Brainstem depolarization–induced lethal apnea associated with gain-of-function SCN1A L263V is prevented by sodium channel blockade
Proceedings of the National Academy of Sciences, vol. 121, pp. e2309000121
Abstract
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 SCN1A L263V 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 Scn1a L263V 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 V 1.1 function effects in transfected HEK293 cells. Sodium channel blockade mitigated the gain-of-function characteristics, rescued lethal apnea in Scn1a L263V mice, and decreased the frequency of severe apneic events in the patient. Hence, this study shows that SCN1A L263V 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.
Authors 9
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands
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Université Côte d'Azur · Institut de Pharmacologie Moléculaire et Cellulaire
Affiliation as printed
Institute of Molecular and Cellular Pharmacology, Valbonne-Sophia Antipolis 06560, France
Université Côte d’Azur, Valbonne-Sophia Antipolis 06560, France
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University Hospitals Bristol NHS Foundation Trust · Bristol Royal Hospital for Children
Affiliation as printed
Department of Paediatric Neurology, Bristol Royal Hospital for Children, University Hospitals Bristol, Bristol BS2 8BJ, United Kingdom
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands
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University Hospitals Bristol NHS Foundation Trust · Bristol Royal Hospital for Children
Affiliation as printed
Department of Paediatric Neurology, Bristol Royal Hospital for Children, University Hospitals Bristol, Bristol BS2 8BJ, United Kingdom
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Else A. Tolner Aachen Department of Human Genetics Department of Neurology, Leiden University Medical Center (LUMC)
Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands
Department of Neurology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands
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Andreas Brunklaus corresponding
Royal Hospital for Children · University of Glasgow
Affiliation as printed
School of Health and Wellbeing, University of Glasgow, Glasgow G12 8TB, United Kingdom
The Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow G51 4TF, United Kingdom
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Massimo Mantegazza corresponding
Inserm · Université Côte d'Azur · Institut de Pharmacologie Moléculaire et Cellulaire
Affiliation as printed
Inserm, Valbonne-Sophia Antipolis 06560, France
Institute of Molecular and Cellular Pharmacology, Valbonne-Sophia Antipolis 06560, France
Université Côte d’Azur, Valbonne-Sophia Antipolis 06560, France
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Arn M. J. M. van den Maagdenberg corresponding Aachen Department of Human Genetics Department of Neurology, Leiden University Medical Center (LUMC)
Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, The Netherlands
Department of Neurology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands
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