{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:33:59Z","timestamp":1789450439392,"version":"build-2803163510"},"reference-count":61,"publisher":"National Academy of Sciences","issue":"14","license":[{"start":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T00:00:00Z","timestamp":1711584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006117","name":"Epilepsiefonds","doi-asserted-by":"publisher","award":["2017-10"],"award-info":[{"award-number":["2017-10"]}],"id":[{"id":"10.13039\/501100006117","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008062","name":"Fundaci\u00f3n Alicia Koplowitz","doi-asserted-by":"publisher","award":["."],"award-info":[{"award-number":["."]}],"id":[{"id":"10.13039\/100008062","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Investissements d&apos;Avenir-Laboratory of Excellence","award":["LabEx ICST ANR-11-LABX-0015-01"],"award-info":[{"award-number":["LabEx ICST ANR-11-LABX-0015-01"]}]},{"name":"University C&amp;#x00F4;te d&apos;Azur-IDEX Jedi","award":["ANR-15-IDEX-01"],"award-info":[{"award-number":["ANR-15-IDEX-01"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,4,2]]},"abstract":"<jats:p>\n                    Apneic events are frightening but largely benign events that often occur in infants. Here, we report apparent life-threatening apneic events in an infant with the homozygous\n                    <jats:italic>SCN1A<\/jats:italic>\n                    <jats:sup>L263V<\/jats:sup>\n                    missense mutation, which causes familial hemiplegic migraine type 3 in heterozygous family members, in the absence of epilepsy. Observations consistent with the events in the infant were made in an\n                    <jats:italic>Scn1a<\/jats:italic>\n                    <jats:sup>L263V<\/jats:sup>\n                    knock-in mouse model, in which apnea was preceded by a large brainstem DC-shift, indicative of profound brainstem depolarization. The L263V mutation caused gain of Na\n                    <jats:sub>V<\/jats:sub>\n                    1.1 function effects in transfected HEK293 cells. Sodium channel blockade mitigated the gain-of-function characteristics, rescued lethal apnea in\n                    <jats:italic>Scn1a<\/jats:italic>\n                    <jats:sup>L263V<\/jats:sup>\n                    mice, and decreased the frequency of severe apneic events in the patient. Hence, this study shows that\n                    <jats:italic>SCN1A<\/jats:italic>\n                    <jats:sup>L263V<\/jats:sup>\n                    can cause life-threatening apneic events, which in a mouse model were caused by profound brainstem depolarization. In addition to being potentially relevant to sudden infant death syndrome pathophysiology, these data indicate that sodium channel blockers may be considered therapeutic for apneic events in patients with these and other gain-of-function\n                    <jats:italic>SCN1A<\/jats:italic>\n                    mutations.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2309000121","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T13:19:43Z","timestamp":1711631983000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":8,"title":["Brainstem depolarization\u2013induced lethal apnea associated with gain-of-function\n                    <i>SCN1A<\/i>\n                    <sup>L263V<\/sup>\n                    is prevented by sodium channel blockade"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9905-054X","authenticated-orcid":false,"given":"Nico A.","family":"Jansen","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5982-1562","authenticated-orcid":false,"given":"Sandrine","family":"Cest\u00e8le","sequence":"additional","affiliation":[{"name":"Universit\u00e9 C\u00f4te d\u2019Azur, Valbonne-Sophia Antipolis 06560, France"},{"name":"Institute of Molecular and Cellular Pharmacology, Valbonne-Sophia Antipolis 06560, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia Sanchez","family":"Marco","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, Bristol Royal Hospital for Children, University Hospitals Bristol, Bristol BS2 8BJ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten","family":"Schenke","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty","family":"Stewart","sequence":"additional","affiliation":[{"name":"West of Scotland Genetic Services, Queen Elizabeth University Hospital, Glasgow G51 4TF, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayesh","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology, Bristol Royal Hospital for Children, University Hospitals Bristol, Bristol BS2 8BJ, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6501-9971","authenticated-orcid":false,"given":"Else A.","family":"Tolner","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands"},{"name":"Department of Neurology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Brunklaus","sequence":"additional","affiliation":[{"name":"The Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow G51 4TF, United Kingdom"},{"name":"School of Health and Wellbeing, University of Glasgow, Glasgow G12 8TB, United Kingdom"}],"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, Valbonne-Sophia Antipolis 06560, France"},{"name":"Institute of Molecular and Cellular Pharmacology, Valbonne-Sophia Antipolis 06560, France"},{"name":"Inserm, Valbonne-Sophia Antipolis 06560, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arn M. J. M.","family":"van den Maagdenberg","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands"},{"name":"Department of Neurology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,3,28]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"125","article-title":"Breath-holding spells in childhood","volume":"146","author":"DiMario F. J.","year":"1992","unstructured":"F. J. DiMario Jr., Breath-holding spells in childhood. Am. J. Dis. Child. 146, 125\u2013131 (1992).","journal-title":"Am. J. Dis. Child."},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/15.4.287"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c130052"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2021.12.004"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14055"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.155"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24596"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2017.129"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0711717105"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1309827110"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI142202"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.6089.732"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2044.2007.05144.x"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2017.11.025"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(14)70220-0"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1683005"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-018-0003-6"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.50971"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1713-19.2019"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600594"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/11.3.249"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-01851-9"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.116.103358"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.112.198887"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1973.tb03976.x"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12657"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1186\/s10194-019-1056-2"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-2982.2008.01721.x"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1177\/0333102414527015"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0803836"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7401163"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaa4050"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy325"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1958.21.5.430"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4886(84)90087-6"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s002130050900"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac210"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000166023.51307.e0"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI142203"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1009239"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-20-07662.1997"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2009.181826"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.440060207"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00388.2003"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2001.81.3.1065"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2023.109513"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2012.40"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.14-11-07087.1994"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.18-09-03416.1998"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.04.004"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5270-06.2007"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/0169-328X(93)90087-6"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1309"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2018.00232"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.413"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhu336"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2016.02.007"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1259\/bjr.72.859.10624317"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12123"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4453-07.2008"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506818102"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2309000121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T13:21:19Z","timestamp":1711632079000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2309000121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,28]]},"references-count":61,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2024,4,2]]}},"alternative-id":["10.1073\/pnas.2309000121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2309000121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,28]]},"assertion":[{"value":"2023-06-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2309000121"}}