SKELETAL MUSCLE CHANNELOPATHIES AND SUDDEN INFANT DEATH SYNDROME

Background Skeletal muscle channelopathies are rare genetic disorders causing periodic paralysis and myotonia. They are generally considered debilitating but not life-threatening. However cases of life-threatening respiratory muscle crises have recently been reported in infants requiring ITU support. We hypothesised muscle channelopathy gene variants may contribute to the risk of sudden infant death. Methods We analysed the SCN4A gene for rare variants in 278 cases of sudden infant death (SIDS) and 729 ethnically matched controls. Biophysical characterisation was performed using a heterologous expression system. Results Four of the 278 SIDS cases (1.4%) had an ultra-rare, functionally disruptive SCN4A variant compared to 0/729 ethnically matched controls (p=0.0057). The degree of channel perturbation associated with these four variants was qualitatively similar to the SCN4A variants previously implicated in infants with life-threatening apnoeic events. Conclusions Rare SCN4A variants that directly alter channel function occur in sudden infant death cases. These variants are predicted to significantly alter muscle membrane excitability compromising respiratory and laryngeal function. Data on pregnancy/post-natal complications is now being collected from parents with genetically confirmed sodium channelopathies via clinic and on-line registry. Laryngospasm has recently been implicated in SUDEP - analysis of SCN4A variants in SUDEP cases is also underway.