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

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 <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system. 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. FUNDING: UK 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.

The critical role of perinatal pathology.

In spite of great advances in imaging and biochemistry, histological examination of tissues remains a vital part of the multidisciplinary approach to the prevention of the onset, morbidity and mortality of preterm birth. There has been increasing interest in the role of infection and inflammatory cytokines in causation both of early labour and the white matter damage in the brain of preterm infants. However, labour itself is associated with the build up of increased numbers of inflammatory cells in the uterine cervix and increased concentrations of inflammatory cytokines and positive microbiological cultures may reflect carriage or contamination. Confirmation of an infective aetiology in an individual case is best achieved by demonstration of a pathological inflammatory response in tissues, for example, by showing the presence of chorioamnionitis in the placenta. A proper understanding of the poor response to neonatal intensive care of some preterm babies often requires histological examination of the lungs after death, where unsuspected pneumonia, interstitial emphysema and/or pulmonary hypoplasia may help provide an explanation for the adverse outcome in individual cases. The pathophysiological mechanism of brain injury in preterm infants is undergoing re-evaluation, and the systemic study of brain tissue using the latest histological techniques may elucidate the importance of apoptosis in this situation and could point the way towards an effective preventative strategy. Paediatric pathology is also essential to explain many cases of sudden unexpected death in preterm infants, as demonstrated by the recent realisation that death may be caused by total parenteral nutrition fluid-associated myocardial necrosis, and acute cardiac tamponade.