Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) [I45.8]

OMIM numbers: 604772180902 (RYR2)114251 (CASQ2) 

Dr. rer. nat. Christoph Marschall

Scientific Background

CPVT is a disorder of the structurally sound heart muscle with an autosomal dominant inheritance pattern and an incidence of 1:10,000. The adrenergic-induced arrhythmias manifest at the average age of 8. Bidirectional or polymorphic ventricular tachycardia is typical. Untreated, in 60% of all cases CPVT leads to syncopes before the age of 40 and in 30–50% of cases to sudden cardiac death before the age of 30. The resting ECG appears normal. The earlier syncopes occur, the worse the prognosis. Therapy is based on beta blockers. However, approx. 30% of all patients remain symptomatic and need an implantable cardioverter defibrillator.

Causative mutations in the ryanodine receptor 2 gene (RYR2) can be identified in 40-70% of CPVT patients. The RYR2 gene codes for the cardiac ryanodine receptor which is the most important Ca2+ releasing channel of the sarcoplasmic reticulum (SR). It plays a decisive role in the activation of cardiomyocytes. Mutations in the calsequestrin gene (CASQ2) are rarer. They can be detected in about 3–5% of patients and lead to an autosomal recessive inherited type of CPVT. Mutations in both genes result in a Ca2+ leakage of the SR. Similar to the mutations in the RYR1 gene which are the cause of malignant hyperthermia, the mutations in the RYR2 gene are more often located at the carboxy-terminal end. More than 40% of mutations are detected in the region of codon 4000–5000. A stepwise diagnostic procedure is recommended (Medeiros-Domingo et al. 2009), as mutations associated with CPVT seem to occur especially cumulatively at the highly conserved transmembrane segment (amino acid 4400–4959).