Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) 3 is a rare arrhythmic disorder characterised by the overlapping features of both CPVT and Long QT Syndrome (LQTS). Affected patients exhibit adrenergic ventricular tachycardia with high prevalence of cardiac arrest and sudden cardiac death. They also suffer from recurrent atrial tachycardia which can trigger ventricular arrhythmias. Interestingly, patients have normal or mildly prolonged QTc at baseline with a paradoxical QT increase during adrenergic stimulation.Arrhythmic episodes are usually induced by exertion or stress. Affected individuals can suffer such episodes in early childhood, often resulting in sudden death. While CPVT has an overall prevalence of 1 in 10,000 individuals, CPVT3 has only been reported in a handful of families thus far. The condition does not have a gender or racial bias.
The disorder can be diagnosed based on clinical features and genetic analysis of the TECRL gene. Early diagnosis and management of CPVT3 is crucial in preventing cardiac episodes. Treatment includes the use of beta-blockers, flecainide therapy and implantable cardioverter defibrillators (ICDs). Genetic counselling is also recommended for asymptomatic family members of affected individuals.
The disorder follows an autosomal recessive pattern of inheritance and is caused by mutations in the TECRL gene. This gene encodes an integral membrane protein with oxidoreductase activity. Knockdown of TECRL in human embryonic stem cell-derived cardiomyocytes results in significantly prolonged action potentials and reduced cell content of the canonical calcium-handling proteins RYR2 and CASQ2. Variants in TECRL associated with CPVT3 include a missense mutation (R196Q) and a splice-site mutation (c.331+1G-A). Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the splice-site mutation have been found to exhibit electrophysiological and calcium-handling abnormalities as well as an increased susceptibility to triggered electrical activity upon catecholaminergic stimulation by noradrenaline.
Devalla et al. (2016) described a multiplex consanguineous Sudanese family in which seven children suffered exertion-induced arrhythmias and/or sudden cardiac death (SCD) during early childhood. The patients were found to have CPVT with prolongation of the QT interval. The arrhythmic episodes proved fatal in 5 of these children. The authors identified a homozygous splice site mutation (c.331+1G>A) in the TECRL gene of affected members. Using patient induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), it was seen that the variant resulted in complete skipping of exon 3. Further, compared to controls, the mutant cardiomyocytes exhibited electrophysiological and calcium-handling abnormalities. They were also prone to an increase in triggered electrical activity upon noradrenaline stimulation which could be significantly reduced by treatment with flecainide, a class Ic antiarrhythmic drug.
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