Alternative titles; symbols
ORPHA: 3286; DO: 0060675;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q43 | Ventricular tachycardia, catecholaminergic polymorphic, 1 | 604772 | Autosomal dominant | 3 | RYR2 | 180902 |
A number sign (#) is used with this entry because of evidence that catecholaminergic polymorphic ventricular tachycardia-1 (CPVT1) is caused by heterozygous mutation in the cardiac ryanodine receptor gene (RYR2; 180902) on chromosome 1q43.
A homozygous 344-kb tandem duplication involving the 5-prime UTR/promoter region and exons 1 through 4 of the RYR2 gene has been reported in 2 Amish families with a phenotype consistent with CPVT1; see CLINICAL FEATURES and CYTOGENETICS.
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
Also see CPVT2 (611938), caused by mutation in the CASQ2 gene (114251) on chromosome 1p13; CPVT3 (614021), caused by mutation in the TECRL gene (617242) on chromosome 4q13; CPVT4 (614916), caused by mutation in the CALM1 gene (114180) on chromosome 14q32; CPVT5 (615441) is caused by mutation in the TRDN gene (603283) on chromosome 6q22; and CPVT6 (see 618782) is caused by mutation in the CALM3 gene (114183) on chromosome 19q13.
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.
Tester et al. (2020) reported 2 large multiply consanguineous Amish families in which a phenotype consistent with CPVT1 segregated with homozygosity for a large tandem duplication involving 26,000 basepairs of intergenic sequence, the RYR2 5-prime UTR/promoter region, and exons 1 through 4 of the RYR2 gene (see CYTOGENETICS). Multiple young members experienced exercise-associated syncope, cardiac arrest, and/or sudden unexplained death. The proband of family 1, who had a normal electrocardiogram (ECG) and exercise stress test after an episode of exercise-associated syncope, died suddenly several years later at age 12 during physical exertion. She had 3 sisters who also experienced exercise-associated sudden cardiac death, at 10, 9, and 3 years of age. In another branch of the extended family, 3 sisters were affected, including 1 who died during her second cardiac arrest at age 4 years. Another sister survived documented ventricular fibrillation and cardiac arrest while swimming; follow-up evaluation showed normal echocardiogram and serial ECGs, whereas exercise stress testing revealed monomorphic ventricular ectopy that was accentuated with low-level exercise but attenuated with increasing heart rates and exertion. The third sister experienced syncope while swimming, despite having had a normal exercise stress test a few weeks before. Family 2 had more than 250 members, of whom 15 experienced exercise-associated sudden death at a young age (mean age at death, 11.7 years). In one family branch, 3 brothers and 1 sister were affected, and 1 of the brothers died at age 11 years; in another branch, 2 sisters were affected, 1 of whom died at age 6 years. A survivor of SCA in family 2 with an implantable cardioverter/defibrillator experienced 3 appropriate ventricular tachycardia/ventricular fibrillation-terminating shocks. Review of device tracings revealed premature ventricular contractions with a short coupling interval and R-on-T phenomena that triggered torsades de pointes and soon degenerated into ventricular fibrillation. The authors noted that the phenotype did not appear to be distinct from autosomal dominant RYR2-mediated CPVT.
Clinical Variability
Rampazzo et al. (1995) performed studies in a large 4-generation Italian family with what they designated as a 'concealed' form of arrhythmogenic right ventricular dysplasia (ARVD; see 107970) mapping to 1q43; affected members showed no change in heart size and had normal standard ECG and functional capacity, but consistently showed effort-induced polymorphic ventricular tachycardias. Juvenile sudden death had occurred in 4 members. Postmortem examination of 2 of these subjects showed a right ventricle of normal size, with no overt abnormalities. However, large areas of fatty-fibrous replacement, mostly localized in the subepicardial layer of the right ventricle, were demonstrated histologically.
Bauce et al. (2000) restudied the large Italian family (family 102) originally described by Rampazzo et al. (1995) and reported another 3-generation Italian family (family 115) with exercise-induced polymorphic ventricular arrhythmias mapping to 1q43. Sudden death had occurred in the second and third decades of life in patients from both families. Bauce et al. (2000) noted that these families exhibited a novel, localized form of ARVD, and stated that the clinical findings differed from those previously reported in other ARVD families. ECGs did not show the typical features of ARVD, such as incomplete right bundle branch block or negative T waves in the right precordial leads, and late potentials were rarely present. Cardiac imaging showed normal or only slightly increased right ventricular (RV) volume, and global RV function was normal. Parietal wall abnormalities were predominantly observed at the RV apex and subtricuspid region, although in 3 cases, left ventricular apical akinesia or dyskinesia was also present. The trabecular architecture was always involved. At autopsy, which was performed in 3 patients, myocardial fibrofatty replacement was segmental and mostly involved the RV apex. The authors noted that the ventricular arrhythmias observed in affected individuals from the 2 families showed some unusual features: the coupling interval of the initial premature beat was never short, because the first premature beat occurred after the end of the T wave; and the QRS morphology was polymorphic in both the frontal and horizontal planes, with right and left bundle branch block patterns and superior or inferior axis deviation, suggesting that the arrhythmias originated from different areas of the ventricle. The QT interval and QT dispersion were normal at rest and during exercise. The authors concluded that altered myocardial automaticity triggered by adrenergic stimulation during exercise was the most likely cause of arrhythmias.
Karmouch et al. (2018) stated that the observed phenotype in the Italian families with mutations in the RYR2 gene reported by Rampazzo et al. (1995) and Bauce et al. (2000) was catecholamine-induced ventricular tachycardia rather than arrhythmogenic cardiomyopathy.
Reviews
Scoote and Williams (2004) reviewed defects in cardiomyocyte calcium homeostasis and the associated arrhythmias.
Priori et al. (2001) reported autosomal dominant inheritance of CPVT1.
Using a CA repeat polymorphism within the ACTN2 (102573) gene in a study of an Italian family (family 102) with exercise-induced polymorphic ventricular tachycardias, Rampazzo et al. (1995) demonstrated linkage of the disorder to 1q42-q43. They obtained a lod score of 4.02 at theta = 0.0, assuming 95% penetrance, and a lod score of 3.32 at theta = 0.0 when 70% penetrance was assumed. The family also showed significantly positive lod scores for markers flanking the ACTN2 gene.
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).
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 heterozygous 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 4 unrelated Italian families segregating autosomal dominant exercise-induced ventricular arrhythmias, including the families (102 and 115) studied by Rampazzo et al. (1995) and Bauce et al. (2000), Tiso et al. (2001) refined the physical mapping of the critical disease-associated region, excluded ACTN2 and nidogen (NID; 131390) as candidate genes, and identified heterozygous missense mutations in the RYR2 gene (see, e.g., 180902.0005-180902.0006). In myocardial cells, the RYR2 protein, activated by Ca(2+), induces the release of calcium from the sarcoplasmic reticulum into the cytosol. The identified RYR2 mutations occurred in 2 highly conserved regions and segregated fully with disease in each family.
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.
In affected members of 2 large multiply consanguineous Amish families with exercise-associated syncope, cardiac arrest, and/or sudden unexplained death, Tester et al. (2020) identified homozygosity for a 344-kb tandem duplication (chr1:237,205,452-237,519,546, GRCh38) including approximately 26,000 bp of intergenic sequence, the 5-prime UTR/promoter region of the RYR2 gene, and exons 1 through 4 of RYR2. The duplication segregated fully with disease in both families. Although a common ancestor was not identified despite pedigree expansion over several generations, the authors stated that the duplication likely represents a founder mutation in the Amish community.
Using CPVT patient-specific induced pluripotent stem cell-derived cardiac muscle (iPSC-CM) cell lines carrying different RYR2 mutations, Polonen et al. (2018) evaluated the antiarrhythmic efficacy of carvedilol and flecainide. Adrenaline induced arrhythmias in all CPVT iPSC-CM cell lines examined, but it abolished arrhythmias in control cells. Both carvedilol and flecainide were equally effective in treating arrhythmias, as both drugs lowered intracellular Ca(2+) level and beating rate of cardiomyocytes significantly in all CPVT iPSC-CM cell lines. However, flecainide caused abnormal Ca(2+) transients in 61% of control cells compared with 26% of those treated with carvedilol. CPVT cardiomyocytes carrying the exon 3 deletion (180902.0011) had the most severe Ca(2+) abnormalities, but they had the best response to drug therapies.
Bauce, B., Nava, A., Rampazzo, A., Daliento, L., Muriago, M., Basso, C., Thiene, G., Danieli, G. A. Familial effort polymorphic ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy map to chromosome 1q42-q43. Am. J. Cardiol. 85: 573-579, 2000. [PubMed: 11078270] [Full Text: https://doi.org/10.1016/s0002-9149(99)00814-0]
Bhuiyan, Z. A., van den Berg, M. P., van Tintelen, J. P., Bink-Boelkens, M. T. E., Wiesfeld, A. C. P., Alders, M., Postma, A. V., van Langen, I., Mannens, M. M. A. M., Wilde, A. A. M. Expanding spectrum of human RYR2-related disease: new electrocardiographic, structural, and genetic features. Circulation 116: 1569-1576, 2007. [PubMed: 17875969] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.711606]
Coumel, P., Fidelle, J., Lucet, V., Attuel, P., Bouvrain, Y. Catecholaminergic-induced severe ventricular arrhythmias with Adams-Stokes syndrome in children: report of four cases. Brit. Heart J. 40 (suppl.): 28-37, 1978.
Karmouch, J., Protonotarios, A., Syrris, P. Genetic basis of arrhythmogenic cardiomyopathy. Curr. Opin. Cardiol. 33: 276-281, 2018. [PubMed: 29543670] [Full Text: https://doi.org/10.1097/HCO.0000000000000509]
Laitinen, P. J., Brown, K. M., Piippo, K., Swan, H., Devaney, J. M., Brahmbhatt, B., Donarum, E. A., Marino, M., Tiso, N., Viitasalo, M., Toivonen, L., Stephan, D. A., Kontula, K. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation 103: 485-490, 2001. [PubMed: 11157710] [Full Text: https://doi.org/10.1161/01.cir.103.4.485]
Leenhardt, A., Lucet, V., Denjoy, I., Grau, F., Ngoc, D. D., Coumel, P. Catecholaminergic polymorphic ventricular tachycardia in children: a 7-year follow-up of 21 patients. Circulation 91: 1512-1519, 1995. [PubMed: 7867192] [Full Text: https://doi.org/10.1161/01.cir.91.5.1512]
Medeiros-Domingo, A., Bhuiyan, Z. A., Tester, D. J., Hofman, N., Bikker, H., van Tintelen, J. P., Mannens, M. M. A. M., Wilde, A. A. M., Ackerman, M. J. The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome. J. Am. Coll. Cardiol. 54: 2065-2074, 2009. [PubMed: 19926015] [Full Text: https://doi.org/10.1016/j.jacc.2009.08.022]
Polonen, R. P., Penttinen, K., Swan, H., Aalto-Setala, K. Antiarrhythmic effects of carvedilol and flecainide in cardiomyocytes derived from catecholaminergic polymorphic ventricular tachycardia patients. Stem Cells Int. 2018: 9109503, 2018. [PubMed: 29760739] [Full Text: https://doi.org/10.1155/2018/9109503]
Priori, S. G., Napolitano, C., Memmi, M., Colombi, B., Drago, F., Gasparini, M., DeSimone, L., Coltorti, F., Bloise, R., Keegan, R., Cruz Filho, F. E. S., Vignati, G., Benatar, A., DeLogu, A. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 106: 69-74, 2002. [PubMed: 12093772] [Full Text: https://doi.org/10.1161/01.cir.0000020013.73106.d8]
Priori, S. G., Napolitano, C., Tiso, N., Memmi, M., Vignati, G., Bloise, R., Sorrentino, V., Danieli, G. A. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 103: 196-200, 2001. [PubMed: 11208676] [Full Text: https://doi.org/10.1161/01.cir.103.2.196]
Rampazzo, A., Nava, A., Erne, P., Eberhard, M., Vian, E., Slomp, P., Tiso, N., Thiene, G., Danieli, G. A. A new locus for arrhythmogenic right ventricular cardiomyopathy (ARVD2) maps to chromosome 1q42-q43. Hum. Molec. Genet. 4: 2151-2154, 1995. [PubMed: 8589694] [Full Text: https://doi.org/10.1093/hmg/4.11.2151]
Scoote, M., Williams, A. J. Myocardial calcium signalling and arrhythmia pathogenesis. Biochem. Biophys. Res. Commun. 322: 1286-1309, 2004. [PubMed: 15336976] [Full Text: https://doi.org/10.1016/j.bbrc.2004.08.034]
Swan, H., Piippo, K., Viitasalo, M., Heikkila, P., Paavonen, T., Kainulainen, K., Kere, J., Keto, P., Kontula, K., Toivonen, L. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J. Am. Coll. Cardiol. 34: 2035-2042, 1999. [PubMed: 10588221] [Full Text: https://doi.org/10.1016/s0735-1097(99)00461-1]
Tester, D. J., Bombei, H. M., Fitzgerald, K. K., Giudicessi, J. R., Pitel, B. A., Thorland, E. C., Russell, B. G., Hamrick, S. K., Kim, C. S. J., Haglund-Turnquist, C. M., Johnsrude, C. L., Atkins, D. L., Ochoa Nunez, L. A., Law, I., Temple, J., Ackerman, M. J. Identification of a novel homozygous multi-exon duplication in RYR2 among children with exertion-related unexplained sudden deaths in the Amish community. JAMA Cardiol. 5: 13-18, 2020. [PubMed: 31913406] [Full Text: https://doi.org/10.1001/jamacardio.2019.5400]
Tiso, N., Stephan, D. A., Nava, A., Bagattin, A., Devaney, J. M., Stanchi, F., Larderet, G., Brahmbhatt, B., Brown, K., Bauce, B., Muriago, M., Basso, C., Thiene, G., Danieli, G. A., Rampazzo, A. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum. Molec. Genet. 10: 189-194, 2001. [PubMed: 11159936] [Full Text: https://doi.org/10.1093/hmg/10.3.189]
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