title: Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy.
abstract: OBJECTIVE
  The aim of this study was to describe a new familial cardiac phenotype and to elucidate the electrophysiological mechanism responsible for the disease.
  
  
  BACKGROUND
  Mutations in several genes encoding ion channels, especially SCN5A, have emerged as the basis for a variety of inherited cardiac arrhythmias.
  
  
  METHODS
  Three unrelated families comprising 21 individuals affected by multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by narrow junctional and rare sinus beats competing with numerous premature ventricular contractions with right and/or left bundle branch block patterns were identified.
  
  
  RESULTS
  Dilated cardiomyopathy was identified in 6 patients, atrial arrhythmias were detected in 9 patients, and sudden death was reported in 5 individuals. Invasive electrophysiological studies demonstrated that premature ventricular complexes originated from the Purkinje tissue. Hydroquinidine treatment dramatically decreased the number of premature ventricular complexes. It normalized the contractile function in 2 patients. All the affected subjects carried the c.665G>A transition in the SCN5A gene. Patch-clamp studies of resulting p.Arg222Gln (R222Q) Nav1.5 revealed a net gain of function of the sodium channel, leading, in silico, to incomplete repolarization in Purkinje cells responsible for premature ventricular action potentials. In vitro and in silico studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine.
  
  
  CONCLUSIONS
  A new SCN5A-related cardiac syndrome, MEPPC, was identified. The SCN5A mutation leads to a gain of function of the sodium channel responsible for hyperexcitability of the fascicular-Purkinje system. The MEPPC syndrome is responsive to hydroquinidine.
authors: CHU Dijon, Service de Cardiologie, Hôpital le Bocage, Dijon, France. gabriel.laurent@chu-dijon.fr
authors: Gabriel
authors: G
authors: Laurent
authors: Samuel
authors: S
authors: Saal
authors: Mohamed Yassine
authors: MY
authors: Amarouch
authors: Delphine M
authors: DM
authors: Béziau
authors: Roos F J
authors: RF
authors: Marsman
authors: Laurence
authors: L
authors: Faivre
authors: Julien
authors: J
authors: Barc
authors: Christian
authors: C
authors: Dina
authors: Geraldine
authors: G
authors: Bertaux
authors: Olivier
authors: O
authors: Barthez
authors: Christel
authors: C
authors: Thauvin-Robinet
authors: Philippe
authors: P
authors: Charron
authors: Véronique
authors: V
authors: Fressart
authors: Alice
authors: A
authors: Maltret
authors: Elisabeth
authors: E
authors: Villain
authors: Estelle
authors: E
authors: Baron
authors: Jean
authors: J
authors: Mérot
authors: Rodolphe
authors: R
authors: Turpault
authors: Yves
authors: Y
authors: Coudière
authors: Flavien
authors: F
authors: Charpentier
authors: Jean-Jacques
authors: JJ
authors: Schott
authors: Gildas
authors: G
authors: Loussouarn
authors: Arthur A M
authors: AA
authors: Wilde
authors: Jean-Eric
authors: JE
authors: Wolf
authors: Isabelle
authors: I
authors: Baró
authors: Florence
authors: F
authors: Kyndt
authors: Vincent
authors: V
authors: Probst
mesh_terms: D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D011690:Purkinje Fibers / Q000503:physiopathology*; D011802:Quinidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology; D013577:Syndrome; D018879:Ventricular Premature Complexes / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
chemical_list: D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; C014486:hydroquinidine; D011802:Quinidine