DiagnosisClinical DiagnosisThe clinical presentation of catecholaminergic polymorphic ventricular tachycardia (CPVT) includes the following main features: Exercise-induced polymorphic ventricular arrhythmias ECG during a graded exercise (exercise stress test) allows ventricular arrhythmias to be reproducibly elicited in the majority of affected individuals. Typically, the onset of ventricular arrhythmias is 100-120 beats/min. With increase in workload, the complexity of arrhythmias progressively increases from isolated premature beats to bigeminy and runs of non-sustained ventricular tachycardia (VT). If the affected individual continues exercising, the duration of the runs of VT progressively increases and VT may become sustained. An alternating 180°-QRS axis on a beat-to-beat basis, so-called bidirectional VT, is often the distinguishing presentation of CPVT-related arrhythmias. Some individuals with CPVT may also present with irregular polymorphic VT without a "stable" QRS vector alternans [Swan et al 1999, Priori et al 2002]. Exercise-induced supraventricular arrhythmias are common [Leenhardt et al 1995, Fisher et al 1999]. Syncope occurring during physical activity or acute emotion; mean onset age seven to nine years. Less frequently, first manifestations may occur later in life; individuals with first event up to age 40 years are reported. History of exercise or emotion-related palpitations and dizziness in some individuals Absence of structural cardiac abnormalities Note: The resting ECG of individuals with CPVT is usually normal, although some authors have reported a lower-than-normal resting heart rate [Postma et al 2005] and others have observed a high incidence of prominent U waves [Leenhardt et al 1995, Aizawa et al 2006]. Overall these features are inconstant and not sufficiently specific to allow diagnosis. Therefore, in many instances, the origin of the syncope may be erroneously attributed to a neurologic disorder. The exercise stress test is the single most important diagnostic test. In the authors' series, the mean time interval to diagnosis after the first symptom was 2±0.8 years [Priori et al 2002]. Molecular Genetic TestingGenes. The three genes in which mutations are known to cause CPVT are: RYR2 (autosomal dominant), encoding the cardiac ryanodine receptor channel [Laitinen et al 2001, Priori et al 2001b]; CASQ2 (autosomal recessive), encoding calsequestrin, a calcium buffering protein of the sarcoplasmic reticulum (SR) [Lahat et al 2001]. TRDN (autosomal recessive), encoding triadin, a CASQ2 and RyR2 partner protein that regulates sarcoplasmic reticulum calcium release [Roux-Buisson et al 2012].Evidence for further locus heterogeneity. Because causative mutations are identified in only approximately 55%-65% of individuals with CPVT, it is likely that other genes (loci) contribute to disease pathogenesis; no additional loci have been mapped to date. ANKB. A mutation in ANKB, the gene encoding ankyrin-B, was reported in a single individual with polymorphic ventricular tachycardia similar to CPVT [Mohler et al 2004]. The role of ANKB mutations in causation of CPVT has yet to be elucidated.KCNJ2. Some authors have claimed that KCNJ2 mutations responsible for Andersen-Tawil syndrome (ATS) may also cause CPVT; however, ATS is a distinct disorder (see Differential Diagnosis).Clinical testing RYR2Sequence analysis/mutation scanning of select exons. Most RYR2 mutations seen in CPVT appear to cluster in specific regions of the gene: codons 2200-2500 (FKBP12.6 binding domain) or starting from codon 3700 (Ca²⁺ binding domain and transmembrane domain [C-terminus]). Therefore, some laboratories sequence only those exons encompassing these critical regions; however, a recent analysis showed that 24% of mutations occur outside such “canonical” clusters. TRDNTRDN mutations have been identified in two families: one 4-bp deletion, one nonsense mutation and one missense mutation.Table 1. Summary of Molecular Genetic Testing Used in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)View in own windowGene SymbolProportion of All CPVT ^{1Test MethodMutations DetectedTest AvailabilityRYR250%-55% 2Select exons 3: sequence analysis / mutation scanning 4Sequence variants in select exons 5, 6ClinicalEntire coding region: sequence analysis 7 Sequence variants 5Deletion / duplication analysis 8Unknown 9TRDNUnknownEntire coding region: sequence analysis / mutation scanning 4Sequence variants 5Research testingCASQ21%-2%Sequence analysis Sequence variants 5ClinicalDeletion / duplication analysis 8Unknown; none detected 101. In individuals meeting diagnostic criteria (see Clinical Diagnosis)2. Priori et al [2002]3. Exons analyzed and detection rates may vary between laboratories.4. Sequence analysis and mutation scanning of the entire gene can have higher mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.6. Sequence analysis of select exons has an average lower yield than does screening of the entire coding sequence. 7. Priori & Chen [2011]. Mutation detection frequency (i.e., the sensitivity of the test method to detect a mutation) is greater than 95%.8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.9. Large genomic rearrangements have been reported [Marjamaa et al 2009, Medeiros-Domingo et al 2009].10. No deletions or duplications of CASQ2 have been reported to cause isolated catecholaminergic polymorphic ventricular tachycardia. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)Interpretation of test results. Sequence analysis cannot detect deletions, duplications, or exonic or multiexonic skipping. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. Molecular genetic testing is indicated in individuals with CPVT: Single gene testingUnless the family history strongly suggests an autosomal recessive pattern of transmission, a proband with CPVT should be tested first for mutations in RYR2 either: By sequence analysis of select exons followed by sequence analysis of the entire coding region if an RYR2 mutation is not identified
orBy sequence analysis of the entire coding region.Non-consanguineous parents of normal phenotype may harbor heterozygous CASQ2 or TRDN [Roux-Buisson et al 2012] mutations. They may have a compound heterozygous, clinically affected baby [di Barletta et al 2006]. Therefore, molecular genetic testing for mutations in CASQ2 and TRND may be indicated if no mutations in RYR2 are detected. If a mutation in RYR2 is not identified in an individual with CVPT who represents a simplex case (i.e., the only affected person in the family) or if the family history is consistent with autosomal recessive inheritance, sequence analysis of CASQ2 is performed.Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having CPVT is use of a multi-gene panel. The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest. . See Differential Diagnosis.Molecular genetic testing may be indicated in individuals who do not have CPVT but have findings (or have a relative with findings) that could be related to CPVT, including the following:Idiopathic ventricular fibrillation, which may be caused by CPVTFamily members of individuals with sudden unexplained death occurring during acute stress [Priori & Chen 2011]. Note: The yield of the analysis in these cases is unknown (and probably low). SIDS (sudden infant death syndrome), which has been associated with mutations in RYR2 [Tester et al 2007]. However, it is unclear whether systematic RYR2 screening is indicated and cost effective for this population [Ackerman et al 2011]. Carrier testing for relatives at risk for autosomal recessive CASQ2-related CPVT requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for autosomal recessive CASQ2-related CPVT and are not at risk of developing the disorder. The risk for heterozygous carriers of TRND mutations is currently unknown. Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation(s) in the proband.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the proband.Genetically Related (Allelic) DisordersAlthough some have suggested that arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) may be caused by RYR2 mutations in a few cases (designated ARVC2) that present with mild or "concealed" right ventricular myocardium abnormalities [Tiso et al 2001], these observations have not been confirmed by others. Thus, the clinical relevance of this possible association is as yet unknown. No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in TRDN.}

Natural HistoryCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by cardiac electrical instability exacerbated by acute activation of the adrenergic nervous system. If untreated the disease is highly lethal since approximately 30% of those affected experience at least one cardiac arrest and up 80% one or more syncopal spells. Two clinical studies [Leenhardt et al 1995, Priori et al 2002] have contributed to the understanding of the natural history of CPVT. The main clinical manifestation of CPVT is episodic syncope occurring during exercise or acute emotion. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery occurs when these arrhythmias self-terminate. In other instances, ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. Of note: As there is no structural abnormality of the myocardium, several individuals have tolerated the arrhythmias rather well, with only mild symptoms such as dizziness or lypothymia. If such symptoms reproducibly recur during exercise, further clinical investigations for CPVT may be indicated. CPVT is a cause of "idiopathic" ventricular fibrillation in previously asymptomatic individuals (no history of syncope or dizziness) who die suddenly during exercise or while experiencing acute emotions. Growing evidence shows that sudden cardiac death can be the first manifestation of CPVT caused by RYR2 mutations [Priori et al 2002, Krahn et al 2005]. The mean age of onset of CPVT is between age seven and nine years [Leenhardt et al 1995, Priori et al 2002, Postma et al 2005]; onset as late as the fourth decade of life has been reported.Instances of SIDS (sudden infant death syndrome) have been associated with mutations in RYR2 [Tester et al 2007]. Others have suggested that RYR2 mutations may underlie near-drowning or drowning, especially after the exclusion of the diagnosis of long QT syndrome type 1 (see Romano-Ward syndrome) [Choi et al 2004].Family history of sudden death in relatives under age 40 years is present in approximately 30% of probands with CPVT [Priori et al 2002].

Genotype-Phenotype CorrelationsAvailable evidence suggests that the clinical features of CASQ2- and RYR2-related CPVT are virtually identical. Lahat et al [2001] reported a mild QT interval prolongation in their initial paper; however, this was not confirmed in subsequent reports [Postma et al 2002].At present no data support a role for genotype in risk stratification and management. Usually CASQ2 mutations appear more severe and more resistant to beta-blockers. Priori et al [2002] and Lehnart et al [2004] reported genotype-phenotype correlations by comparing the clinical characteristics of affected individuals with and without RYR2 mutations. These data show the following: The natural history of the disease does not appear to differ when affected individuals with and without RYR2 mutations are compared. The average age of onset of the disease in both study groups (i.e., age of the first syncope) is seven to nine years. The mutation-specific clinical course of CPVT was analyzed by Lehnart et al [2004], who did not find a significant difference in mortality rates or pattern of arrhythmias among a small cohort of individuals with the RYR2 mutations p.Pro2328Ser, p.Gln4201Arg, and p.Val4653Phe.

Differential DiagnosisMulti-gene panels may include testing for a number of the genes associated with disorders discussed in this section. Given the absence of structural cardiac abnormalities, individuals presenting with cardiac arrest could be misclassified as having "idiopathic ventricular fibrillation" [Priori et al 2001a]. Therefore, if a careful analysis of the factors triggering ventricular fibrillation in an otherwise healthy individual indicates a possible causative role for adrenergic stimuli (e.g., cardiac arrest occurring in the setting of acute stresses such as fear or anger), catecholaminergic polymorphic ventricular tachycardia (CPVT) should be considered in the differential diagnosis. (See Testing Strategy.) Cardiac evaluation (including an exercise stress test to unmask CPVT arrhythmias) of relatives of persons dying a sudden cardiac death may reveal the underlying disease and identify asymptomatic family members at risk for cardiac events [Tan et al 2005]. The yield of genetic testing in relatives is yet to be established. However, it is justified to consider the diagnosis of CPVT (and to consider genetic testing) in cases of sudden cardiac death or aborted cardiac arrest occurring during acute stress. (See Testing Strategy.)The presence/absence of structural abnormalities of the right ventricle (right ventricle enlargement, fibro-fatty infiltrations) must be evaluated in all individuals with RYR2 mutations in order to exclude the presence of a rare variant and “atypical” form of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVDC2) allelic to RYR2-related CPVT (see Genetically Related Disorders). Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) presents with structural abnormalities (dilatation, increased fibrosis/fat, micro-aneurysms) of the right ventricle. Typical ARVC is caused by mutations in genes that code for desmosomal proteins. RYR2 mutations have been found in few (<5) families labeled as ARVC. However, in all cases the structural abnormalities were atypical and very mild. This raises the unresolved question of whether RYR2-ARVC is a real clinical entity or an incorrect classification of some families with CPVT who have unspecific abnormalities of the right ventricle.Short-coupled ventricular tachycardia (SC-TdP) is a clinical entity presenting with life-threatening polymorphic ventricular arrhythmias resembling in part the pattern of arrhythmias observed in individuals with CPVT. SC-TdP presents with polymorphic VT occurring in the setting of a structurally normal heart and in the absence of any overt baseline electrocardiographic abnormality. However, the onset of SC-TdP is not clearly related to adrenergic stimuli (exercise or emotion) and is not associated with the typical bidirectional pattern of CPVT-related tachycardia. Distinguishing between the two disorders is important as there is no known effective therapy for SC-TdP, whereas CPVT usually responds to beta-blocking agents. Exercise-related syncope is also typically found in the LQT1 variant of long QT syndrome. Since incomplete penetrance is possible in LQT1, some individuals may have a normal QT interval and may therefore appear to have the typical CPVT clinical presentation (exercise-related syncope and normal ECG). However, individuals with LQT1 do not usually show any inducible arrhythmia during graded exercise (exercise stress test). The initial description of CPVT by Philippe Coumel included cases with borderline or mildly prolonged QT interval. For this reason it has been suggested that an overlap phenotype (LQTS-CPVT) is possible. This hypothesis has not been thoroughly investigated.A possible parallelism between CPVT and Andersen-Tawil syndrome (ATS), an inherited arrhythmogenic disorder caused by mutations in KCNJ2, has been reported. ATS is characterized by cardiac (QT prolongation, prominent U waves) and extra-cardiac features (distinctive facial features, periodic paralysis). The authors and others [Postma et al 2006, Tester et al 2006] have observed that some individuals with ATS may develop bidirectional VT similar to that of CPVT. However, ATS is to be considered as a distinct disorder with manifestations that may overlap with CVPT in rare instances. In ATS the presence of extracardiac manifestations, the low or absent risk of sudden death, and the lack of a direct relationship of arrhythmias to adrenergic activation distinguish it from CPVT.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Autosomal dominant CPVTAutosomal recessive CPVT

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT), the following evaluations are recommended:Resting ECG Holter monitoring as arrhythmias develop when heart rate increases Exercise stress test both for diagnosis and monitoring of therapy Echocardiogram to evaluate for structural defectsNote: Although the association between RYR2 mutations and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) has not been conclusively established, cardiac echo and/or nuclear magnetic resonance may be indicated to assess structural abnormalities in the right ventricle. Treatment of ManifestationsBeta-blockers are the only therapeutic choice of proven efficacy for about 60% of individuals with CPVT [Leenhardt et al 1995, Priori et al 2002]. Beta-blockers antagonize the effect of catecholamines by reducing heart rate and by a direct electrophysiologic effect at the myocyte level. The proposed mechanism of action on an individual with CPVT is inhibition of adrenergic-dependent triggered activity. Chronic treatment with full-dose beta-blocking agents prevents recurrence of syncope in the majority of individuals. The reproducible induction of arrhythmia during exercise allows effective dose titration and monitoring. Recommended drugs are nadolol (1-2.5 mg/kg/day) or propranolol (2-4 mg/kg/day), because of long-standing experience with their use in inherited arrhythmogenic diseases; however, other compounds may be equally effective. No data or controlled studies are available to suggest which beta-blocker is more effective. The above-mentioned doses are those most widely used; however, the dose of beta-blockers should always be individualized, if possible, until arrhythmias are not inducible on exercise stress testing. It is important to note that efficacy needs to be periodically retested [Heidbuchel et al 2006] (see Surveillance).Recent clinical [van der Werf et al 2011] and experimental [Liu et al 2011] data suggest that to improve arrhythmia control, flecainide can be given along with beta-blockers to persons who are not responsive to beta-blockers alone (i.e., persons who have recurrence of syncope or complex arrhythmias during exercise).Implantable cardioverter defibrillator (ICD). Although beta-blockers have been reported to be highly effective [Postma et al 2005], an implantable cardioverter defibrillator (ICD) may become necessary for secondary prevention of recurrent cardiac arrest. Furthermore, in those individuals in whom the highest tolerated dose of beta-blockers fails to adequately control arrhythmias [Priori et al 2002, Sumitomo et al 2003], an ICD can be considered for primary prevention of cardiac arrest/sudden death [Zipes et al 2006]. Whenever possible pharmacologic therapy should be maintained/optimized even in individuals with ICD in order to reduce the probability of ICD firing. Prevention of Primary ManifestationsBeta-blockers are indicated for primary prevention in all clinically affected individuals (see Treatment of Manifestations). Although no quantitative data on actual risk for cardiac arrest as the first manifestation of the disease are available, this treatment is probably also indicated for individuals with an RYR2 mutation and no history of cardiac events (syncope) or no ventricular arrhythmias on exercise stress testing. Recommended drugs are nadolol (1-2.5 mg/kg/day) or propranolol (2-4 mg/kg/day). For symptomatic individuals with CPVT, the maximum tolerated dosage should be maintained. Prevention of Secondary ComplicationsSecondary complications are mainly related to therapy.Beta-blockers could worsen allergic asthma. Therefore, cardiac-specific beta-blocker, metoprolol, could be indicated in some individuals with CPVT who have a history of asthma.For persons with an ICD, anticoagulation to prevent formation of thrombi may be necessary (particularly in children who require looping of the right ventricular catheter). SurveillanceRegular follow-up visits every six to 12 months (depending on the severity of clinical manifestations) are required in order to monitor therapy efficacy. These visits should include the following:Resting ECG Exercise stress test, performed at the maximal age-predicted heart rate. For individuals on beta-blocker therapy (in whom maximal heart rate cannot be reached), the test should be performed at least at the highest tolerated workload. Holter monitoring Agents/Circumstances to AvoidCompetitive sports and other strenuous exercise are always contraindicated. All individuals showing exercise-induced arrhythmias should avoid physical activity, with the exception of light training for those individuals showing good suppression of arrhythmias on exercise stress testing while on therapy. It is important to note that efficacy needs to be periodically retested [Heidbuchel et al 2006]. A single case report highlighted the possible proarrhythmic effect of an insulin tolerance test (ITT), driven by severe hypokalemia and adrenergic activation secondary to the metabolic imbalance induced by the test [Binder et al 2004].Evaluation of Relatives at RiskBecause treatment and surveillance are available to reduce morbidity and mortality, first-degree relatives should be offered clinical work up and molecular genetic testing if the family-specific mutation is known. If the family-specific mutation is not known, all first-degree relatives of an affected individual should be evaluated with resting ECG, Holter monitoring, and – most importantly – exercise stress testing. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Beta-blockers (preferentially nadolol or propranolol) should be administered throughout pregnancy in affected women. Therapies Under InvestigationA clinical trial is ongoing to test for the effectiveness and safety of flecainide in CPVT (NCT01117454). Left cardiac sympathetic denervation (LCSD). The direct pathophysiologic role of sympathetic activation could support surgical removal of sympathetic nerves to the heart (i.e., LCSD). LCSD reduces the amount of catecholamines released in the heart when the sympathetic nervous system is activated. Of course this intervention does not affect circulating catecholamines. Recently Wilde et al [2008] demonstrated that LCSD was effective in three patients whose symptoms were not adequately controlled by beta-blockers. This approach may also be considered for individuals with intractable arrhythmic storms in order to reduce the number of ICD shocks. Additional pharmacologic treatments. Additional pharmacologic treatment has been proposed for CPVT, but in the past failures with sodium channel blockers [Leenhardt et al 1995, Sumitomo et al 2003] and amiodarone [Leenhardt et al 1995] have been reported. Other authors have reported partial effectiveness with verapamil [Sumitomo et al 2003, Swan et al 2005]. However, these reports remain anecdotal and have not been independently confirmed. Furthermore, the effect of chronic treatment with high doses of beta-blockers and calcium antagonists on cardiac contractility in children is not known. At present, calcium antagonists cannot be considered an alternative for persons unresponsive to ICDs. Recently Watanabe et al [2009] demonstrated that flecainide prevents arrhythmias in a mouse model of CPVT. Furthermore, flecainide completely prevented CPVT in two persons who were previously highly symptomatic on conventional drug therapy. These data have been recently confirmed and the underlying mechanism explained [Liu et al 2011, van der Werf et al 2011].JTV519 (also known as K201) is an experimental drug that stabilizes the ryanodine receptor and has proven to be effective in vitro in counteracting the RyR2 channel instability caused by some CPVT-causing mutations [Lehnart et al 2004]. However, experimental data obtained in a CPVT mouse model do not support a significant antiarrhythmic effect with this drug [Liu et al 2006].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Catecholaminergic Polymorphic Ventricular Tachycardia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDRYR21q43Ryanodine receptor 2Gene Connection for the Heart - Ryanodyne receptor mutation database
RYR2 homepage - Mendelian genesRYR2CASQ21p13​.1Calsequestrin-2Gene Connection for the Heart - Inherited Arrythmias database
CASQ2 homepage - Mendelian genesCASQ2TRDN6q22​.31TriadinTRDN homepage - Leiden Muscular Dystrophy pagesTRDNCALM114q32​.11Calmodulin CALM1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Catecholaminergic Polymorphic Ventricular Tachycardia (View All in OMIM) View in own window 114180CALMODULIN 1; CALM1 114251CALSEQUESTRIN 2; CASQ2 180902RYANODINE RECEPTOR 2; RYR2 603283TRIADIN; TRDN 604772VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 1, WITH OR WITHOUT ATRIAL DYSFUNCTION AND/OR DILATED CARDIOMYOPATHY; CPVT1 611938VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 2; CPVT2 614916VENTRICULAR TACHYCARDIA, CATECHOLAMINERGIC POLYMORPHIC, 4; CPVT4Molecular Genetic PathogenesisRYR2, CASQ2, and TRDN are involved in the same intracellular metabolic pathway, devoted to the control of intracellular calcium fluxes and the cytosolic free Ca²⁺ concentration. The RYR2 mutations found in individuals with catecholaminergic polymorphic ventricular tachycardia (CPVT) have been shown to cause Ca²⁺ “leakage” from the sarcoplasmic reticulum (SR) in conditions of sympathetic (catecholamine) activation [Jiang et al 2002, George et al 2003, Wehrens et al 2003]. The consequent abnormal increase of the cytosolic free Ca²⁺ concentration creates an electrically unstable substrate. In a CPVT knock-in mouse model [Cerrone et al 2005, Liu et al 2006], it has been clearly shown that the pathogenesis of arrhythmias in CPVT is related to the onset of delayed after depolarizations (DADs) and triggered activity. Furthermore, cardiac cells isolated from mice with a mutation orthologous to the human p.Arg4497Cys (a typical and relatively common CPVT-causing mutation) present DAD also at baseline, suggesting that RyR2 function is also altered in the unstimulated setting.In vitro expression of CASQ2 mutations has consistently shown an enhanced responsiveness of RyR2s to luminal Ca²⁺, which in turn leads to the generation of extrasystolic spontaneous Ca²⁺ transients, DADs, and arrhythmogenic action potentials. This effect may be the result of altered Ca²⁺ buffering capacity of the calsequestrin polymer or to impaired CASQ2-RyR2 interaction [Viatchenko-Karpinski et al 2004, di Barletta et al 2006].Expression of the human TRDN p.Thr59Arg in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed by in vivo expression of the mutant in triadin knock-out mice by viral transduction. The loss of triadin protein is likely to lead to the loss of control of RyR2 opening by CASQ2 (luminal calcium sensor). However, direct functional studies are lacking.RYR2 Normal allelic variants. The RYR2 coding region encompasses 14901 nucleotides on 104 exons. Pathologic allelic variants. To date more than 150 RYR2 pathologic allelic variants causing CPVT have been reported [Priori & Chen 2011]. The majority of mutations appear to cluster in three regions of the predicted RyR2 protein topology: an FKBP12.6-(an RyR regulatory protein) binding region (mid portion, intracytoplasmatic loop), a calcium-binding domain, and the transmembrane domain (C-terminus). However, a recent analysis showed that 24% of mutations occur outside such “canonical” clusters. Thus, complete sequencing of the coding region and flanking intronic regions is often needed [Priori & Chen 2011]. No mutation hot spots have been reported to date. See Table 2.Table 2. Selected RYR2 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.6982C>Tp.Pro2328SerNM_001035​.2
NP_001026​.2c.12602A>Gp.Gln4201Argc.13489C>Tp.Arg4497Cysc.13957G>Tp.Val4653PheSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. The ryanodine receptor (RyR2) is the main Ca²⁺-releasing channel of the SR in the heart [George et al 2003]. It plays a central role in the so-called “calcium-induced calcium release” process that couples the electrical activation with the contraction phase of the cardiac myocytes. Following the Ca²⁺ entry through the voltage-gated channels of the plasmalemma, the ryanodine receptor releases the Ca²⁺ ions stored in the SR that are required for contraction of the muscle fibers. Abnormal gene product. The calcium concentration gradient between the SR (in the mM range) and cytosol (in the nanomolar range) is remarkable. Thus, when RyR2 channels open, the Ca²⁺ ions may flow easily along their concentration gradient. Every condition that destabilizes the RyR2 structure may cause uncontrolled flux since the electrochemical calcium gradient is high. In vitro studies have shown that defective RyR2 proteins lose the capability to finely control the calcium release process upon adrenergic (catecholamine) stimulation. The presence of an abnormal RyR2 basal activity (i.e., Ca²⁺ leakage in unstimulated conditions) and an altered RyR2 binding with its regulatory subunit, FKBP12.6, has also been postulated, but experimental data are contradictory. More recently the “store overload-induced calcium release” hypothesis has been put forth by Jiang et al [2004] and Jiang et al [2005]. According to their model, the effect of RYR2 mutations would be to reduce the amount of Ca²⁺ in the SR required to determine spontaneous spillover. George et al [2006] demonstrated that ryanodine receptor mutations may alter the domain-domain interactions with consequent “unzipping” of the channel leading to RyR2 hyperactivation or hypersensitization. Finally, increased sensitivity (increased open probability at a given calcium concentration) to luminal or cytosolic calcium has been reported [Priori & Chen 2011]. CASQ2 Normal allelic variants. The CASQ2 coding regions encompass 1197 nucleotides and 11 exons. Pathologic allelic variants. Fifteen CASQ2 mutations, all of which cause the clinical phenotype in homozygous or compound heterozygous forms, have been associated with CPVT. The latter occur in non-consanguineous parents [di Barletta et al 2006]. Heterozygotes for one CASQ2 mutation are usually healthy. See Table 3.Table 3. Selected CASQ2 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.62delAp.Glu21Glyfs*15NM_001232​.3
NP_001223​.2c.97C>Tp.Arg33*c.919G>Cp.Asp307HisSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. CASQ2 encodes for the cardiac isoform of calsequestrin, calsequestrin-2, an SR protein functionally and physically related to the ryanodine receptor. CASQ2 protein forms polymers at the level of the terminal cisternae of the SR in close proximity to the ryanodine receptor; its function is that of buffering the Ca²⁺ ions. Abnormal gene product. Only one CASQ2 mutation has been functionally characterized in vitro. The available data suggest that the pathophysiology of CASQ2-related CPVT may be related to the following mechanisms: loss of polymerization of CASQ monomeres, loss of calcium buffering capability, and indirect destabilization of the RyR channel opening process. TRDNNormal allelic variants. The TRDN isoform 1 coding regions encompass 2190 nucleotides and 41 exons. Pathologic allelic variants. Three TRDN mutations, all of which cause the clinical phenotype in homozygous or compound heterozygous forms, have been associated with CPVT. See Table 4.Table 4. TRDN Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.53_56delACAGp.Asp18Alafs*14JN900469
CCDS55053​.1c.176C>G ^{1p.Thr59Argc.613C>T 1p.Gln205*See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. These variants have been found in the same patient, who was compound heterozygous.Normal gene product. TRDN, on chromosome 6, encodes triadin (OMIM 603283), an SR protein functionally and physically related to the ryanodine receptor. Lack of triadin is associated with a reduction of CASQ2 protein levels and ultrastructural abnormalities of the T tubules similar to those observed in the CASQ2 knock out. This affects the calcium release process and, more specifically, results in a calcium leak during diastole similar to that observed for RYR2 mutants.Abnormal gene product. Mutations in TRDN found in persons with CPVT (in 2 families) have been associated with a reduction of protein expression. Although functional studies are lacking it is possible that the loss of TRDN leads to an indirect destabilization of the RyR2 channel opening process similar to that observed for CASQ2 mutations.}