Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study

Roope Mannikko, Leonie Wong, David J. Tester, Michael G. Thor, Richa Sud, Dimitri M. Kullmann, Mary G. Sweeney, Costin Leu, Sanjay M. Sisodiya, David R. FitzPatrick, Margaret J. Evans, Iona J. M. Jeffrey, Jacob Tfelt-Hansen, Marta C. Cohen, Peter J. Fleming, Amie Jaye, Michael A. Simpson, Michael J. Ackerman, Michael G. Hanna*, Elijah R. BehrEmma Matthews

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over-represented in infants who died from SIDS.

Methods We did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency

Findings Four (1.4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0.0057).

Interpretation Rare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths. Copyright (C) The Author(s). Published by Elsevier Ltd.

Original languageEnglish
Pages (from-to)1483-1492
Number of pages10
JournalThe Lancet
Volume391
Issue number10129
DOIs
Publication statusPublished - 14 Apr 2018

Keywords

  • TRIPLE-RISK MODEL
  • PERIODIC PARALYSIS
  • NONDYSTROPHIC MYOTONIA
  • CONGENITAL MYOPATHY
  • MYASTHENIC SYNDROME
  • FAST INACTIVATION
  • LARYNGEAL MUSCLE
  • FIBER TYPES
  • SCN4A
  • MUTATIONS

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