554-8","volume":"47","author":"X Wang","year":"2022","unstructured":"Wang X, Guo Z, Mei D, Zhang Y, Zhao S, Hu S, et al. The GluN2B-Trp373 NMDA receptor variant is associated with Autism-, Epilepsy-Related phenotypes and reduces NMDA receptor currents in rats. Neurochem Res United States. 2022;47:1588\u201397.","journal-title":"Neurochem Res United States"},{"key":"4055_CR39","doi-asserted-by":"publisher","first-page":"104850","DOI":"10.1016\/j.nbd.2020.104850","volume":"140","author":"X Chen","year":"2020","unstructured":"Chen X, Keramidas A, Harvey RJ, Lynch JW. Effects of GluN2A and GluN2B gain-of-function epilepsy mutations on synaptic currents mediated by diheteromeric and triheteromeric NMDA receptors. Neurobiol Dis United States. 2020;140:104850.","journal-title":"Neurobiol Dis United States"},{"key":"4055_CR40","doi-asserted-by":"crossref","unstructured":"Sceniak MP, Fedder KN, Wang Q, Droubi S, Babcock K, Patwardhan S et al. An autism-associated mutation in GluN2B prevents NMDA receptor trafficking and interferes with dendrite growth. J Cell Sci. England. 2019;132: jcs232892.","DOI":"10.1242\/jcs.232892"},{"key":"4055_CR41","doi-asserted-by":"publisher","unstructured":"Soto D, Olivella M, Grau C, Armstrong J, Alcon C, Gasull X et al. L-Serine dietary supplementation is associated with clinical improvement of loss-of-function GRIN2B-related pediatric encephalopathy. Sci Signal. United States. 2019;12: eaaw0936. https:\/\/doi.org\/10.1126\/scisignal.aaw0936","DOI":"10.1126\/scisignal.aaw0936"},{"key":"4055_CR42","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1002\/mds.26737","volume":"31","author":"E Trist\u00e1n-Clavijo","year":"2016","unstructured":"Trist\u00e1n-Clavijo E, Scholl FG, Macaya A, Iglesias G, Rojas AM, Lucas M, et al. Dominant-negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia. Mov Disord United States. 2016;31:1743\u20138.","journal-title":"Mov Disord United States"},{"key":"4055_CR43","doi-asserted-by":"publisher","first-page":"1975","DOI":"10.1212\/WNL.0000000000003309","volume":"87","author":"MA Corbett","year":"2016","unstructured":"Corbett MA, Bellows ST, Li M, Carroll R, Micallef S, Carvill GL, et al. Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy. Neurology. 2016;87:1975\u201384.","journal-title":"Neurology"},{"key":"4055_CR44","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1002\/ana.24080","volume":"75","author":"G Orhan","year":"2014","unstructured":"Orhan G, Bock M, Schepers D, Ilina EI, Reichel SN, Loffler H, et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol United States. 2014;75:382\u201394.","journal-title":"Ann Neurol United States"},{"key":"4055_CR45","first-page":"7111","volume":"24","author":"A Bergareche","year":"2015","unstructured":"Bergareche A, Bednarz M, S\u00e1nchez E, Krebs CE, Ruiz-Martinez J, De La Riva P, et al. SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and May increase susceptibility to epilepsy. Hum Mol Genet Engl. 2015;24:7111\u201320.","journal-title":"Hum Mol Genet Engl"},{"key":"4055_CR46","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1016\/j.neuropharm.2017.05.017","volume":"123","author":"B Mullier","year":"2017","unstructured":"Mullier B, Wolff C, Sands ZA, Ghisdal P, Muglia P, Kaminski RM, et al. GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors. Neuropharmacol Engl. 2017;123:322\u201331.","journal-title":"Neuropharmacol Engl"},{"key":"4055_CR47","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1093\/brain\/awy304","volume":"142","author":"V Strehlow","year":"2019","unstructured":"Strehlow V, Heyne HO, Vlaskamp DRM, Marwick KFM, Rudolf G, de Bellescize J, et al. GRIN2A-related disorders: genotype and functional consequence predict phenotype. Brain Engl. 2019;142:80\u201392.","journal-title":"Brain Engl"},{"key":"4055_CR48","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.brainres.2015.03.031","volume":"1610","author":"H Jiang","year":"2015","unstructured":"Jiang H, Jiang W, Zou J, Wang B, Yu M, Pan Y, et al. The GluN2B subunit of N-methy-D-asparate receptor regulates the radial migration of cortical neurons in vivo. Brain Res Neth. 2015;1610:20\u201332.","journal-title":"Brain Res Neth"},{"key":"4055_CR49","first-page":"507","volume":"45","author":"PP Hollenshead","year":"2024","unstructured":"Hollenshead PP, Jackson CN, Cross JV, Witten TE, Anwar AI, Ahmadzadeh S, et al. Treatment modalities for infantile spasms: current considerations and evolving strategies in clinical practice. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol Italy. 2024;45:507\u201314.","journal-title":"Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol Italy"},{"key":"4055_CR50","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1111\/dmcn.15109","volume":"64","author":"S Demarest","year":"2022","unstructured":"Demarest S, Calhoun J, Eschbach K, Yu H-C, Mirsky D, Angione K, et al. Whole-exome sequencing and adrenocorticotropic hormone therapy in individuals with infantile spasms. Dev Med Child Neurol Engl. 2022;64:633\u201340.","journal-title":"Dev Med Child Neurol Engl"},{"key":"4055_CR51","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1038\/s41586-018-0039-9","volume":"556","author":"X Song","year":"2018","unstructured":"Song X, Jensen M\u00d8, Jogini V, Stein RA, Lee C-H, Mchaourab HS, et al. Mechanism of NMDA receptor channel block by MK-801 and memantine. Nat Engl. 2018;556:515\u20139.","journal-title":"Nat Engl"},{"key":"4055_CR52","doi-asserted-by":"publisher","first-page":"773455","DOI":"10.3389\/fphar.2021.773455","volume":"12","author":"JR Gale","year":"2021","unstructured":"Gale JR, Kosobucki GJ, Hartnett-Scott KA, Aizenman E. Imprecision in precision medicine: differential response of a Disease-Linked GluN2A mutant to NMDA channel blockers. Front Pharmacol Switz. 2021;12:773455.","journal-title":"Front Pharmacol Switz"},{"key":"4055_CR53","doi-asserted-by":"publisher","first-page":"e00495","DOI":"10.1002\/prp2.495","volume":"7","author":"KFM Marwick","year":"2019","unstructured":"Marwick KFM, Skehel PA, Hardingham GE, Wyllie DJA. The human NMDA receptor GluN2A(N615K) variant influences channel blocker potency. Pharmacol Res Perspect United States. 2019;7:e00495.","journal-title":"Pharmacol Res Perspect United States"},{"key":"4055_CR54","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1002\/acn3.39","volume":"1","author":"TM Pierson","year":"2014","unstructured":"Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T, et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol United States. 2014;1:190\u20138.","journal-title":"Ann Clin Transl Neurol United States"},{"key":"4055_CR55","doi-asserted-by":"publisher","first-page":"108247","DOI":"10.1016\/j.neuropharm.2020.108247","volume":"177","author":"W Tang","year":"2020","unstructured":"Tang W, Liu D, Traynelis SF, Yuan H. Positive allosteric modulators that target NMDA receptors rectify loss-of-function GRIN variants associated with neurological and neuropsychiatric disorders. Neuropharmacol Engl. 2020;177:108247.","journal-title":"Neuropharmacol Engl"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-025-04055-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-025-04055-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-025-04055-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:02:46Z","timestamp":1761609766000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-025-04055-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,27]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["4055"],"URL":"https:\/\/doi.org\/10.1186\/s13023-025-04055-x","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,27]]},"assertion":[{"value":"23 February 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"541"}}