A novel gain‐of‐function mutation in SCN5A responsible for multifocal ectopic Purkinje‐related premature contractions. Issue 4 (25th January 2020)

• Record Type: Journal Article
• Authors: Doisne, Nicolas; Waldmann, Victor; Redheuil, Alban; Waintraub, Xavier; Fressart, Véronique; Ader, Flavie; Fossé, Lucie; Hidden‐Lucet, Françoise; Gandjbakhch, Estelle; Neyroud, Nathalie
• Is Part Of: Human mutation. Volume 41:Issue 4(2020)
• Page Start: 850
• Page End: 859
• Publication Date: 2020-01-25
• Subjects: dilated cardiomyopathy -- electrophysiology -- gain‐of‐function mutation -- polymorphic premature ventricular complexes -- Purkinje -- SCN5A; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23981
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Recently, four SCN5A mutations have been associated with Multifocal Ectopic Purkinje‐related Premature Contractions (MEPPC), a rare cardiac syndrome combining polymorphic ventricular arrhythmia with dilated cardiomyopathy (DCM). Here, we identified a novel heterozygous mutation in SCN5A (c.611C>A, pAla204Glu) in a young woman presenting with polymorphic premature ventricular contractions (PVCs) and DCM. After failure of antiarrhythmic drugs and an attempt of radiofrequency catheter ablation showing three exit‐sites of PVCs, all with presystolic Purkinje potentials, a treatment by hydroquinidine was tried, leading to an immediate and spectacular disappearance of all PVCs and normalization of cardiac function. Electrophysiological studies showed that Nav 1.5‐A204E mutant channels exhibited a significant leftward shift of 8 mV of the activation curve, leading to a larger hyperpolarized window current when compared to wild‐type. Action potential modeling using Purkinje fiber and ventricular cell models predicted an arrhythmogenic effect predominant in Purkinje fibers for the A204E mutation. Comparison with other MEPPC‐associated Nav 1.5 mutations revealed a common electrophysiological pattern of abnormal voltage‐dependence of activation leading to a larger hyperpolarized window current as a shared biophysical mechanism of this syndrome. These features of the mutant sodium channels are likely to be responsible for the hyperexcitability of the fascicular‐Purkinje system observed in patients with MEPPC.