Brainstem depolarization-induced lethal apnea associated with gain- of- function SCN1AL263V is prevented by sodium channel blockade

• 成果类型: Article
• 署名作者: Jansen, Nico A.; Cestele, Sandrine; Marco, Silvia Sanchez; Schenke, Maarten; Stewart, Kirsty; Patel, Jayesh; Tolner, Else A.; Brunklaus, Andreas; Mantegazza, Massimo; van den Maagdenberg, Arn M. J. M.
• 署名单位: Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Universite Cote d'Azur; Universite Cote d'Azur; University of Bristol; Bristol Royal Hospital For Children; Queen Elizabeth University Hospital (QEUH); Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; University of Glasgow; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Cote d'Azur
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9813
• DOI: 10.1073/pnas.2309000121
• 发表日期: 2024-04-04
• 关键词: familial hemiplegic migraine; sudden unexpected death; spreading depression; inferior colliculus; respiratory rhythm; adult-rat; Mutation; mechanisms; seizures; epilepsy

摘要

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 SCN1AL263V 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 Scn1aL263V 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 NaV1.1 function effects in transfected HEK293 cells. Sodium channel blockade mitigated the gain- of- function characteristics, rescued lethal apnea in Scn1aL263V mice, and decreased the frequency of severe apneic events in the patient. Hence, this study shows that SCN1AL263V 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 SCN1A mutations.