Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited, highly lethal arrhythmogenic cardiac disorder characterized by ventricular tachycardia in the absence of structural abnormalities of the heart. The mortality rate for untreated patients is 30% to 50% before 35 years of age.
| Clinical Features | CPVT commonly presents in prepubertal or adolescent years, mean age of onset being 12 years.Although, syncope triggered by exercise or acute emotion is the typical symptom of CPVT, approximately half of the patients elicit a primary clinical presentation of sudden death or aborted cardiac arrest. A family history of exercise-related syncope, seizure or sudden death is reported in 30% of the patients.
The resting electrocardiogram (ECG) of a CPVT patient is unremarkable. During graded exercise, these patients typically and consistently develop ventricular ectopic beats at a threshold rate of 100-120 beats/min, followed by progressive worsening with increasing workload. The duration of nonsustained ventricular tachycardia (VT) progressively increases with continued exercise. Bidirectional VT is a distinguishing presentation of CPVT. |
| Incidence | Estimated to be 1:10,000 |
| Genetics | To date, 5 genes are associated with CPVT. The major genes contributing to CPVT are RYR2 andCASQ2. CALM1, KCNJ2, and TRDN are regarded as minor CPVT genes |
| Inheritance | Two types of CPVT are recognized: An autosomal dominant form of CPVT due to mutations in the cardiac ryanodine receptor (RYR2), and a less common autosomal recessive form resulting from mutations in calsequestrin (CASQ2). |
| Penetrance | 60-70% |
| Disease Pathogenesis | Cardiac ryanodine receptor and calsequestrin proteins are crucial in intracellular calcium handling. Mutations in RYR2 and CASQ2 lead to uncontrolled calcium ion leakage from the sarcoplasmic reticulum to the cytosol that worsen on adrenergic stimulation increasing the susceptibility to arrhythmias. |
| Clinical Utility | Differential Diagnostics: Andersen-Tawil syndrome (LQTS type 7) caused by mutations in KCNJ2 may also demonstrate bidirectional VT Predictive testing Risk assessment in relatives Disease Management: Physical activity is restricted and avoidance of acute stress/emotions is mandatory for all mutation carriers Therapy: Since sudden death is usually the first manifestation of CPVT, mutation carriers should be treated with beta blockers |
| Indications for Molecular Testing | Comprehensive or targeted CPVT genetic testing is recommended for any patient in whom a cardiologist has established a clinical index of suspicion for CPVT based on examination of the patient’s clinical history, family history, and expressed electrocardiographic phenotype during provocative stress testing with cycle, treadmill, or catecholamine infusion. Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the CPVT– causative mutation in an index case. |
| Test Information | CASQ2 sequencing is warranted when an autosomal recessive inheritance is compatible with the clinical presentation.
Targeted sequencing of RYR2 exons most likely to harbor disease-causing mutations. Gene exons and intron/exon boundaries are analyzed subsequent to Sanger sequencing. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. Exonic or whole-gene deletions/duplications will not be detected. Additionally, a negative result does not rule out causal gene mutations as the promoter region and cryptic splicing mutations are not investigated. |
| Clinical Sensitivity | 55% |
| Turnaround Time | 4-6 weeks |
| CPT Codes | RYR2: 81408 CASQ2: 81405 |
Sample and Shipping Information
| Specimen | Whole blood drawn in lavender top (EDTA) tube in a volume of 3-5cc (Adults/Children) and 3 cc (infant |
| Shipping | Refrigerate sample until time of shipping. Ship sample at room temperature in an insulated container by overnight delivery. |
| Causes for Rejection | Frozen specimen; hemolysis; quantity not sufficient for analysis; improper container. |
References
Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013 Dec;10(12):1932-63.
Jabbari J, Jabbari R, Nielsen MW, Holst AG, Nielsen JB, Haunsø S, Tfelt-Hansen J, Svendsen JH, Olesen MS. New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia. Circ Cardiovasc Genet. 2013 Oct;6(5):481-9.
Leenhardt A, Denjoy I, Guicheney P. Catecholaminergic polymorphic ventricular tachycardia. Circ Arrhythm Electrophysiol. 2012 Oct;5(5):1044-52.
Resources
American Heart Association (AHA)
7272 Greenville Avenue
Dallas TX 75231
Phone: 800-242-8721
review.personal.info@heart.org
www.americanheart.org
Sudden Arrhythmia Death Syndromes (SADS) Foundation
508 East South Temple
Suite #20
Salt Lake City UT 84102
Phone: 800-786-7723
Toll-Free: 801-531-0937
sads@sads.org
www.sads.org