Description of a novel RyR2 mutation in a juvenile patient with symptomatic catecholaminergic polymorphic ventricular tachycardia in sleep and during exercise: a case report

Abstract

BackgroundCatecholaminergic polymorphic ventricular tachycardia is an inherited disease presenting with arrhythmic events during physical exercise or emotional stress. If untreated, catecholaminergic polymorphic ventricular tachycardia is a highly lethal condition: About 80% of affected individuals experience recurrent syncope, and 30% experience cardiac arrest. Catecholaminergic polymorphic ventricular tachycardia is caused by mutations in genes encoding ryanodine receptor type 2 (RyR2) and cardiac calsequestrin (CASQ2). In cases of sympathoadrenergic activation, both mutations result in a spontaneous Ca2+ release in cardiac cells, facilitating ventricular arrhythmias.Case presentationWe present a case of a 17-year-old Caucasian boy who survived sudden cardiac death caused by ventricular fibrillation while performing running exercise in a fitness center. The diagnostic workup included blood tests, coronary angiography, electrophysiological testing, and cardiac magnetic resonance imaging, but all results were normal. Because the patient’s medical history included recurrent syncope during physical and emotional stress, we strongly suspected catecholaminergic polymorphic ventricular tachycardia as the underlying disease. Genetic screening was performed and confirmed the diagnosis, revealing a new heterozygous point mutation in the gene for RyR2, c.12520T>A (p.F4174 l, exon 90, RyR2 gene). The patient was discharged from our hospital after undergoing implantation of an implantable cardioverter defibrillator for secondary prevention. Shortly after implantation, the implantable cardioverter defibrillator terminated a sustaining ventricular tachycardia episode by antitachycardic pacing. This episode occurred early in the morning while the patient was asleep.ConclusionsWe present a case of catecholaminergic polymorphic ventricular tachycardia associated with a novel single point mutation in the RyR2 gene, which, to the best of our knowledge, has not been described in the literature so far. Our patient experienced arrhythmic events under both resting conditions and physical activity, an uncommon finding in patients with catecholaminergic polymorphic ventricular tachycardia. This novel mutation may cause arrhythmias independent of sympathoadrenergic stimulation, but further evidence is needed to prove causality.

“Ryanopathies” and RyR2 dysfunctions: can we further decipher them using in vitro human disease models?

“…However, further investigations are needed to prove its causality. [ 50 ] V2193L The RyR2-V2193L mutation was identified in a 9-year-old Chinese boy who presented with both epilepsy and CPVT syndrome. The exercise stress test revealed frequent PPVB and PMVT with the presence of R on T. His electroencephalogram (EEG) showed frequent epileptiform discharges during stage II, stage III and REM sleep.…”

“…Interestingly, a novel reported heterozygous mutation RyR2-F4174I in a 17 years old Caucasian patient caused polymorphic VT both at rest and under stress conditions. This mutation may cause arrhythmia independently of the sympatho-adrenergic stimulation via unclear pathophysiological mechanism [ 50 ].…”

Sudden Death by Catecholaminergic Polymorphic Ventricular Tachycardia in Children

“…CPVT treatment is performed with behavioral measures, such as restraining intense physical activities and avoiding situations of strong emotions, in association to medicament therapy with beta-blockers as the first choice of pharmaceutical treatment, with the control of the disease in two thirds of the cases 2,4 , and flecainide, antiarrhythmic from I-C class, not commercially available in Brazil, for the non-responders or intolerant to betablocking 9 . For refractory patients to the medicament therapy, there is still the option of left sympathetic denervation to diminish the CPVT and implantable cardiac defibrillators for the prevention of sudden death 5 .…”

Taquicardia ventricular polimórfica catecolaminérgica en adolescente: un diagnóstico clínico, electrocardiográfico y genético

“…La prevalencia estimada de TVPC es de 1-5 por 10 000 individuos y cerca del 30% de los pacientes tiene una historia familiar de muerte cardiaca súbita (1,2) . Generalmente, las manifestaciones clínicas debutan entre los 6 -10 años de edad (2) y las más comunes son: el síncope recurrente (80%) desencadenado durante la actividad física, parada cardiorrespiratoria (30%) y, en el peor de los casos, muerte súbita que en niños y adolescentes es infrecuente, aunque en adultos jóvenes sin tratamiento se han registrado en el 30% de los casos (3,4) .…”