@article{e2e4cb0c68bc452a877e17f79f6e9a63,
title = "Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia",
abstract = "BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain.OBJECTIVE The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients.METHODS We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders.RESULTS Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy.CONCLUSION Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.",
keywords = "Catecholaminergic polymorphic ventricular tachycardia, RYR2, Supraventricular arrhythmia, Ventricular arrhythmia, MOLECULAR-IDENTIFICATION, RYANODINE RECEPTORS, NODE DYSFUNCTION, RELEASE CHANNEL, EXPRESSION, ARRHYTHMIA, CHILDREN, DEATH",
author = "Lieve, {Krystien V. V.} and Verhagen, {Judith M. A.} and Jinhong Wei and Bos, {J. Martijn} and {van der Werf}, Christian and {Roses i Noguer}, Ferran and Mancini, {Grazia M. S.} and Wenting Guo and Ruiwu Wang and {van den Heuvel}, Freek and Frohn-Mulder, {Ingrid M. E.} and Wataru Shimizu and Akihiko Nogami and Hitoshi Horigome and Roberts, {Jason D.} and Antoine Leenhardt and Crijns, {Harry J. G.} and Blank, {Andreas C.} and Takeshi Aiba and Wiesfeld, {Ans C. P.} and Blom, {Nico A.} and Naokata Sumitomo and Jan Till and Ackerman, {Michael J.} and Chen, {S. R. Wayne} and {van de laar}, {Ingrid M. B. H.} and Wilde, {Arthur A. M.}",
note = "Funding Information: This work was supported by a Research Grant for Cardiovascular Diseases from the Ministry of Health, Labor and Welfare, Japan (H26-040, H27-032) to Drs Shimizu and Aiba; the Libin Cardiovascular Institute of Alberta and Cumming School of Medicine Postdoctoral Fellowship Award to Dr Wei; the Alberta Innovates - Health Solutions (AIHS) Studentship Award to Wenting Guo, MSc; the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program to Dr Ackerman; the Canadian Institutes of Health Research, the Heart and Stroke Foundation Chair in Cardiovascular Research to Dr Chen; The Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation (2014T007) to Dr van de Laar; The Netherlands Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences (CVON 2012-10 PREDICT) to Dr Wilde; and E-Rare Joint Transnational Call for Proposals 2015 “Improving Diagnosis and Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: Integrating Clinical and Basic Science” to Drs Chen and Wilde. Dr Ackerman is a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St. Jude Medical. Dr Ackerman and Mayo Clinic also have an equity/royalty relationship with AliveCor, Blue Ox Health Corporation, and StemoniX. Dr Wilde is member of the scientific advisory board of LivaNovaa. However, none of these entities participated in this study in any way. All other authors have nothing to disclose. Publisher Copyright: {\textcopyright} 2018",
year = "2019",
month = feb,
doi = "10.1016/j.hrthm.2018.08.025",
language = "English",
volume = "16",
pages = "220--228",
journal = "Heart Rhythm",
issn = "1547-5271",
publisher = "Elsevier B.V.",
number = "2",
}