Skeletal muscle channelopathy: a new risk for sudden infant death syndrome
Authors: Stephen C Cannon
Journal: The Lancet (2018)

Sudden infant death syndrome (SIDS) remains a leading cause of infant mortality, despite a steadily decreasing incidence since the 1990s.1Kinney HC Thach BT The sudden infant death syndrome.N Engl J Med. 2009; 361: 795-805Crossref PubMed Scopus (351) Google Scholar 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.2Willinger M Hoffman HJ Hartford RB Infant sleep position and risk for sudden infant death syndrome: report of meeting held January 13 and 14, 1994, National Institutes of Health, Bethesda, MD.Pediatrics. 1994; 93: 814-819PubMed Google Scholar 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 colleagues3Männikkö R Wong L Tester DJ et al.Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.Lancet. 2018; (published online March 28.)http://dx.doi.org/10.1016/S0140-6736(18)30021-7Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar 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 SIDS4Spinelli J Collins-Praino L Van Den Heuvel C Byard RW Evolution and significance of the triple risk model in sudden infant death syndrome.J Paediatr Child Health. 2017; 53: 112-115Crossref PubMed Scopus (17) Google Scholar 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).5Towbin JA The A, B, Cs of sudden infant death syndrome: an electrical disorder?.Heart Rhythm. 2010; 7: 779-780Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar Männikkö and colleagues3Männikkö R Wong L Tester DJ et al.Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.Lancet. 2018; (published online March 28.)http://dx.doi.org/10.1016/S0140-6736(18)30021-7Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar 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.6Gay S Dupuis D Faivre L et al.Severe neonatal non-dystrophic myotonia secondary to a novel mutation of the voltage-gated sodium channel (SCN4A) gene.Am J Med Genet A. 2008; 146: 380-383Crossref PubMed Scopus (53) Google Scholar, 7Lion-Francois L Mignot C Vicart S et al.Severe neonatal episodic laryngospasm due to de novo SCN4A mutations: a new treatable disorder.Neurology. 2010; 75: 641-645Crossref PubMed Scopus (64) Google Scholar 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.8Horga A Raja Rayan DL Matthews E et al.Prevalence study of genetically defined skeletal muscle channelopathies in England.Neurology. 2013; 80: 1472-1475Crossref PubMed Scopus (85) Google Scholar 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.9Hayward LJ Brown Jr, RH Cannon SC Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker.J Gen Physiol. 1996; 107: 559-576Crossref PubMed Scopus (114) Google Scholar, 10Mitrovic N George Jr, AL Lerche H Wagner S Fahlke C Lehmann-Horn F Different effects on gating of three myotonia-causing mutations in the inactivation gate of the human muscle sodium channel.J Physiol. 1995; 487: 107-114Crossref PubMed Scopus (91) Google Scholar Are variants of SCN4A a plausible risk factor for SIDS? In the study by Männikkö and colleagues,3Männikkö R Wong L Tester DJ et al.Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.Lancet. 2018; (published online March 28.)http://dx.doi.org/10.1016/S0140-6736(18)30021-7Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar 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 (Gly1306Glu9Hayward LJ Brown Jr, RH Cannon SC Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker.J Gen Physiol. 1996; 107: 559-576Crossref PubMed Scopus (114) Google Scholar and Ala799Ser11Simkin D Lena I Landrieu P et al.Mechanisms underlying a life-threatening skeletal muscle Na+ channel disorder.J Physiol. 2011; 589: 3115-3124Crossref PubMed Scopus (14) Google Scholar) 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.7Lion-Francois L Mignot C Vicart S et al.Severe neonatal episodic laryngospasm due to de novo SCN4A mutations: a new treatable disorder.Neurology. 2010; 75: 641-645Crossref PubMed Scopus (64) Google Scholar 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.12Steinmeyer K Ortland C Jentsch TJ Primary structure and functional expression of a developmentally regulated skeletal muscle chloride channel.Nature. 1991; 354: 301-304Crossref PubMed Scopus (363) Google Scholar Reduced chloride conductance of skeletal muscle promotes myotonia,13Adrian RH Bryant SH On the repetitive discharge in myotonic muscle fibres.J Physiol. 1974; 240: 505-515Crossref PubMed Scopus (237) Google Scholar and the risk increases synergistically when combined with a gain-of-function defect in sodium channels.14Skov M Riisager A Fraser JA Nielsen OB Pedersen TH Extracellular magnesium and calcium reduce myotonia in ClC-1 inhibited rat muscle.Neuromuscul Disord. 2013; 23: 489-502Summary Full Text Full Text PDF PubMed Scopus (21) Google Scholar Two other SCN4A variants from the SIDS cohort in Männikkö and colleagues' study had loss-of-function defects (primarily reduced current density). The mechanistic link to a risk for SIDS is less clear because, although SCN4A loss-of-function changes in both alleles cause congenital myasthenia or myopathy with hypotonia, both of which often include breathing difficulties, a single affected allele (even if null) is asymptomatic.15Zaharieva I Thor M Oates E et al.Recessive loss-of-function SCN4A mutations associated with a novel phenotype of congenital myopathy.Brain. 2015; 15: S275-S276Google Scholar Overall, the evidence is compelling that variants of SCN4A with disruption of channel function are over-represented in SIDS. Expression studies in fibroblasts show gain-of-function changes for some cases, and thereby demonstrate a plausible developmentally restricted mechanism for increased risk of SIDS. Other variants might produce functional defects that will be apparent only in skeletal muscle. One clinical implication of this study is that pharmacotherapy with sodium channel blockers during the period of developmental risk could prevent SIDS, as these drugs can do for laryngospasm, stridor, and myotonia. Should we be more vigilant about monitoring for SIDS in infants with non-dystrophic myotonia? And are SIDS cases in this population under-reported? A crucial subject for future research is to determine whether laryngeal and respiratory muscles are especially susceptible to even mild disruption of sodium channel function during the first year of life, thereby causing apnoea and an increased risk for SIDS. I receive consulting fees from, and have been on advisory boards and educate sales teams for, Strongbridge Biopharma, in areas not directly related to sudden infant death syndrome commented on here and I have received grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the US National Institutes of Health and from the Muscular Dystrophy Association. Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control studyRare 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. Full-Text PDF Open Access