Skeletal muscle channelopathy: a new risk for sudden infant death syndrome

www.thelancet.com Published online March 28, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30477-X 1 Sudden infant death syndrome (SIDS) remains a leading cause of infant mortality, despite a steadily decreasing incidence since the 1990s. The reasons for this decline are debated, but it could be due to methodological reasons (eg, changes in reporting or advances in diagnosis of specific diseases) or a reduction of risks, such as an increase in supine sleeping position for infants, as advocated by the Back to Sleep campaign. A better understanding of the causes of SIDS is needed to identify infants at high risk and to develop interventions and guidelines that will prevent SIDS for all infants. In The Lancet, Roope Männikkö and colleagues identify a new risk factor for SIDS: a skeletal muscle genetic channelopathy that could compromise respiratory and laryngeal function. Most experts agree that respiratory failure during sleep is the major contributor to infant mortality in SIDS. The so-called triple risk model for SIDS has been refined since the original proposal in 1972, and defines three overlapping contributors to SIDS: a vulnerable infant; being in a critical period of development; and an environmental stressor. One such vulnerability is genetic variation. Most notably, about 10% of infants who die of SIDS have ion channel-related arrhythmias, half of which are caused by mutations in the cardiac sodium channel gene (SCN5A) or one of its subunits (SCN1B–4B). Männikkö and colleagues report rare variants of the skeletal muscle specific sodium channel gene (SCN4A), identified in combined SIDS registries from the UK and the USA. Mutations of SCN4A can cause non-dystrophic myotonia and can, in rare instances, present at infancy with laryngospasm, severe stridor, and respiratory compromise requiring intubation or tracheostomy. Based on this observation, the authors postulated that SCN4A variants capable of disrupting muscle excitability might be over-represented in SIDS. In their whole exome sequencing study, which focused on the muscle sodium channel gene, four (1·4%) of the 278 infants who died of SIDS had ultra-rare, functionally disruptive SCN4A variants, compared with 0 of 729 ethnically matched controls (p=0·0057). This frequency of SCN4A variants is remarkably high because the prevalence of genetically defined skeletal muscle channelopathy in patients with SCN4A mutations in the UK is 0·4 per 100 000 people. Moreover, the gain-of-function changes in the SIDS variants were qualitatively similar to the channel defects previously implicated in life-threatening apnoeic events in infants. Are variants of SCN4A a plausible risk factor for SIDS? In the study by Männikkö and colleagues, four of the six SIDS variants disrupted sodium channel function, as demonstrated by voltage-clamp studies of mutant channels expressed in fibroblasts. Two variants caused gain-of-function changes (by disrupting sodium channel inactivation), including Arg1463Ser, which the authors had previously detected in an adult with myotonia. While gain-of-function defects of mutant sodium channels are a well established cause of myotonia, the severity of the functional changes for the SIDS-associated variants in this study was modest (eg, for Arg1643Ser) or very mild (for Ser682Trp). By contrast, the SCN4A mutations associated with severe neonatal laryngospasm cause a greater disruption of inactivation (Gly1306Glu and Ala799Ser) and are clinically associated with early-onset myotonic stiffness (in the limbs and trunk, and difficulty swallowing), muscle hypertrophy, and florid myotonic discharges by needle electromyogram. Männikkö and colleagues propose a plausible explanation for this discrepancy based on the triple risk model. The increased risk for SIDS arises from the combination of a modest gain-of-function change for variant SCN4A (vulnerable infant) plus the change after birth from the embryonic predominance of SCN5A mRNA to SCN4A expression in skeletal muscle (developmental susceptibility). They also propose that respiratory muscle fibre type switching from mainly fast (in neonates) to slow (infants >2 years of age) presents another developmental risk because fast twitch fibres have a greater reliance on high sodium current density to maintain excitability. Another developmental effect, not mentioned in the Article, would be expected from the low expression level of the skeletal muscle chloride channel at birth. Reduced chloride conductance of skeletal muscle promotes myotonia, and the risk increases synergistically when combined with a gain-of-function defect in sodium channels. Two other SCN4A variants from the SIDS cohort in Männikkö and Skeletal muscle channelopathy: a new risk for sudden infant death syndrome