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

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 John Ackerman, Michael G. Hanna, Elijah R. BehrEmma Matthews

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1483-1492
Number of pages10
JournalThe Lancet
Volume391
Issue number10129
DOIs
StatePublished - Apr 14 2018

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Voltage-Gated Sodium Channels
Sudden Infant Death
Case-Control Studies
Skeletal Muscle
National Institutes of Health (U.S.)
Sodium Channels
Congenital Myasthenic Syndromes
Laryngismus
Myotonia Congenita
Myotonia
Myoclonic Epilepsy
Exome
Muscles
Respiratory Muscles
Sudden Cardiac Death
Human Development
Apnea
Gene Frequency
Paralysis
England

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Männikkö, R., Wong, L., Tester, D. J., Thor, M. G., Sud, R., Kullmann, D. M., ... Matthews, E. (2018). Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study. The Lancet, 391(10129), 1483-1492. https://doi.org/10.1016/S0140-6736(18)30021-7

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

In: The Lancet, Vol. 391, No. 10129, 14.04.2018, p. 1483-1492.

Research output: Contribution to journalArticle

Männikkö, R, Wong, L, Tester, DJ, Thor, MG, Sud, R, Kullmann, DM, Sweeney, MG, Leu, C, Sisodiya, SM, FitzPatrick, DR, Evans, MJ, Jeffrey, IJM, Tfelt-Hansen, J, Cohen, MC, Fleming, PJ, Jaye, A, Simpson, MA, Ackerman, MJ, Hanna, MG, Behr, ER & Matthews, E 2018, 'Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study', The Lancet, vol. 391, no. 10129, pp. 1483-1492. https://doi.org/10.1016/S0140-6736(18)30021-7
Männikkö, Roope ; Wong, Leonie ; Tester, David J. ; Thor, Michael G. ; Sud, Richa ; Kullmann, Dimitri M. ; Sweeney, Mary G. ; Leu, Costin ; Sisodiya, Sanjay M. ; FitzPatrick, David R. ; Evans, Margaret J. ; Jeffrey, Iona J.M. ; Tfelt-Hansen, Jacob ; Cohen, Marta C. ; Fleming, Peter J. ; Jaye, Amie ; Simpson, Michael A. ; Ackerman, Michael John ; Hanna, Michael G. ; Behr, Elijah R. ; Matthews, Emma. / Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome : a case-control study. In: The Lancet. 2018 ; Vol. 391, No. 10129. pp. 1483-1492.
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T1 - Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome

T2 - a case-control study

AU - Männikkö, Roope

AU - Wong, Leonie

AU - Tester, David J.

AU - Thor, Michael G.

AU - Sud, Richa

AU - Kullmann, Dimitri M.

AU - Sweeney, Mary G.

AU - Leu, Costin

AU - Sisodiya, Sanjay M.

AU - FitzPatrick, David R.

AU - Evans, Margaret J.

AU - Jeffrey, Iona J.M.

AU - Tfelt-Hansen, Jacob

AU - Cohen, Marta C.

AU - Fleming, Peter J.

AU - Jaye, Amie

AU - Simpson, Michael A.

AU - Ackerman, Michael John

AU - Hanna, Michael G.

AU - Behr, Elijah R.

AU - Matthews, Emma

PY - 2018/4/14

Y1 - 2018/4/14

N2 - 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.

AB - 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.

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