Intellectual and Neurodevelopmental Delays in Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: Distinct Characteristics and a More Malignant Neurocardiac Phenotype.

Marked intellectual and neurodevelopmental delay (INDD) was noted in 6 unrelated patients diagnosed with RYR2-related catecholaminergic polymorphic ventricular tachycardia (CPVT) from a single center. Patients exhibited similar distinct phenotypic features not previously described. We aimed to determine the prevalence of INDD in CPVT, compare clinical characteristics between patients with CPVT with and without INDD, and investigate the possibility of a unique neurocardiac CPVT phenotype. Retrospective combined review of patients with RYR2-related CPVT diagnosed ≤18 years with and without INDD from a single center and the International Pediatric CPVT Registry. Patients with hypoxic ischemic insult were excluded unless INDD preceded injury. Among a total of 168 patients, INDD was reported in 19 (11.3% [95% CI, 7.0%-17.1%]). When compared with cases without INDD, patients with INDD exhibited distinct features including (1) younger age at onset of symptoms (median 7.0 versus 10.0 years; P=0.04); (2) higher frequency of atrial tachyarrhythmias (84.2% versus 16.3%, P<0.001); (3) atrial or ventricular tachycardia without adrenergic stimulation (81.3% versus 2.2%, P<0.001, 31.6% versus 4.5%, P=0.001 respectively); (4) cardiac structural changes or systolic dysfunction (36.8% versus 1.3%, P<0.001); and (5) higher incidence of cardiac arrest or sudden death after diagnosis (26.3% versus 2.7%, P=0.001). INDD-related RYR2 genetic variants clustered within the central and channel domains and may be specific to certain variants. This study demonstrates a wider spectrum of RYR2-related disease, with a subset associated with extracardiac manifestations. Certain RYR2 variants may lead to a neurocardiac phenotype with distinct features that are important to recognize, as these patients may be at higher risk.