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

Abstract

SummaryBackgroundSudden 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.MethodsWe 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 <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system.FindingsFour (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).InterpretationRare 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.FundingUK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, the Epilepsy Society, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

EF hand‐like motif mutations of Nav1.4 C‐terminus cause myotonic syndrome by impairing fast inactivation

“…Patient II‐a demonstrated repeated episodes of rhabdomyolysis that were induced by swimming or traumatic injury, which indicated that her myotonia was very severe. Laryngospasm, a symptom observed in patient II‐b who carried E1702K, could be related to SIDS . On the other hand, a previous clinical report of the E1702K mutation showed milder symptoms than those in our cases .…”

“…Importantly, SCN4A variants have also been found in infant cases of life‐threatening apnea and laryngospasm, or so‐called “severe neonatal episodic laryngospasm (SNEL)” . The severe apnea and laryngospasm can be a contributing factor in sudden infant death syndrome (SIDS), which is the leading cause of postneonatal infant death in high‐income countries …”

Possible role of SCN4A skeletal muscle mutation in apnea during seizure

“…We recently described a similar gain-of-function mutation in sudden infant death, 8 and such mutations are a recognized cause of recurrent life-threatening apneas in infants with myotonia and laryngospasm. 4,5 In children with the latter, there is clear evidence that the muscle phenotype evolves with age; that is, apneas are prominent and symptomatic in early life but diminish with age.…”

Noncardiac genetic predisposition in sudden infant death syndrome

“…In fact, for one of the "other neurological genes", SCN4A, we recently demonstrated a significant (p= 0.0057) overrepresentation of functionally disruptive variants in European SIDS versus ethnic-matched controls. 33 The SCN4A encoded skeletal muscle voltage-gated sodium channel (Nav1.4)…”