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Homozygous C-terminal loss-of-function NaV1.4 variant in a patient with congenital myasthenic syndrome
  1. Andoni Echaniz-Laguna1,2,3,
  2. Valérie Biancalana4,5,
  3. Aleksandra Nadaj-Pakleza6,
  4. Emmanuel Fournier7,
  5. Emma Matthews8,
  6. Michael G Hanna8,
  7. Roope Männikkö8
  1. 1 Department of Neurology, APHP, CHU de Bicêtre, Le Kremlin Bicêtre, France
  2. 2 French National Reference Center for Rare Neuropathies (NNERF), Le Kremlin Bicêtre, France
  3. 3 INSERM U1195 & Paris-Sud University, Le Kremlin Bicêtre, France
  4. 4 Laboratoire Diagnostic Génétique, CHR, Strasbourg, France
  5. 5 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Illkirch, France
  6. 6 Department of Neurology, Strasbourg University Hospital, Strasbourg, France
  7. 7 Department of Neurophysiology, APHP, CHU Pitié-Salpêtrière, Paris, France
  8. 8 Department of Neuromuscular disease, UCL Queen Sqaure Institute of Neurology, London, United Kingdom
  1. Correspondence to Dr Roope Männikkö, Department of Neuromuscular disease, UCL Queen Square Institute of Neurology, London, UK; r.mannikko{at}

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Congenital myasthenic syndromes (CMS) are a group of rare inherited disorders of neuromuscular transmission.1 Clinical presentations range from predominant ptosis, ophthalmoparesis, facial and bulbar weakness, and generalised muscle weakness to predominant limb girdle weakness with sparing of the eye and face muscles. Symptoms may appear during the neonatal period, late childhood, adolescence or even adulthood. Clinical presentation and response to treatment may be influenced by the underlying molecular mechanism.

Mutations in more than 30 genes have been identified as causing CMS.1 The primary pathogenic mechanism is defective neuromuscular junction (NMJ) transmission but may include central nervous system and skeletal muscle involvement. Biallelic loss-of-function (LOF) genetic mutations in SCN4A encoding skeletal muscle sodium channel NaV1.4 are a rare cause of CMS.2–6 Heterozygous carriers are asymptomatic, demonstrating recessive inheritance. NaV1.4 conducts the depolarising current of the skeletal muscle action potential that when reduced results in attenuated action potentials and muscle force.

Biallelic SCN4A LOF mutations can also be found in patients diagnosed with congenital myopathy6–8 and occasionally hypokalaemic periodic paralysis (hypoPP).9 10 A common pathogenic mechanism can account for the notion that patients diagnosed with SCN4A-associated CMS may present with additional features of myopathy5 or hypoPP.4 The mutant NaV1.4 channels within SCN4A LOF clinical spectra show distinct functional defects. Mutations associated with congenital myopathy show a range of alterations on NaV1.4 channel function but one allele is often null.6–8 Hitherto reported CMS-associated mutations enhance channel inactivation2–5 and typically affect fourth voltage sensing domain (VSD) of NaV1.4, the key VSD implicated in control of …

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  • Contributors AE-L, VB, AN-P, EF, EM, MGH and RM designed and performed research, and collected the data. AE-L, EM and RM wrote the manuscript. VB, AN-P, EF and MGH critically revised the manuscript for important intellectual content.

  • Funding The molecular study (MYOdiagHTS panel) was supported by Association Française contre les Myopathies (AFM-16992) and CREGEMES.The work was supported by the UK Medical Research Council (grant MR/M006948/1).

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.