Short QT syndrome in a boy diagnosed on screening for heart disease

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Abstract

We report on an asymptomatic 10-year-old boy who had a short QT interval (corrected QT interval, 260 ms). Short QT syndrome (SQTS) was detected in a school screening program for heart disease and the patient was subsequently diagnosed as having N588K mutation in the KCNH2 gene. Quinidine prolonged the QT interval, but not the QU interval. During treadmill exercise stress test, QT and QU intervals responded differently to heart rate changes, suggesting a mechanoelectrical hypothesis for the origin of the U wave. Although rare, attention should be paid to SQTS, which is associated with potential fatal arrhythmias.

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Most cited references 10

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Sudden death associated with short-QT syndrome linked to mutations in HERG.

Ramon Brugada, Guido Pollevick, M Menéndez … (2004)

Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG. Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers. We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.

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Long-term follow-up of patients with short QT syndrome.

Pascal Sbragia, Martin Borggrefe, Olli Anttonen … (2011)

The aim of this study was to investigate the clinical characteristics and the long-term course of a large cohort of patients with short QT syndrome (SQTS). SQTS is a rare channelopathy characterized by an increased risk of sudden death. Data on the long-term outcome of SQTS patients are not available. Fifty-three patients from the European Short QT Registry (75% males; median age: 26 years) were followed up for 64 ± 27 months. A familial or personal history of cardiac arrest was present in 89%. Sudden death was the clinical presentation in 32%. The average QTc was 314 ± 23 ms. A mutation in genes related to SQTS was found in 23% of the probands; most of them had a gain of function mutation in HERG (SQTS1). Twenty-four patients received an implantable cardioverter defibrillator, and 12 patients received long-term prophylaxis with hydroquinidine (HQ), which was effective in preventing the induction of ventricular arrhythmias. Patients with a HERG mutation had shorter QTc at baseline and a greater QTc prolongation after treatment with HQ. During follow-up, 2 already symptomatic patients received appropriate implantable cardioverter defibrillator shocks and 1 had syncope. Nonsustained polymorphic ventricular tachycardia was recorded in 3 patients. The event rate was 4.9% per year in the patients without antiarrhythmic therapy. No arrhythmic events occurred in patients receiving HQ. SQTS carries a high risk of sudden death in all age groups. Symptomatic patients have a high risk of recurrent arrhythmic events. HQ is effective in preventing ventricular tachyarrhythmia induction and arrhythmic events during long-term follow-up. Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

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Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6).

Firat Duru, Charles Antzelevitch, C Puleo … (2011)

Short QT syndrome (SQTS) is a genetically determined ion-channel disorder, which may cause malignant tachyarrhythmias and sudden cardiac death. Thus far, mutations in five different genes encoding potassium and calcium channel subunits have been reported. We present, for the first time, a novel loss-of-function mutation coding for an L-type calcium channel subunit. The electrocardiogram of the affected member of a single family revealed a QT interval of 317 ms (QTc 329 ms) with tall, narrow, and symmetrical T-waves. Invasive electrophysiological testing showed short ventricular refractory periods and increased vulnerability to induce ventricular fibrillation. DNA screening of the patient identified no mutation in previously known SQTS genes; however, a new variant at a heterozygous state was identified in the CACNA2D1 gene (nucleotide c.2264G > C; amino acid p.Ser755Thr), coding for the Ca(v)α(2)δ-1 subunit of the L-type calcium channel. The pathogenic role of the p.Ser755Thr variant of the CACNA2D1 gene was analysed by using co-expression of the two other L-type calcium channel subunits, Ca(v)1.2α1 and Ca(v)β(2b), in HEK-293 cells. Barium currents (I(Ba)) were recorded in these cells under voltage-clamp conditions using the whole-cell configuration. Co-expression of the p.Ser755Thr Ca(v)α(2)δ-1 subunit strongly reduced the I(Ba) by more than 70% when compared with the co-expression of the wild-type (WT) variant. Protein expression of the three subunits was verified by performing western blots of total lysates and cell membrane fractions of HEK-293 cells. The p.Ser755Thr variant of the Ca(v)α(2)δ-1 subunit was expressed at a similar level compared with the WT subunit in both fractions. Since the mutant Ca(v)α(2)δ-1 subunit did not modify the expression of the pore-forming subunit of the L-type calcium channel, Ca(v)1.2α1, it suggests that single channel biophysical properties of the L-type channel are altered by this variant. In the present study, we report the first pathogenic mutation in the CACNA2D1 gene in humans, which causes a new variant of SQTS. It remains to be determined whether mutations in this gene lead to other manifestations of the J-wave syndrome.

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Author and article information

Journal

Journal ID (nlm-ta): Pediatr Int

Journal ID (iso-abbrev): Pediatr Int

Journal ID (publisher-id): ped

Title: Pediatrics International

Publisher: BlackWell Publishing Ltd (Oxford, UK )

ISSN (Print): 1328-8067

ISSN (Electronic): 1442-200X

Publication date (Print): October 2014

Publication date (Electronic): 22 October 2014

Volume: 56

Issue: 5

Pages: 774-776

Affiliations

[1 ]Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences Niigata, Japan

[2 ]Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences Niigata, Japan

[3 ]Department of Tachikawa Medical Center Niigata, Japan

Author notes

Correspondence: Hiroshi Suzuki, MD PhD, Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan. Email: hsuzukc5@ 123456med.niigata-u.ac.jp

Article

DOI: 10.1111/ped.12308

PMC ID: 4241042

PubMed ID: 25335996

SO-VID: f36e623b-ffaf-4df8-9012-e0d604c40817

License:

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 06 December 2013

Date accepted : 23 January 2014

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