Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia

Krystien V. V. Lieve, Judith M. A. Verhagen, Jinhong Wei, J. Martijn Bos, Christian van der Werf, Ferran Roses i Noguer, Grazia M. S. Mancini, Wenting Guo, Ruiwu Wang, Freek van den Heuvel, Ingrid M. E. Frohn-Mulder, Wataru Shimizu, Akihiko Nogami, Hitoshi Horigome, Jason D. Roberts, Antoine Leenhardt, Harry J. G. Crijns, Andreas C. Blank, Takeshi Aiba, Ans C. P. WiesfeldNico A. Blom, Naokata Sumitomo, Jan Till, Michael J. Ackerman, S. R. Wayne Chen, Ingrid M. B. H. van de laar, Arthur A. M. Wilde*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)220-228
Number of pages9
JournalHeart Rhythm
Issue number2
Publication statusPublished - Feb 2019


  • Catecholaminergic polymorphic ventricular tachycardia
  • RYR2
  • Supraventricular arrhythmia
  • Ventricular arrhythmia

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