Arrhythmogenic cardiomyopathy (AC) is characterized by fibrofatty infiltration of the right ventricle. AC is now recognized as a genetically determined heart muscle disease that extends across the entire heart due to the frequent and early finding of left ventricular wall involvement and the occurrence of a predominantly left sided variant of the disease. AC accounts for nearly 20% of sudden cardiac death (SCD) cases, being a prominent cause of SCD among young athletes.
| Clinical Features | AC manifests during adolescence and young adulthood.Conventionally, AC progresses in 4 phases –
Accordingly, symptoms range from palpitations to syncope and sudden cardiac death. A history of syncope represents an important prognostic event for AC. Heart failure occurs in a minority of patients. However, heart failure is a predominant cause of death in those protected by implantable cardioverter defibrillator (ICD) implantation |
| Incidence | 1:2000 to 1:5000 in the general population Familial in 30% – 50% of AC cases |
| Genetics | Plakophilin (PKP2)- Individuals with mutations in PKP2 present at younger ages and are more likely to have malignant arrhythmias Desmoplakin (DSP)- Also causes Carvajal syndrome, a familial cardiocutaneous syndrome consisting of woolly hair, palmoplantar keratoderma, and heart disease Desmoglein 2 (DSG2) Desmocollin 2 (DSC2) Plakoglobin (JUP)- Causes Naxos disease in which there is co-segregation of cardiac (AC), skin (palmoplantar keratosis) and hair (wooly hair) abnormalities Transmembrane protein 43 (TMEM43)- Mutations are highly lethal and fully penetrant |
| Inheritance | Autosomal dominant for all of the above, except JUP. Autosomal recessive inheritance is seen in Naxos disease (JUP) and Carvajal syndrome (DSP) |
| Penetrance | Incomplete (20% – 50%) with variable expression |
| Disease Pathogenesis | The genes implicated in AC are components of specialized cell-cell adhesion structures called desmosomes. Mutations in these components compromise the desmosomal integrity in tissues subjected to high mechanical stress, such as the heart and skin. Under conditions of mechanical stress, myocytes detach at the intercalated discs leading to progressive myocyte degeneration and death. This is subsequently repaired by fibrofatty replacement. An alternative molecular mechanism implicates the inhibition of the canonical Wnt/β-catenin signaling through Tcf/Lef transcription factors in the pathogenesis of AC. |
| Clinical Utility | Early diagnosis Phenotype prediction Arrhythmia risk stratification Timely therapeutic interventions with β-blockers and/or ICD to prevent sudden death |
| Indications for Molecular Testing | Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the AC- causative mutation in an index case Comprehensive or targeted (DSC2, DSG2, DSP, JUP, PKP2 and TMEM43) AC genetic testing can be useful for patients satisfying task force diagnostic criteria for AC. Genetic testing may be considered for patients with possible AC (1 major or 2 minor criteria) Genetic testing is not recommended for patients with only a single minor criterion |
| Test Information | Molecular analysis of PKP2, DSP, DSG2, DSC2, JUP and TMEM43 genes is available for patients who have a confident diagnosis of AC. A significant proportion of individuals with AC may have more than one potentially pathogenic variant across these genes.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 | 30% – 40% |
| Turnaround time | 6-8 weeks |
| CPT Codes | PKP2 – 81406 DSG2 – 81406 DSP – 81406 DSC2 – 81406 JUP – 81406 TMEM43 – 81406 |
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
Sen-Chowdhry S, Syrris P, Ward D, Asimaki A, Sevdalis E, McKenna WJ. Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression. Circulation. 2007;115:1710–20.
Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, Frigo G, Vettori A, Valente M, Towbin J, Thiene G, Danieli GA, Rampazzo A. Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation. 2006;113:1171–9.
Hamid MS, Norman M, Quraishi A, Firoozi S, Thaman R, Gimeno JR, Sachdev B, Rowland E, Elliott PM, McKenna WJ. Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria. J Am Coll Cardiol. 2002;40:1445–50
McKenna WJ, Thiene G, Nava A, Fontaliran F, Blomstrom-Lundqvist C, Fontaine G, Camerini F. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J. 1994;71:215–8
Marcus FI, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL, Malergue C, Grosgogeat Y. Right ventricular dysplasia: a report of 24 adult cases. Circulation. 1982;65:384–98
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
ARVD Patient Registry
The Johns Hopkins Hospital
600 North Wolfe Street
Carnegie 592
Baltimore MD 21287
Phone: 410-502-7161
Fax: 410-502-9148
ctichnell@jhmi.edu
ARVD Patient Registry
North American ARVD Registry
1501 North Campbell
Room 5153
PO Box 245037
Tucson AZ 85724-5037
Phone: 520-626-1416
Fax: 520-626-4333
kgear@email.arizona.edu
fmarcus@shc.arizona.edu
www.arvd.org