{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T16:58:18Z","timestamp":1777395498171,"version":"3.51.4"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T00:00:00Z","timestamp":1661472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:p>We present a now 18-year-old female patient with a severe congenital myopathy phenotype, originally diagnosed as mitochondrial myopathy, however later revealed to constitute a <jats:italic>SCN4A<\/jats:italic>-related myopathy based on genetic testing. After birth, floppiness, bradycardia and respiratory insufficiency ensued, and moderately reduced mitochondrial complex I activity was found in muscle tissue (tested at 3 weeks and 3 years of age, respectively). She was treated with riboflavin, carnitine, creatine and a ketogenic diet. At the age of 13 years, whole exome sequencing challenged the initial diagnosis by identifying two (compound heterozygous) <jats:italic>SCN4A<\/jats:italic> variants affecting the highly conserved voltage sensor and pore regions of the voltage-gated sodium channel Na<jats:sub>V<\/jats:sub>1.4: a known pathogenic loss of function (LOF) variant [c.4360C&amp;gt;T; p.(Arg1454Trp)] and a novel variant of uncertain significance [c.3615C&amp;gt;G; p.(Asn1205Lys)]. For this novel variant, a LOF effect was predicted by <jats:italic>in silico<\/jats:italic>, clinical and functional evidence from paralog human sodium channels, and the variant was accordingly classified as likely pathogenic. The patient's phenotype is in line with the few published cases of autosomal recessive <jats:italic>SCN4A<\/jats:italic>-related myopathy. There was limited benefit from treatment with salbutamol and acetazolamide, while pyridostigmine caused side effects at a minor dose. This report highlights the importance of genetic testing in severe myopathies particularly in regard to treatment options and the value of paralog information in evaluating ion channel variations.<\/jats:p>","DOI":"10.3389\/fped.2022.944784","type":"journal-article","created":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T06:05:20Z","timestamp":1661493920000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Case report: Novel SCN4A variant associated with a severe congenital myasthenic syndrome\/myopathy phenotype"],"prefix":"10.3389","volume":"10","author":[{"given":"Veronika M.","family":"Berghold","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahmoud","family":"Koko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riccardo","family":"Berutti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Plecko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"re15","DOI":"10.1126\/stke.2532004re15","article-title":"The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis","volume":"2004","author":"Yu","year":"2004","journal-title":"Sci STKE."},{"key":"B2","doi-asserted-by":"publisher","first-page":"7377","DOI":"10.1073\/pnas.1230273100","article-title":"Myasthenic syndrome caused by mutation of the SCN4A sodium channel","volume":"100","author":"Tsujino","year":"2003","journal-title":"Proc Natl Acad Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1002\/ana.24389","article-title":"Defective fast inactivation recovery of Nav 14 in congenital myasthenic syndrome","volume":"77","author":"Arnold","year":"2015","journal-title":"Ann Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1212\/WNL.0000000000002264","article-title":"A recessive Nav14 mutation underlies congenital myasthenic syndrome with periodic paralysis","volume":"86","author":"Habbout","year":"2016","journal-title":"Neurology."},{"key":"B5","doi-asserted-by":"publisher","first-page":"77","DOI":"10.3389\/fneur.2020.00181","article-title":"Myotonic myopathy with secondary joint and skeletal anomalies from the c.2386C>G, p.L769V mutation in SCN4A","volume":"11","author":"Elia","year":"2020","journal-title":"Front Neurol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1093\/brain\/awv352","article-title":"Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or \u2018classical' congenital myopathy","volume":"139","author":"Zaharieva","year":"2016","journal-title":"Brain."},{"key":"B7","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1002\/mds.26808","article-title":"Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up","volume":"32","author":"Zech","year":"2017","journal-title":"Mov Disord."},{"key":"B8","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1016\/S1474-4422(20)30312-4","article-title":"Monogenic variants in dystonia: an exome-wide sequencing study","volume":"19","author":"Zech","year":"2020","journal-title":"Lancet Neurol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1002\/0471250953.bi1110s43","article-title":"From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline","volume":"43","author":"Van der","year":"2013","journal-title":"Curr Protoc Bioinform."},{"key":"B10","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac006","article-title":"Gene variant effects across sodium channelopathies predict function and guide precision therapy","author":"Brunklaus","year":"2022","journal-title":"Brain."},{"key":"B12","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1126\/scitranslmed.aay6848","article-title":"Predicting functional effects of missense variants in voltage-gated sodium and calcium channels","volume":"12","author":"Heyne","year":"2020","journal-title":"Sci Transl Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"46227","DOI":"10.1038\/srep46227","article-title":"Unexplained early infantile epileptic encephalopathy in Han Chinese children: next-generation sequencing and phenotype enriching","volume":"7","author":"Arafat","year":"2017","journal-title":"Sci Rep."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1038\/gim.2017.195","article-title":"Proband-only medical exome sequencing as a cost-effective first-tier genetic diagnostic test for patients without prior molecular tests and clinical diagnosis in a developing country: the China experience","volume":"20","author":"Hu","year":"2018","journal-title":"Genet Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1111\/j.1468-1331.2010.03077.x","article-title":"Brugada-like cardiac disease in myotonic dystrophy type 2: report of two unrelated patients","volume":"18","author":"Rudnik-Schoneborn","year":"2011","journal-title":"Eur J Neurol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.1016\/j.jacc.2012.04.037","article-title":"Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing: implications for genetic testing","volume":"60","author":"Crotti","year":"2012","journal-title":"J Am Coll Cardiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1016\/j.hrthm.2014.04.010","article-title":"A comprehensive electrocardiographic, molecular, and echocardiographic study of Brugada syndrome: validation of the 2013 diagnostic criteria","volume":"11","author":"Savastano","year":"2014","journal-title":"Heart Rhythm."},{"key":"B18","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1093\/europace\/euv078","article-title":"Novel SCN10A variants associated with Brugada syndrome","volume":"18","author":"Fukuyama","year":"2016","journal-title":"Europace."},{"key":"B19","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.ajhg.2020.05.015","article-title":"High-throughput reclassification of SCN5A variants","volume":"107","author":"Glazer","year":"2020","journal-title":"Am J Hum Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.ajhg.2017.01.004","article-title":"InterVar: clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines","volume":"100","author":"(20) Li","year":"2017","journal-title":"Am J Hum Genet"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.1093\/brain\/aww070","article-title":"Cannon SC. Mice with an NaV14 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis","volume":"139","author":"Wu","year":"2016","journal-title":"Brain."},{"key":"B22","doi-asserted-by":"publisher","first-page":"3395","DOI":"10.1093\/hmg\/ddw262","article-title":"Motor neuron mitochondrial dysfunction in spinal muscular atrophy","volume":"25","author":"Miller","year":"2016","journal-title":"Hum Mol Genet."},{"key":"B23","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.spen.2013.10.010","article-title":"Mitochondrial dysfunction in neuromuscular disorders","volume":"20","author":"Katsetos","year":"2013","journal-title":"Semin Pediatr Neurol."}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.944784\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,26]],"date-time":"2022-08-26T06:05:23Z","timestamp":1661493923000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2022.944784\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,26]]},"references-count":23,"alternative-id":["10.3389\/fped.2022.944784"],"URL":"https:\/\/doi.org\/10.3389\/fped.2022.944784","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,26]]},"article-number":"944784"}}