{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:52:19Z","timestamp":1791640339028,"version":"4.3.4"},"reference-count":15,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24K02230"],"award-info":[{"award-number":["JP24K02230"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009438","name":"National Center of Neurology and Psychiatry","doi-asserted-by":"publisher","award":["6\u20106"],"award-info":[{"award-number":["6\u20106"]}],"id":[{"id":"10.13039\/501100009438","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009438","name":"National Center of Neurology and Psychiatry","doi-asserted-by":"publisher","award":["6\u2010Waka\u20101"],"award-info":[{"award-number":["6\u2010Waka\u20101"]}],"id":[{"id":"10.13039\/501100009438","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24ek0109617"],"award-info":[{"award-number":["JP24ek0109617"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24ek0109648"],"award-info":[{"award-number":["JP24ek0109648"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24ek0109674"],"award-info":[{"award-number":["JP24ek0109674"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24ek0109677"],"award-info":[{"award-number":["JP24ek0109677"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24ek0109760"],"award-info":[{"award-number":["JP24ek0109760"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      A large number of cases with Dravet syndrome (DS) has been attributed to\n                      <jats:italic>SCN1A<\/jats:italic>\n                      loss of function (LOF), whereas\n                      <jats:italic>SCN1A<\/jats:italic>\n                      gain\u2010of\u2010function (GOF) causes early infantile developmental and epileptic encephalopathy (EIDEE) and familial hemiplegic migraine 3. We retrospectively analyzed 37 individuals with\n                      <jats:italic>SCN1A<\/jats:italic>\n                      pathogenic variants at our institute between January 2012 and October 2024 to investigate phenotype\u2013function correlations. Variant functions were classified as LOF, GOF, or mixed, based on existing patch\u2010clamp data, paralog sodium channel experimental findings, and in silico prediction tools. Clinical characteristics, antiseizure medication (ASM) responses, and variant location were compared. Nine variants were novel. One variant with insufficient data for functional prediction was excluded. Of the 36 cases with predictable functions, five cases (14%) were classified as GOF\/mixed (DS\u2009=\u20094, EIDEE\u2009=\u20091) and 31 (86%) as LOF (DS\u2009=\u200931). GOF\/mixed\u2010DS had earlier epilepsy onset but otherwise resembled LOF\u2010DS. Sodium channel blocking ASMs (SCB\u2010ASMs) did not exacerbate seizures in GOF\/mixed DS cases, with carbamazepine reducing seizures in one case. GOF\/mixed variants clustered in the intracellular S6 segment, whereas LOF variants clustered in the S5\u2013S6 pore loop. These findings highlight a potential GOF effect for certain DS cases, suggesting that SCB\u2010ASMs may be effective for GOF\/mixed DS. This underscores the importance of functional characterization for tailored therapy, warranting further research to confirm and extend these results.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Plain Language Summary<\/jats:title>\n                    <jats:p>\n                      Dravet syndrome is a severe epilepsy that usually begins in infancy and is linked to changes in a gene called\n                      <jats:italic>SCN1A<\/jats:italic>\n                      . Most cases are caused by gene changes that reduce function, but in some cases, the gene may become overactive. In this study, we found that some patients with Dravet syndrome had these overactive changes and still showed typical symptoms. We found that people with overactive SCN1A function might respond differently to certain medications.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi4.70080","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T06:43:54Z","timestamp":1750229034000},"page":"1236-1243","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["<scp>SCN1A<\/scp>\n                    gain of function effects in Dravet syndrome: Insights into clinical phenotypes and therapeutic implications"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6235-4184","authenticated-orcid":false,"given":"Yoko","family":"Kobayashi Takahashi","sequence":"first","affiliation":[{"name":"Department of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenshiro","family":"Tabata","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cellular Biology National Institute of Neuroscience, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0596-3338","authenticated-orcid":false,"given":"Shimpei","family":"Baba","sequence":"additional","affiliation":[{"name":"Department of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eri","family":"Takeshita","sequence":"additional","affiliation":[{"name":"Department of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriko","family":"Sumitomo","sequence":"additional","affiliation":[{"name":"Department of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Shimizu\u2010Motohashi","sequence":"additional","affiliation":[{"name":"Department of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8253-7906","authenticated-orcid":false,"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Ishii","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6796-3790","authenticated-orcid":false,"given":"Shinichi","family":"Hirose","sequence":"additional","affiliation":[{"name":"General Medical Research Center, School of Medicine Fukuoka University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuhiro","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Showa Medical University School of Medicine  Tokyo Japan"},{"name":"Epilepsy Medical Center Showa Medical University Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9846-6500","authenticated-orcid":false,"given":"Naomichi","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Yokohama City University Graduate School of Medicine  Yokohama Japan"},{"name":"Department of Rare Disease Genomics Yokohama City University Hospital  Yokohama Japan"},{"name":"Department of Clinical Genetics Yokohama City University Hospital  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Komaki","sequence":"additional","affiliation":[{"name":"Department of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry  Tokyo 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