SCN1A gain of function effects in Dravet syndrome: Insights into clinical phenotypes and therapeutic implications
Abstract A large number of cases with Dravet syndrome (DS) has been attributed to SCN1A loss of function (LOF), whereas SCN1A gain‐of‐function (GOF) causes early infantile developmental and epileptic encephalopathy (EIDEE) and familial hemiplegic migraine 3. We retrospectively analyzed 37 individual...
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Wiley
2025-08-01
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| Series: | Epilepsia Open |
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| Online Access: | https://doi.org/10.1002/epi4.70080 |
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| author | Yoko Kobayashi Takahashi Kenshiro Tabata Shimpei Baba Eri Takeshita Noriko Sumitomo Yuko Shimizu‐Motohashi Takashi Saito Eiji Nakagawa Atsushi Ishii Shinichi Hirose Mitsuhiro Kato Naomichi Matsumoto Hirofumi Komaki Ken Inoue |
| author_facet | Yoko Kobayashi Takahashi Kenshiro Tabata Shimpei Baba Eri Takeshita Noriko Sumitomo Yuko Shimizu‐Motohashi Takashi Saito Eiji Nakagawa Atsushi Ishii Shinichi Hirose Mitsuhiro Kato Naomichi Matsumoto Hirofumi Komaki Ken Inoue |
| author_sort | Yoko Kobayashi Takahashi |
| collection | DOAJ |
| description | Abstract A large number of cases with Dravet syndrome (DS) has been attributed to SCN1A loss of function (LOF), whereas SCN1A gain‐of‐function (GOF) causes early infantile developmental and epileptic encephalopathy (EIDEE) and familial hemiplegic migraine 3. We retrospectively analyzed 37 individuals with SCN1A pathogenic variants at our institute between January 2012 and October 2024 to investigate phenotype–function correlations. Variant functions were classified as LOF, GOF, or mixed, based on existing patch‐clamp 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 = 4, EIDEE = 1) and 31 (86%) as LOF (DS = 31). GOF/mixed‐DS had earlier epilepsy onset but otherwise resembled LOF‐DS. Sodium channel blocking ASMs (SCB‐ASMs) 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–S6 pore loop. These findings highlight a potential GOF effect for certain DS cases, suggesting that SCB‐ASMs 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. Plain Language Summary Dravet syndrome is a severe epilepsy that usually begins in infancy and is linked to changes in a gene called SCN1A. 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. |
| format | Article |
| id | doaj-art-a4834bd1db144a7da6f5aedb325c0e07 |
| institution | DOAJ |
| issn | 2470-9239 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Epilepsia Open |
| spelling | doaj-art-a4834bd1db144a7da6f5aedb325c0e072025-08-20T03:07:34ZengWileyEpilepsia Open2470-92392025-08-011041236124310.1002/epi4.70080SCN1A gain of function effects in Dravet syndrome: Insights into clinical phenotypes and therapeutic implicationsYoko Kobayashi Takahashi0Kenshiro Tabata1Shimpei Baba2Eri Takeshita3Noriko Sumitomo4Yuko Shimizu‐Motohashi5Takashi Saito6Eiji Nakagawa7Atsushi Ishii8Shinichi Hirose9Mitsuhiro Kato10Naomichi Matsumoto11Hirofumi Komaki12Ken Inoue13Department of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry Tokyo JapanDepartment of Biochemistry and Cellular Biology National Institute of Neuroscience, National Center of Neurology and Psychiatry Tokyo JapanDepartment of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry Tokyo JapanDepartment of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry Tokyo JapanDepartment of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry Tokyo JapanDepartment of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry Tokyo JapanDepartment of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry Tokyo JapanDepartment of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry Tokyo JapanDepartment of Neurology University of Arizona Tucson Arizona USAGeneral Medical Research Center, School of Medicine Fukuoka University Fukuoka JapanDepartment of Pediatrics Showa Medical University School of Medicine Tokyo JapanDepartment of Human Genetics Yokohama City University Graduate School of Medicine Yokohama JapanDepartment of Child Neurology National Center Hospital, National Center of Neurology and Psychiatry Tokyo JapanDepartment of Biochemistry and Cellular Biology National Institute of Neuroscience, National Center of Neurology and Psychiatry Tokyo JapanAbstract A large number of cases with Dravet syndrome (DS) has been attributed to SCN1A loss of function (LOF), whereas SCN1A gain‐of‐function (GOF) causes early infantile developmental and epileptic encephalopathy (EIDEE) and familial hemiplegic migraine 3. We retrospectively analyzed 37 individuals with SCN1A pathogenic variants at our institute between January 2012 and October 2024 to investigate phenotype–function correlations. Variant functions were classified as LOF, GOF, or mixed, based on existing patch‐clamp 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 = 4, EIDEE = 1) and 31 (86%) as LOF (DS = 31). GOF/mixed‐DS had earlier epilepsy onset but otherwise resembled LOF‐DS. Sodium channel blocking ASMs (SCB‐ASMs) 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–S6 pore loop. These findings highlight a potential GOF effect for certain DS cases, suggesting that SCB‐ASMs 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. Plain Language Summary Dravet syndrome is a severe epilepsy that usually begins in infancy and is linked to changes in a gene called SCN1A. 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.https://doi.org/10.1002/epi4.70080Dravet syndromeepilepsyepileptic encephalopathygain of functionSCN1Asodium channel |
| spellingShingle | Yoko Kobayashi Takahashi Kenshiro Tabata Shimpei Baba Eri Takeshita Noriko Sumitomo Yuko Shimizu‐Motohashi Takashi Saito Eiji Nakagawa Atsushi Ishii Shinichi Hirose Mitsuhiro Kato Naomichi Matsumoto Hirofumi Komaki Ken Inoue SCN1A gain of function effects in Dravet syndrome: Insights into clinical phenotypes and therapeutic implications Epilepsia Open Dravet syndrome epilepsy epileptic encephalopathy gain of function SCN1A sodium channel |
| title | SCN1A gain of function effects in Dravet syndrome: Insights into clinical phenotypes and therapeutic implications |
| title_full | SCN1A gain of function effects in Dravet syndrome: Insights into clinical phenotypes and therapeutic implications |
| title_fullStr | SCN1A gain of function effects in Dravet syndrome: Insights into clinical phenotypes and therapeutic implications |
| title_full_unstemmed | SCN1A gain of function effects in Dravet syndrome: Insights into clinical phenotypes and therapeutic implications |
| title_short | SCN1A gain of function effects in Dravet syndrome: Insights into clinical phenotypes and therapeutic implications |
| title_sort | scn1a gain of function effects in dravet syndrome insights into clinical phenotypes and therapeutic implications |
| topic | Dravet syndrome epilepsy epileptic encephalopathy gain of function SCN1A sodium channel |
| url | https://doi.org/10.1002/epi4.70080 |
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