Dynamic QT Changes in Long QT Syndrome Type 8

Gain-of-function CACNA1C mutations have been shown to cause long QT syndrome type 8 (LQT8), an inherited arrhythmia with a marked QT prolongation and a bizarre form of polymorphic ventricular tachycardia (torsade de pointes) on electrocardiogram (ECG). Resting as well as dynamic ECG change is an important diagnostic hallmark for long QT syndrome, but the dynamic feature has not been previously reported in LQT8. The index patient was a 7-year-old asymptomatic boy referred to hospital because of abnormal ECG findings at a school health checkup (Figure A). The 12-lead ECG at rest showed a QT prolongation and a late-onset T wave. Genetic testing identified a heterozygous de novo CACNA1C mutation (p.Arg518Cys; R518C; Figure B,C), confirming the diagnosis of LQT8.¹ Exercise stress test showed a transient normalization of a corrected QT interval (QTc) at peak exercise. The QTc prolongation returned to that of the control level before exercise at 4 min of recovery (Figure D). Similar ECG features at rest have been reported in LQT type 3 (LQT3). Similarly, in LQT3 patients, exercise tolerance test shortened QTc at peak exercise. Thus, dynamic and resting ECG features in the present LQT8 case mimicked those reported in LQT3, suggesting a similarity in that both result from gain-of-function mutations in genes encoding cardiac inward currents.

Figure.

(A) Resting electrocardiogram (ECG) at school health checkup at the age of 6 years and 11 months showed relative sinus bradycardia, a heart rate (HR) of 61 beats/min with QT prolongation of a corrected QT interval (QTc) of 496 ms (using Bazett formula), and a late-onset T wave with a steep descending limb (V2 and V3). (B) Electropherograms of CACNA1C from (Left) a healthy control and (Right) the patient. Arrows, nucleotide variation, resulting in p.Arg518Cys in the patient, a gain-of-function mutation. This mutation is known to cause slower inactivation and a lower peak L-type calcium current. WT, wild type. (C) Index case pedigree. Black arrow, proband; gray, positive phenotype; (+), (−), positive and negative genotypes, respectively. I-1, I-2, parents’ ECG with normal QT intervals (QTc, 412 ms; HR, 65 beats/min, QTc, 417 ms; HR, 87 beats/min, respectively). Proband was affected by long QT syndrome. No structural abnormality was found on echocardiogram or contrast magnetic resonance imaging. (D) Exercise stress test using the modified Bruce protocol at the age of 7 years and 11 months, showing shortening of the QT interval (QTc, 406 ms; HR, 171 beats/min) with T-wave morphological changes at peak exercise and QT interval prolongation after 4 min of recovery (QTc, 450 ms; HR, 69 beats/min).

Disclosures

The authors declare no conflicts of interest.

Reference

• 1.   Boczek NJ, Ye D, Jin F, Tester DJ, Huseby A, Bos JM, et al. Identification and functional characterization of a novel CACNA1C-mediated cardiac disorder characterized by prolonged QT intervals with hypertrophic cardiomyopathy, congenital heart defects, and sudden cardiac death. Circ Arrhythm Electrophysiol 2015; 8: 1122–1132.