Thursday, March 29, 2018

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

Roope Männikkö, Leonie Wong, David J Tester, Michael G Thor, Richa Sud, Dimitri M Kullmann, Mary G Sweeney, Costin Leu, Sanjay M Sisodiya, David R FitzPatrick,  Margaret J Evans, Iona J M Jeffrey, , Jacob Tfelt-Hansen, Marta C Cohen, Peter J Fleming, Amie Jaye, Michael A Simpson, Michael J Ackerman, Michael G Hanna, Elijah R Behr, Emma Matthews.  Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study. Lancet.  Online first.


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.

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.

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).

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.

From the manuscript

Research in context

Evidence before this study

Sudden infant death syndrome (SIDS) is the sudden and unexpected death of an apparently healthy infant. It is the leading cause of post-neonatal infant death in high-income countries. Placing infants to sleep in a prone position is associated with a higher risk of sudden death but unidentified risk factors remain. We searched PubMed for papers published in English up to March 1, 2017, reviewing the cause or risk of SIDS using the terms “sudden infant death”, “SIDS”, “sudden unexpected death in infancy”, and “risk factors”. Multiple risk factors have been proposed on the basis of epidemiological, pathological, and genetic studies that include the notion of a vulnerable infantile period due to immature homoeostatic and autonomic regulatory pathways or genetic variation—eg, cardiac channel gene variants. Respiratory failure is ultimately believed to contribute to death.

Added value of this study

To our knowledge, this study is the first to consider direct failure of the respiratory muscles due to dysfunction of the skeletal muscle ion channel NaV1.4 in the pathogenesis of SIDS. We compared rare variants in the SCN4A gene, which codes for the NaV1.4 channel, among infants who had died of SIDS with variants from ethnically matched controls. We also studied the functional consequences of rare variants in both cases and controls using a heterologous cell system. Only infants who had died from SIDS carried variants that significantly disrupted channel function.

Implications of all the available evidence

Our data are compatible with the clinical features of SIDS and provides new mechanistic clues to death. Developmental regulation of the sodium channel and respiratory muscle fibre types might affect the risk of SIDS. Future research is required to define this relationship, and our findings should be retested in similar and other ethnic groups. Sodium channel dysfunction found in muscle channelopathies can be treated. Studies should assess whether such treatments could ameliorate the risk of sudden death for infants carrying SCN4A gene variants…

Two developmental factors might combine with the functional effects of the SCN4A variants we identified to render respiratory muscles more susceptible to contractile failure—eg, in response to hypoxia. First, developmental alterations in skeletal muscle sodium channel expression: during embryogenesis two different sodium channel isoforms, the cardiac isoform NaV1.5 (encoded by SCN5A) and the skeletal muscle isoform NaV1.4 are expressed in skeletal muscle although NaV1.4 predominates. The expression of NaV1.5 progressively decreases over the first 2 years after birth. The expression of NaV1.4 progressively increases after birth but the level before the age of 5 years is 25–40% of that seen in adulthood. The presence of NaV1.5 expression could compensate to some degree for variant-induced NaV1.4 dysfunction and to the delay in onset of symptoms reported in patients with myotonia who have NaV1.4 dysfunction.

Low expression of NaV1.4 in infantile muscle is likely to be particularly crucial in fast twitch respiratory muscles because their ability to maintain the amplitude of successive action potentials when under increased demand—eg, in the presence of hypoxia—is dependent on the density of sodium channels. This suggestion is supported by the observation that the capacity of muscle fibres from NaV1.4 heterozygous null mice to generate sustained action potentials diminishes with repeated stimulation. The enhanced sodium channel inactivation we observed with the Val1442Met variant will reduce channel availability, which could be particularly detrimental during such high frequency stimulation.

Second, developmental alterations in respiratory muscle fibre typing: the proportion of fast and slow twitch fibres in respiratory muscles is regulated developmentally. Fast twitch fibres that rely more heavily on the density of sodium channels predominate in these muscles in infants, compared with those older than 2 years of age.

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