{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:16:30Z","timestamp":1792790190243,"version":"4.5.0"},"reference-count":28,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000893","name":"Simons Foundation","doi-asserted-by":"publisher","award":["SFARI 732132"],"award-info":[{"award-number":["SFARI 732132"]}],"id":[{"id":"10.13039\/100000893","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      GRIN\u2010related disorders due to pathogenic variants in\n                      <jats:italic>GRIN1<\/jats:italic>\n                      ,\n                      <jats:italic>GRIN2A<\/jats:italic>\n                      ,\n                      <jats:italic>GRIN2B<\/jats:italic>\n                      , or\n                      <jats:italic>GRIN2D<\/jats:italic>\n                      genes are associated with altered N\u2010methyl\u2010D\u2010aspartate receptor (NMDAR) function. Functional changes include gain (GoF) and loss of receptor function (LoF). Clinical reports describing the use of the NMDAR blocker memantine in GRIN\u2010related disorders show a diverse and inconsistent spectrum of treatment responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To evaluate clinical responses to memantine, we collected retrospective data on 34 individuals with GRIN variants, including 20 unpublished and 14 published cases. Variants were reclassified following American College of Medical Genetics and Genomics guidelines, and six in\u00a0vitro functional assays were used to assess receptor function. We compared individuals with pathogenic GoF versus LoF in terms of associated clinical improvements, memantine sensitivity, and variant localization within the gene.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In 19 of the 34 variants, a pathogenic likely or possible GoF of the receptor was detected. Fourteen of 19 individuals (74%) benefited from memantine, comprising improvements in behavior (71%), development (50%), and seizure frequency (39%). Individuals with either LoF or a functionally indeterminate or no effect GRIN variant (15\/34 individuals) showed significantly less benefit from memantine treatment but nevertheless rare adverse events (3\/15). An increased distance of the variant from the memantine binding site was associated with a clinical benefit.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Our retrospective observational study outlines the importance of correct classification of GRIN variants with regard to pathogenicity and functional consequence prior to applying memantine or other precision medicine approaches in clinical trials. Furthermore, the distance from a GoF variant to the memantine binding site correlated with a positive treatment response and may, at least in part, explain different degrees of therapeutic benefit.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70090","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T14:06:02Z","timestamp":1767621962000},"page":"1961-1974","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Memantine treatment in individuals with\n                    <scp>GRIN<\/scp>\n                    gain\u2010of\u2010function variants is associated with improvements in behavior, development, and seizure frequency"],"prefix":"10.1002","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0619-7493","authenticated-orcid":false,"given":"Maike","family":"Karnstedt","sequence":"first","affiliation":[{"name":"Institute of Human Genetics University of Leipzig Medical Center  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8283-7709","authenticated-orcid":false,"given":"Riley E.","family":"Perszyk","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6689-3978","authenticated-orcid":false,"given":"Scott J.","family":"Myers","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology Emory University School of Medicine  Atlanta Georgia USA"},{"name":"Center for Functional Evaluation of Rare Variants Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellington","family":"McDaniels","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology Emory University School of Medicine  Atlanta Georgia USA"},{"name":"Center for Functional Evaluation of Rare Variants Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1171-3965","authenticated-orcid":false,"given":"Marta","family":"Somorai","sequence":"additional","affiliation":[{"name":"Center for Rare Developmental Disorders, Technical University of Munich, kbo Children's Center Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8484-5945","authenticated-orcid":false,"given":"Ingo","family":"Borggraefe","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Developmental Medicine, and Social Pediatrics, Department of Pediatrics University Hospital Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6468-6521","authenticated-orcid":false,"given":"Danielle C. M.","family":"Veenma","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Erasmus MC Sophia Children's Hospital  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7545-518X","authenticated-orcid":false,"given":"An\u2010Sofie","family":"Schoonjans","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology Antwerp University Hospital  Edegem Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9686-6678","authenticated-orcid":false,"given":"Pasquale","family":"Striano","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa  Genoa Italy"},{"name":"IRCCS Istituto Giannina Gaslini  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4218-068X","authenticated-orcid":false,"given":"Tadeu A.","family":"Fantaneanu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Ottawa Hospital, Ottawa Hospital Research Institute University of Ottawa  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2543-4844","authenticated-orcid":false,"given":"Steffen","family":"Syrbe","sequence":"additional","affiliation":[{"name":"Division of Pediatric Epileptology, Center for Pediatrics and Adolescent Medicine University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5527-3047","authenticated-orcid":false,"given":"Kristen","family":"Park","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, Pharmacology, Neurology, and Otolaryngology, School of Medicine and Children's Hospital Colorado University of Colorado  Boulder Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8127-7145","authenticated-orcid":false,"given":"Hongjie","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology Emory University School of Medicine  Atlanta Georgia USA"},{"name":"Center for Functional Evaluation of Rare Variants Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3750-9615","authenticated-orcid":false,"given":"Stephen 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