Co-Phenotype of Left Ventricular Non-Compaction Cardiomyopathy and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia in Association With R169Q, a <i>Ryanodine Receptor Type 2</i> Missense Mutation

Abstract

Background: Left ventricular non-compaction (LVNC) is a cardiomyopathy characterized by prominent trabeculae and intertrabecular recesses. We present the cases of 3 girls with the same ryanodine receptor type 2 (RYR2) mutation who had phenotypes of both catecholaminergic polymorphic ventricular tachycardia (CPVT) and LVNC. Methods and Results: Clinical characteristics and genetic background of the 3 patients were analyzed retrospectively. Age at onset was 5, 6, and 7 years, respectively. Clinical presentation included syncope during exercise in all 3 patients and cardiac arrest in 2 patients. LVNC diagnosis was confirmed on echocardiography according to previously defined criteria. Exercise stress testing provoked ventricular arrhythmia in two of the patients. Beta-blockers (n=3) and flecainide (n=2) were given, and an implantable cardioverter defibrillator was used in 1 patient. Genotyping identified the same RYR2-R169Q missense mutation and no other CPVT-or LVNC-related gene mutations. Functional analysis of the mutation using HEK293 cells with single-cell Ca 2+ imaging and [ 3 H]ryanodine binding analysis, indicated a gain of function: a reduced threshold for overload-induced Ca 2+ release from the sarcoplasmic reticulum and increased fractional Ca 2+ release. Conclusions: The rare association of LVNC and CPVT phenotypes with RYR2 mutations is less likely to be coincidental. Screening for life-threatening arrhythmias using exercise or pharmacologic stress tests is recommended in LVNC patients to prevent sudden cardiac death in those with preserved LV function.

Molecular basis for gating of cardiac ryanodine receptor: underlying mechanisms for gain- and loss-of function mutations

“…Gain-of-function and loss-of-function mutations cause different diseases; the former are responsible for CPVT and LVNC (5,(8)(9)(10) and the latter IVF and LQTS (12)(13)(14)30). Different drugs are required to treat these diseases, such as RyR2 inhibitors for gain-of-function mutations and RyR2 activators for loss-of-function mutations.…”

“…catecholaminergic polymorphic ventricular tachycardia (CPVT) (5)(6)(7)(8), left ventricular non compaction (LVNF) (9)(10)(11), and idiopathic ventricular fibrillation (IVF) (12)(13)(14).…”

RYR2 p.R169L mutation and left ventricular hypertrophy in a child with emotion-triggered sudden death

“…More importantly, all of these three patients had left ventricular non-compaction cardiomyopathy and two of them initially presented with sudden cardiac arrest. 10 It is noteworthy that there is a considerable overlap between left ventricular non-compaction and hypertrophic cardiomyopathies and the same mutations have been associated with expression of either of these two phenotypes. 11 These three patients were screened for other mutations in cardiomyopathyassociated genes but were negative for the same.…”

“…In vitro functional analysis of the RYR2 p.R169Q has shown decreased thresholds for overload-induced Ca 2þ release and increased fractional Ca 2þ release from the sarcoplasmic reticulum. 10 The average age at diagnosis of catecholaminergic polymorphic ventricular tachycardia has been reported to be between 11 and 27 years in unselected cohorts of RYR2 mutation carriers 4,5 and only 50-65% of unselected RYR2 mutation carriers identified by familial screening of probands express catecholaminergic polymorphic ventricular tachycardia phenotype. 5,12 An acute event rate of 58% has been reported in a cohort which consisted of untreated asymptomatic and symptomatic RYR2 mutation carriers over 8 years of follow-up.…”

“…It is noteworthy that the same mechanism, impaired allosteric regulation, has been proposed in patients with RYR2 exon 3 deletions, which are known to be associated with cardiomyopathies and a more severe catecholaminergic polymorphic ventricular tachycardia phenotype. 3,10,15,16 Though less likely, it is possible that the patient also carried a yet unidentified hypertrophic cardiomyopathy-associated mutation which had arisen de novo. The chance of simultaneous expression of catecholaminergic polymorphic ventricular tachycardia and hypertrophic cardiomyopathy phenotypes at 8 years of age is however less than 1 in 5 million.…”