Brainstem depolarization-induced lethal apnea associated with gain-of-function SCN1AL263V is prevented by sodium channel blockade.
Proc Natl Acad Sci U S A
; 121(14): e2309000121, 2024 04 02.
Article
em En
| MEDLINE
| ID: mdl-38547067
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 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Apneia
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Bloqueadores dos Canais de Sódio
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Mutação com Ganho de Função
Limite:
Animals
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Female
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Humans
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Infant
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
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Proc. Natl. Acad. Sci. U. S. A
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Proceedings of the national academy of sciences of the United States of America
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Holanda