Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients

• Published in: Journal of medical genetics 2005-11, Vol.42 (11), p.863-870
• Main Authors: Postma, A V, Denjoy, I, Kamblock, J, Alders, M, Lupoglazoff, J-M, Vaksmann, G, Dubosq-Bidot, L, Sebillon, P, Mannens, M M A M, Guicheney, P, Wilde, A A M
• Format: Article
• Language: English
• Subjects: Adolescent; Age; Amino Acid Sequence; arrhythmia; Biological and medical sciences; Bradycardia - genetics; calsequestrin 2; Cardiac arrhythmia; Cardiac dysrhythmias; Cardiology. Vascular system; CASQ2; catecholaminergic polymorphic ventricular tachycardia; Catecholamines - metabolism; CCD; central core disease; Child; Child, Preschool; Chromosomes; CPVT; ECG; electrocardiogram; Electrocardiography; Families & family life; Female; Gender; General aspects. Genetic counseling; genetics; Genotype & phenotype; Heart; Humans; ICD; implantable cardioverter defibrillator; Letter to JMG; Male; Medical genetics; Medical sciences; Middle Aged; Molecular Sequence Data; Mortality; Mutation; Polymorphism, Genetic; premature ventricular contraction; Proteins; PVC; ryanodine receptor; Ryanodine Receptor Calcium Release Channel - genetics; ryanodine type 2 receptor; RYR2; sarcoplasmic reticulum; Sequence Homology, Amino Acid; sino-atrial; syncope; Syncope - genetics; tachycardia; Tachycardia - genetics; Tachycardia, Ventricular - genetics
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2004.028993

Background: The aim of the study was to assess underlying genetic cause(s), clinical features, and response to therapy in catecholaminergic polymorphic ventricular tachycardia (CPVT) probands. Methods and results: We identified 13 missense mutations in the cardiac ryanodine receptor (RYR2) in 12 probands with CPVT. Twelve were new, of which two are de novo mutations. A further 11 patients were silent gene carriers, suggesting that some mutations are associated with low penetrance. A marked resting sinus bradycardia off drugs was observed in all carriers. On β blocker treatment, 98% of the RYR2 mutation carriers remained symptom free with a median follow up of 2 (range: 2–37) years. Conclusion: CPVT patients with RYR2 mutation have bradycardia regardless of the site of the mutation, which could direct molecular diagnosis in (young) patients without structural heart disease presenting with syncopal events and a slow heart rate but with normal QTc at resting ECG. Treatment with β blockers has been very effective in our CPVT patients during initial or short term follow up. Given the risk of sudden death and the efficacy of β blocker therapy, the identification of large numbers of RYR2 mutations thus calls for genetic screening, early diagnosis, and subsequent preventive strategies.