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Original research
Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia
  1. Edgard Verdura1,2,
  2. Carme Fons2,3,4,
  3. Agatha Schlüter1,2,
  4. Montserrat Ruiz1,2,
  5. Stéphane Fourcade1,2,
  6. Carlos Casasnovas1,2,5,
  7. Antonio Castellano6,7,
  8. Aurora Pujol1,2,8
  1. 1 Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalunya, Spain
  2. 2 Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
  3. 3 Pediatric Neurology Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Catalunya, Spain
  4. 4 Sant Joan de Déu Research Institute (IRSJD), Esplugues de Llobregat, Barcelona, Catalunya, Spain
  5. 5 Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Catalunya, Spain
  6. 6 Institute of Biomedicine of Seville (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
  7. 7 Medical Physiology and Biophysics Departament, Universidad de Sevilla, Sevilla, Spain
  8. 8 Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalunya, Spain
  1. Correspondence to Dr Aurora Pujol, Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Spain; apujol{at}idibell.cat

Abstract

Background Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events.

Methods A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings.

Results WES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures.

Conclusion This newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.

  • KCNA1
  • neonatal epileptic encephalopathy
  • dyskinesia
  • Kv1.1
  • WES
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Footnotes

  • AC and AP contributed equally.

  • Contributors EV, AC and AP designed and conceptualised the study. EV, CF, AS, MR, SF, CC and AC performed analysis and interpreted the data. EV, CF, AC and AP drafted the manuscript. All authors critically revised the manuscript, contributed significantly to this work and declare to meet the ICMJE criteria for authorship.

  • Funding This study was supported by the Centre for Biomedical Research on Rare Diseases (CIBERER) (ACCI14-759), the URDCat program (PERIS SLT002/16/00174), the Hesperia Foundation and the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia (2017SGR1206) to AP and Instituto de Salud Carlos III (PI14/00581) (cofunded by European Regional Development Fund. ERDF, a way to build Europe) and la Marató de TV3 (345/C/2014) to CC and AP. EV was funded by a grant from the Ministerio de Economia, Industria y Competividad (Juan de la Cierva programme FJCI-2016-28811). SF was funded by the Instituto de Salud Carlos III (Miguel Servet programme CPII16/00016, cofunded by European Social Fund. ESF investing in your future) and MR was funded by CIBERER.

  • Competing interests None declared.

  • Patient consent for publication Parental/guardian consent obtained.

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

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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