Knowledge on rare diseases and orphan drugs

The prevalence of catecholaminergic polymorphic ventricular tachycardia (CPVT) is estimated to be 1/10,000. Both sexes are equally affected.

Typical age of onset of CPVT is between 7 and 15 years of age. Exercise- or emotion-induced syncopal spells are frequently the first symptom. In a subset of patients (10-20%), the disease is clinically silent, presenting only in the event of sudden death. Up to one third of CPVT patients experience life-threatening arrhythmic events prior to starting treatment. The typical arrhythmias of CPVT are bidirectional VT, and, less frequently, supraventricular tachycardias.

The disorder is genetically heterogeneous; in 70% of cases, the cardiac ryanodine receptor (RYR2, 1q43) gene is implicated with autosomal dominant inheritance. Mutations in the cardiac calsequestrin gene (CASQ2, 1p13.1) cause an autosomal recessive form of CPVT in 2% to 5% of patients, and in rare instances may cause autosomal dominant CPVT. Other, rarer genes causing CPVT include Trans-2,3-enoyl-CoA reductase-like (TECRL, 4q13.1), calmodulin-1 (CALM1, 14q32.11), and cardiac triadin (TRDN, 6q22.31).

Subjects with a family history of CPVT, or emotion- or exercise-induced sudden death or syncope should undergo exercise stress test and Holter monitoring. Given the reproducibility of arrhythmias, graded exercise stress test is of utmost diagnostic importance. Holter monitoring is also indicated for the rarer cases where acute emotion represents a more powerful trigger. Resting electrocardiogram is usually unremarkable. Cardiac imaging (echocardiogram and MRI) is unremarkable.

The principal differential diagnoses are long QT syndrome (LQTS), arrhythmogenic right ventricular cardiomyopathy (ARVC), and Andersen-Tawil syndrome.

Antenatal diagnosis can be performed in families with high penetrance and a highly lethal mutation.

Screening for the RYR2 mutation and CASQ2 mutation is indicated in all patients with confirmed or suspected CPVT. Screening forTECRL, CALM1, and TRDN mutations may be considered as a second-line analysis. According to the mutation identified, the appropriate genetic counseling should be offered to affected families.

Lifestyle changes such as limitation of physical activity, avoidance of strong emotion and stressful environments should be recommended to all CPVT patients. Beta blockers (BB; particularly nadolol) are the first treatment option for patients with CPVT and the maximum tolerated dose should be administered to control arrhythmias. Flecainide, a sodium channel blocker, can be considered in patients with BB-resistant arrhythmias. Implantable cardioverter defibrillator (ICD) is recommended in CPVT patients who survived a cardiac arrest, and in those experiencing recurrent syncope or breakthrough arrhythmias despite compliance to an optimal medical treatment.

Although CPVT is a severe disease with high mortality if untreated, early diagnosis and adequate treatment can greatly increase life expectancy. Lifestyle modifications along with optimal medical therapy and ICD implantation in patients with recurrent symptoms portends a favorable prognosis.

Last update: January 2021 - Expert reviewer(s): Pr Silvia PRIORI