Ventricular Tachycardia, Catecholaminergic Polymorphic, 1, With Or Without Atrial Dysfunction And/or Dilated Cardiomyopathy

A number sign (#) is used with this entry because catecholaminergic polymorphic ventricular tachycardia-1 (CPVT1) is caused by heterozygous mutation in the cardiac ryanodine receptor gene (RYR2; 180902) on chromosome 1q43.

Description

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disorder of the heart characterized by a reproducible form of polymorphic ventricular tachycardia induced by physical activity, stress, or catecholamine infusion, which can deteriorate into ventricular fibrillation. Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress. Typically, clinical cardiologic examinations, such as baseline ECG and echocardiogram, reveal mostly normal findings, and postmortem examinations, when carried out, have not disclosed any significant morphologic alterations in the fine structure of the heart, with the exception of mild fatty myocardial infiltration in a few patients. The hallmark of CPVT comprises ventricular arrhythmias of varying morphology not present under resting conditions but appearing only with physical exercise, excitement, or catecholamine administration. These arrhythmias are first seen as ventricular premature complexes, later in bigeminy, followed by bidirectional or polymorphic ventricular tachycardia, which eventually leads to ventricular fibrillation. CPVT can be inherited as an autosomal dominant or recessive trait. Clinical penetrance in this disease ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Beta-blockers without sympathomimetic activity are clinically effective in the reduction of syncope, but implantation of an automatic internal defibrillator is occasionally needed in these patients (summary by Bhuiyan et al., 2007).

Genetic Heterogeneity of Catecholaminergic Polymorphic Ventricular Tachycardia

CPVT2 (611938) is caused by mutation in the CASQ2 gene (114251) on chromosome 1p13; CPVT3 (614021) has been mapped to chromosome 7p22-p14; CPVT4 (614916) is caused by mutation in the CALM1 gene (114180) on chromosome 14q32; and CPVT5 (615441) is caused by mutation in the TRDN gene (603283) on chromosome 6q22.

Clinical Features

Catecholaminergic polymorphic ventricular tachycardia (CPVT) occurring in the structurally intact heart was described by Coumel et al. (1978) and by Leenhardt et al. (1995) as a distinct clinical entity with manifestations in childhood and adolescence. Affected individuals present with syncopal events and with a distinctive pattern of highly reproducible, stress-related, bidirectional ventricular tachycardia in the absence of both structural heart disease and a prolonged QT interval. A family history of juvenile sudden death and stress-induced syncope is present in approximately one-third of cases. Swan et al. (1999) described 2 unrelated Finnish families with an autosomal dominant cardiac syndrome causing stress-induced polymorphic ventricular tachycardia and syncope in the absence of structural myocardial changes (see 192605). Of 24 affected individuals, 10 had succumbed, including 6 cases of sudden death; the 14 survivors showed evidence of the disease. Exercise stress test induced ventricular bigeminy or polymorphic ventricular tachycardia in affected individuals. Three children initially examined before 10 years of age developed arrhythmias during a 4-year follow-up. Administration of flecainide did not induce electrocardiographic abnormalities of the type seen in familial idiopathic ventricular fibrillation (603829). The cumulative cardiac mortality by the age of 30 years was 31%.

Priori et al. (2002) studied 30 probands with CPVT, 14 of whom were known to have a mutation in the RYR2 gene. Nine family members were identified as RYR2 mutation carriers, 5 of whom had exercise-induced arrhythmias at clinical evaluation and 4 of whom were phenotypically silent (incomplete penetrance). Syncope occurred in 26 of 30 probands and was the first sign of disease in 16 probands. Age at first manifestation extended into adulthood (7 of 30 probands); the authors suggested that the diagnosis of CPVT should include individuals of any age with adrenergically mediated asymptomatic ventricular tachycardia occurring in a structurally intact heart.

Scoote and Williams (2004) reviewed defects in cardiomyocyte calcium homeostasis and the associated arrhythmias.

Bhuiyan et al. (2007) studied 2 families with CPVT in which, in addition to exercise-induced ventricular arrhythmias, affected individuals exhibited abnormalities in sinoatrial and atrioventricular node function, atrial fibrillation, and atrial standstill. Several affected individuals also developed left ventricular dysfunction and dilation.

Mapping

By linkage analysis, Swan et al. (1999) assigned the disease locus to 1q42-q43, with a maximum lod score of 4.74 in the 2 families combined. The 1q42-q43 region contains the KCNK1 gene (601745), which encodes a potassium channel. However, sequence analysis of the entire KCNK1 coding region identified no mutations or polymorphisms. Only 1 heterozygous carrier, aged 30 years, was unaffected, suggesting high disease penetrance in adulthood.

In a large 3-generation family segregating autosomal dominant CPVT associated with nodal dysfunction, atrial arrhythmias, and dilated cardiomyopathy, Bhuiyan et al. (2007) performed linkage analysis and identified a single locus on chromosome 1 between markers D1S2785 and D1S2850 that cosegregated with disease (2-point lod score of 4.5).

Molecular Genetics

On the basis of the typical electrocardiographic pattern in this disorder and on the hypothesis that delayed afterdepolarizations underlie the arrhythmia in this disorder, as well as the map location of the clinical phenotype, Priori et al. (2001) proposed that mutations of the cardiac ryanodine receptor gene (RYR2; 180902), which maps to 1q42-q43, may be associated with catecholaminergic polymorphic ventricular tachycardia. In studies of 12 probands presenting with bidirectional ventricular tachycardia that was reproducibly induced by exercise stress testing and/or isoproterenol infusion without structural heart abnormalities, they found 4 missense mutations (see 180902.0001-180902.0004) cosegregating with the clinical phenotype. A family history of syncope and sudden death was present in 5 of the 12 patients. All patients had a normal ECG at enrollment, normal atrioventricular conduction, and a normal QT interval. Three additional missense mutations in the RYR2 gene (see 180902.0007-180902.0009) were described by Laitinen et al. (2001): all were associated with a typical family history of stress-induced ventricular arrhythmia and sudden unexplained death.

In a large 3-generation family segregating autosomal dominant CPVT associated with nodal dysfunction, atrial arrhythmias, and dilated cardiomyopathy mapping to chromosome 1q, Bhuiyan et al. (2007) screened the coding exons of the candidate genes RYR2 and ACTN2 (102573), but found no mutations. MLPA-based fine mapping and PCR analysis identified a heterozygous 1.1-kb deletion of exon 3 and parts of introns 2 and 3 of the RYR2 gene (180902.0011). This deletion was found in all affected genotyped individuals in this family and in 2 affected sibs from a second, unrelated family with a similar phenotype.

Medeiros-Domingo et al. (2009) analyzed all 105 RYR2 exons using PCR, HPLC, and sequencing in 110 unrelated patients with a clinical diagnosis of CPVT and in 45 additional unrelated patients with an initial diagnosis of exercise-induced long QT syndrome (LQTS; see 192500) but who had a QTc of less than 480 ms and who were negative for mutation in 12 genes known to cause LQTS. The authors identified 63 putative disease-causing mutations that were not found in 400 reference alleles in 73 (47%) of the 155 patients; 13 new mutation-containing exons were identified, with two-thirds of the patients having mutations in 1 of 16 exons. Three large genomic rearrangements involving exon 3 were detected in 3 unrelated cases. Medeiros-Domingo et al. (2009) suggested that a tiered targeting strategy for CPVT would uncover approximately 65% of CPVT1-positive cases by selective analysis of just 16 exons out of the 105 exons of the RYR2 gene.