Co-phenotype of left ventricular non-compaction cardiomyopathy and atypical catecholaminergic polymorphic ventricular tachycardia in association with R169q, a ryanodine receptor type 2 missense mutation

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 Ca²⁺ imaging and [³H]ryano-dine binding analysis, indicated a gain of function: a reduced threshold for overload-induced Ca²⁺ release from the sarcoplasmic reticulum and increased fractional Ca²⁺ 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.