Novel trans-2,3-enoyl-CoA reductase–like variant associated with catecholaminergic polymorphic ventricular tachycardia type 3

Q: What is the clinical evidence from this study?

Study design: Case Report. Population: Catecholaminergic polymorphic ventricular tachycardia type 3 (CPVT3) / Long QT syndrome (LQTS) overlap caused by homozygous TECRL mutation (n=2). Intervention: Dual therapy with nadolol and flecainide plus primary prevention transvenous ICD. Primary outcome: Suppression of exercise-induced ventricular ectopy, clinical events, and ICD shocks at 7 months.

Q: What does this research mean for the field?

Dual therapy with nadolol and flecainide suppresses exercise-induced ventricular ectopy in patients with homozygous TECRL-associated catecholaminergic polymorphic ventricular tachycardia type 3. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Fatmeh Charafeddine; Nada Assaf; Ali Mohamed Ali Ismail; Ziad Bulbul

doi:10.1016/j.hrcr.2022.12.013

December 20, 2022HeartRhythm Case ReportsOpen Access

Novel trans-2,3-enoyl-CoA reductase–like variant associated with catecholaminergic polymorphic ventricular tachycardia type 3

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Why the study?

Does dual therapy with nadolol and flecainide suppress exercise-induced ventricular ectopy and prevent arrhythmic events in pediatric patients with CPVT type 3 due to homozygous TECRL mutation?

Key Points

To evaluate the pathogenicity of a novel biallelic loss-of-function variant in the TECRL gene and describe clinical management in siblings presenting with catecholaminergic polymorphic ventricular tachycardia type 3.
Clinical evaluations, resting 12-lead electrocardiography, sprint exercise stress testing, and echocardiography were conducted in two symptomatic siblings with a family history of juvenile sudden death.
Whole exome sequencing was performed on peripheral blood samples to identify underlying pathogenic variants.
Whole exome sequencing identified a novel homozygous frameshift variant in the TECRL gene in both symptomatic siblings, with asymptomatic parents confirmed as heterozygous carriers.
Sprint exercise stress testing provoked bidirectional ventricular ectopic couplets, bigeminy, and trigeminy during peak exertion, with resting QTc of 0.47 prolonging up to 0.496 and 0.5 during recovery.
Addition of flecainide to baseline beta-blocker therapy successfully suppressed exercise-induced ventricular ectopy.

Study Design

Type

Case Report (n=2)

Multicenter

No

Structured PICO

Does dual therapy with nadolol and flecainide suppress exercise-induced ventricular ectopy and prevent arrhythmic events in pediatric patients with CPVT type 3 due to homozygous TECRL mutation?

P

Population

2 Lebanese siblings (aged 9 and 13 years, 50% female) with a novel homozygous TECRL frameshift mutation presenting with CPVT type 3 / LQTS overlap, followed for 7 months.

I

Intervention

Dual medical therapy with nadolol (starting dose 1 mg/kg/day) and flecainide (after switching from low-dose propranolol and persistent PVCs on nadolol monotherapy), combined with primary prevention transvenous implantable cardioverter-defibrillator (ICD) implantation (with lengthened VF detection rate and anti-tachycardia pacing turned off) and trigger avoidance for 7 months.

O

Outcome

Suppression of exercise-induced ventricular ectopy/arrhythmias, clinical events, and ICD shocks at 7 months follow-up.hard clinical

Limitations

No molecular or tissue autopsy was performed for the 2 deceased siblings
ECG tracings of the isolated PVCs observed in the heterozygous father were not available
More data are needed to draw definitive conclusions about the cardiac phenotype in heterozygous TECRL carriers
Unclear whether the mild bileaflet mitral valve prolapse observed in both patients is related to the genetic mutation
No molecular or tissue autopsy was done for either of the 2 deceased siblings
ECG tracings of the 4 isolated monomorphic PVCs observed in the heterozygous father during maximal exercise were not provided
More data are needed to draw definitive conclusions regarding the cardiac phenotype in heterozygous TECRL carriers
Observation of mild bileaflet mitral valve prolapse in both homozygous siblings requires further investigation to determine if it is related to the genetic mutation

Implication

Identifies a novel homozygous TECRL frameshift mutation causing CPVT type 3/LQTS overlap in two siblings and demonstrates that adding flecainide to nadolol completely suppresses exercise-induced ventricular ectopy.

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by polymorphic ventricular tachycardia, usually provoked by emotional stress or exercise, in the absence of any structural cardiac abnormality, and in the presence of often normal resting electrocardiogram (ECG).1 It is a highly lethal disease with an overall mortality of 30%–40% if left untreated.2 Studies have shown that almost 35% of affected individuals become symptomatic before the age of 10 and 75% before the age of 20 years.

Discussion

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Cite This Study

Charafeddine et al. (2022) conducted a case report in Catecholaminergic polymorphic ventricular tachycardia type 3 (CPVT3) / Long QT syndrome (LQTS) overlap caused by homozygous TECRL mutation (n=2). Dual therapy with nadolol and flecainide plus primary prevention transvenous ICD was evaluated on Suppression of exercise-induced ventricular ectopy, clinical events, and ICD shocks at 7 months.

synapsesocial.com/papers/6a778b576c53f758bc1e9a19 https://doi.org/10.1016/j.hrcr.2022.12.013

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Novel trans-2,3-enoyl-CoA reductase–like variant associated with catecholaminergic polymorphic ventricular tachycardia type 3

Figures

Key Points

Study Design

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

Novel trans-2,3-enoyl-CoA reductase–like variant associated with catecholaminergic polymorphic ventricular tachycardia type 3

Figures

Key Points

Study Design

Structured PICO

Limitations

Implication

Abstract

Discussion

Cite This Study

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