Abstract
Background: SCN5A mutations can lead to different cardiac diseases. Recently, SCN5A
mutations have been linked to the clinical entity multifocal ectopic Purkinje-related
premature contractions (MEPPC) characterized by ventricular ectopy and dilated cardiomyopathy.
Methods & Results: A family with a uniform MEPPC-like phenotype, associated with complex
atrial and ventricular arrhythmias and dilated cardiomyopathy caused by a high frequency
of ventricular ectopy was clinically assessed. Screening of the SCN5A gene revealed
a missense mutation in the linker between segments 3 and 4 in domain 1 of the Nav1.5 protein, resulting in a glycine to aspartate substitution at position 213 (G213D).
The phenotype co-segregated with the missense mutation. Electrophysiological studies
of wild type (WT) hNav1.5 and hNav1.5_G213D expressed in CHO-K cells showed that the voltage of half-maximal activation
(V½) was significantly more negative for hNav1.5_G213D compared to WT (V½ = −38.7 ± 0.5 mV for WT and V½ = −42.4 ± 0.5 mV for G213D; P < 0.001). This suggests activation of Nav1.5_G231D at more negative potentials. The V½ of steady-state inactivation was significantly shifted towards more positive values
for Nav1.5_G213D (V½ = −86.7 ± 0.2 mV for WT and −82.2 ± 0.3 mV for G213D; P < 0.001), also contributing to a gain-of-function phenotype. Flecainide and amiodarone
markedly reduced premature atrial and ventricular contractions in four patients.
Conclusion: The Nav1.5_G213D mutation is associated with a gain-of-function phenotype, multifocal atrial
and ventricular ectopy and dilated cardiomyopathy. Since patients with a MEPPC-like
phenotype may specifically benefit from Class-1 antiarrhythmic drugs or amiodarone,
clinical identification of this disease entity is important.
Abbreviations:
AF (atrial fibrillation), DCM (dilated cardiomyopathy), ECG (electrocardiogram), EPS (electrophysiological study), LA (left atrium), LV (left ventricle), LVEF (left ventricular ejection fraction), MEPPC (multifocal ectopic Purkinje-related premature contractions), CMR (cardiac magnetic resonance imaging), MAT (multifocal atrial tachycardia), PAC (premature atrial contractions), PVC (premature ventricular contractions), V½ (the half-maximal activation or inactivation voltage)Keywords
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Article info
Publication history
Accepted:
November 27,
2017
Received in revised form:
October 24,
2017
Received:
September 24,
2017
Footnotes
☆“All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation”
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© 2017 Elsevier B.V. All rights reserved.
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- Multifocal ectopic Purkinje-related premature contractions: Sorting the wheat from the chaffInternational Journal of CardiologyVol. 257
- PreviewEven in the modern age, new diseases continue to be reported. Some – for example, infectious disorders – are caused by previously undetected or unknown noxious agents or pathogens, but others are discovered by careful clinical observation and pattern recognition; the new entity of multifocal ectopic Purkinje-related premature contractions (MEPPC) caused by mutations in the gene SCN5A is one such condition.
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