{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T23:36:49Z","timestamp":1792885009484,"version":"4.5.0"},"reference-count":57,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T00:00:00Z","timestamp":1655078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009712","name":"Dravet Syndrome Foundation","doi-asserted-by":"crossref","award":["272016"],"award-info":[{"award-number":["272016"]}],"id":[{"id":"10.13039\/100009712","id-type":"DOI","asserted-by":"crossref"}]},{"name":"BMBF","award":["01GM1907"],"award-info":[{"award-number":["01GM1907"]}]},{"name":"NIH"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals.<\/jats:p>\n                  <jats:p>Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants.<\/jats:p>\n                  <jats:p>We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and\/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3\u2005days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2\u2005weeks and 3\u2005months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3\u2005months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4\u201369.3; P = 1.3 \u00d7 10\u22127). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function.<\/jats:p>\n                  <jats:p>Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation.<\/jats:p>\n                  <jats:p>Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.<\/jats:p>","DOI":"10.1093\/brain\/awac210","type":"journal-article","created":{"date-parts":[[2022,6,13]],"date-time":"2022-06-13T13:50:09Z","timestamp":1655128209000},"page":"3816-3831","source":"Crossref","is-referenced-by-count":172,"title":["The gain of function\n                    <i>SCN1A<\/i>\n                    disorder spectrum: novel epilepsy phenotypes and therapeutic implications"],"prefix":"10.1093","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7728-6903","authenticated-orcid":false,"given":"Andreas","family":"Brunklaus","sequence":"first","affiliation":[{"name":"Institute of Health and Wellbeing, University of Glasgow , Glasgow , UK"},{"name":"The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE , Glasgow , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Br\u00fcnger","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics, University of Cologne , Cologne , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Feng","sequence":"additional","affiliation":[{"name":"Institute of Health and Wellbeing, University of Glasgow , Glasgow , UK"},{"name":"The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE , Glasgow , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Fons","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Department, CIBERER-ISCIII, Sant Joan de D\u00e9u Universitary Hospital, Institut de Recerca Sant Joan de D\u00e9u, Member of the ERN EpiCARE , Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anni","family":"Lehikoinen","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Department, Kuopio University Hospital, Member of the ERN EpiCARE , Kuopio , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Panagiotakaki","sequence":"additional","affiliation":[{"name":"Department of Paediatric Clinical Epileptology, sleep disorders and functional neurology, Member of the ERN EpiCARE, University Hospitals of Lyon (HCL) and Inserm U1028\/CNRS UMR5292 , Lyon , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela-Adela","family":"Vintan","sequence":"additional","affiliation":[{"name":"\u2018Iuliu Hatieganu\u2019 University of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology and Pediatric Neurology , Victor Babes, 43, 400012 Cluj-Napoca , Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2141-4216","authenticated-orcid":false,"given":"Joseph","family":"Symonds","sequence":"additional","affiliation":[{"name":"Institute of Health and Wellbeing, University of Glasgow , Glasgow , UK"},{"name":"The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE , Glasgow , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Andrew","sequence":"additional","affiliation":[{"name":"The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE , Glasgow , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Arzimanoglou","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Department, CIBERER-ISCIII, Sant Joan de D\u00e9u Universitary Hospital, Institut de Recerca Sant Joan de D\u00e9u, Member of the ERN EpiCARE , Barcelona , Spain"},{"name":"Department of Paediatric Clinical Epileptology, sleep disorders and functional neurology, Member of the ERN EpiCARE, University Hospitals of Lyon (HCL) and Inserm U1028\/CNRS UMR5292 , Lyon , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Delima","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, IU Health Riley Hospital for Children, Department of Neurology, Division of Pediatric Neurology , Indianapolis, IN , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Gallois","sequence":"additional","affiliation":[{"name":"Louisiana State University Health Sciences Center School of Medicine , New Orleans, LA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donncha","family":"Hanrahan","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, Royal Belfast Hospital for Sick Children , Belfast , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetan","family":"Lesca","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Lyon University Hospital, Member of the ERN EpiCARE , Universit\u00e9 Claude Bernard Lyon 1, Lyon , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stewart","family":"MacLeod","sequence":"additional","affiliation":[{"name":"The Paediatric Neurosciences Research Group, Royal Hospital for Children, Member of the ERN EpiCARE , Glasgow , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragan","family":"Marjanovic","sequence":"additional","affiliation":[{"name":"The Danish Epilepsy Centre, Member of the ERN EpiCARE , Dianalund , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"McTague","sequence":"additional","affiliation":[{"name":"Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health , London , UK"},{"name":"Department of Neurology, Great Ormond Street Hospital for Children, Member of the ERN EpiCARE , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noemi","family":"Nu\u00f1ez-Enamorado","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Department, 12 Octubre Universitary Hospital , Madrid , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Perez-Palma","sequence":"additional","affiliation":[{"name":"Universidad del Desarrollo, Centro de Gen\u00e9tica y Gen\u00f3mica, Facultad de Medicina Cl\u00ednica Alemana , Santiago , Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Scott Perry","sequence":"additional","affiliation":[{"name":"Jane and John Justin Neurosciences Center, Cook Children\u2019s Medical Center , Ft Worth, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Pysden","sequence":"additional","affiliation":[{"name":"Paediatric Neurology Department, Leeds Teaching Hospitals, Leeds General Infirmary , Leeds , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie J","family":"Russ-Hall","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health , Melbourne , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid E","family":"Scheffer","sequence":"additional","affiliation":[{"name":"Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health , Melbourne , Australia"},{"name":"Florey Institute of Neuroscience and Mental Health , Melbourne , Australia"},{"name":"Murdoch Children\u2019s Research Institute and Department of Paediatrics, University of Melbourne, Royal Children\u2019s Hospital , Melbourne , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krystal","family":"Sully","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine , Houston, TX , USA"},{"name":"Texas Children\u2019s Hospital , Houston, TX , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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"}]},{"given":"Ulvi","family":"Vaher","sequence":"additional","affiliation":[{"name":"Children\u2019s Clinic of Tartu University Hospital, Faculty of Medicine of Tartu University, Member of the ERN EpiCARE , Tartu , Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murugan","family":"Velayutham","sequence":"additional","affiliation":[{"name":"Birmingham Children\u2019s Hospital , Birmingham , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Vogt","sequence":"additional","affiliation":[{"name":"West Midlands Regional Genetics Service, Birmingham Women\u2019s and Children\u2019s Hospital , Birmingham , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelly","family":"Weiss","sequence":"additional","affiliation":[{"name":"Division of Neurology, SickKids, University of Toronto , Toronto , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Wirrell","sequence":"additional","affiliation":[{"name":"Divisions of Epilepsy and Child and Adolescent Neurology, Department of Neurology, Mayo Clinic , Rochester, MN , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4489-4697","authenticated-orcid":false,"given":"Sameer M","family":"Zuberi","sequence":"additional","affiliation":[{"name":"Institute of Health and Wellbeing, University of Glasgow , 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Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1070-7929","authenticated-orcid":false,"given":"Massimo","family":"Mantegazza","sequence":"additional","affiliation":[{"name":"Universit\u00e9 C\u00f4te d\u2019Azur , 06560 Valbonne-Sophia Antipolis , France"},{"name":"CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC) , 06560 Valbonne-Sophia Antipolis , France"},{"name":"Inserm , 06560 Valbonne-Sophia Antipolis , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Cest\u00e8le","sequence":"additional","affiliation":[{"name":"Universit\u00e9 C\u00f4te d\u2019Azur , 06560 Valbonne-Sophia Antipolis , France"},{"name":"CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC) , 06560 Valbonne-Sophia Antipolis , France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,6,13]]},"reference":[{"key":"2022112205315719800_awac210-B1","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1152\/physrev.00025.2020","article-title":"Sodium channelopathies of skeletal muscle and brain","volume":"101","author":"Mantegazza","year":"2021","journal-title":"Physiol Rev"},{"key":"2022112205315719800_awac210-B2","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1086\/320609","article-title":"De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy","volume":"68","author":"Claes","year":"2001","journal-title":"Am J Hum Genet"},{"key":"2022112205315719800_awac210-B3","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1093\/brain\/awx054","article-title":"Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related 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