Arrhythmogenic Right Ven t r i c u l a r C ardiomyopat hy C aus ed by a Novel Frameshift Mutation Marwan M. Refaat, MD, FHRS, FESCa,b,c,*, Paul Tang, PhDd, Nassier Harfouch, BSe, Julianne Wojciak, MSf, Pui-Yan Kwok, MD, PhDd, Melvin Scheinman, MDf KEYWORDS  Arrhythmogenic right ventricular cardiomyopathy  PKP2 gene  Syncope  Palpitations

KEY POINTS  ARVC is a rare cardiomyopathy that might be asymptomatic or symptomatic, causing palpations or syncope, and might lead to sudden cardiac death.  It is recommended that physical exertion be reduced.  It is also recommended that those with syncope and ventricular tachycardia/ventricular fibrillation have an ICD placed.  b-Blockers, antiarrhythmic drugs, and radiofrequency ablation should be used to control the ventricular arrhythmia burden in ARVC.

A middle-aged man whose brother had arrhythmogenic right ventricular cardiomyopathy (ARVC) presented for genetic evaluation because he met the 2010 Revised Task force criteria for ARVC. The patient had dilatation of his right ventricle on echocardiography and he had ventricular arrhythmias. A 12-lead electrocardiogram (ECG) of a patient with ARVC with inverted T waves (V1, V2, V3) and ventricular tachycardia (VT) with left bundle branch block morphology in the same patient are shown in Fig. 1 and two-dimensional

echocardiogram of the same patient shows right ventricular enlargement in the apical fourchamber view (Fig. 2). Our patient was found to be heterozygous for a novel frameshift mutation H91fsX94 on the exon 2 of plakophilin 2 gene (PKP2), which led to a truncated PKP2 protein.

DISCUSSION ARVC is characterized by the loss of cardiomyocytes and replacement by fibrofatty tissue. Patients with ARVC can be asymptomatic or can complain from symptoms related to palpitations

Disclosure: None. a Division of Cardiology, Department of Internal Medicine, American University of Beirut Medical Center, PO Box 11-0236, Riad el Solh, Beirut 1107.2020, Lebanon; b Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon; c Cardiac Electrophysiology, Cardiology, Department of Internal Medicine, American University of Beirut Faculty of Medicine and Medical Center, 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017, USA; d Institute for Human Genetics, University of California, San Francisco, CA, USA; e University of South Florida College of Medicine, Tampa, FL, USA; f Division of Cardiology, Department of Medicine, University of California San Francisco Medical Center, San Francisco, CA, USA * Corresponding author. Department of Internal Medicine, Division of Cardiology, American University of Beirut Medical Center, PO Box 11-0236, Riad el Solh, Beirut 1107.2020, Lebanon. E-mail address: [email protected] Card Electrophysiol Clin 8 (2016) 217–221 1877-9182/16/$ – see front matter Crown Copyright Ó 2016 Published by Elsevier Inc. All rights reserved.



Refaat et al

Fig. 1. (A) A 12-lead ECG of a patient with ARVC with inverted T waves (V1, V2, V3). (B) Ventricular tachycardia with left bundle branch block morphology in the same patient.

Arrhythmogenic Right Ventricular Cardiomyopathy

Fig. 2. Two-dimensional echocardiography of a patient with ARVC showing right ventricular enlargement in the apical four-chamber view.

from arrhythmias (that commonly precede structural changes, might be life threatening, and cause sudden cardiac death) or to right heart failure from right ventricular structural changes. ARVC occurs with an incidence of 1:2000 to 1:5000. It is mostly caused by a genetic background; however, about 50% of the time there is no familial pattern to inheritance. ARVC is seen to affect men more than women, with a ratio of about 3:1. The genetics of ARVC has been attributed in 40% to 50% of the cases to malfunction in desmosomal proteins. PKP2 is a main component of the desmosome and truncated PKP2 proteins have been shown to be associated with ARVC in the past.1–4 PKP2 is made up of two main parts: the N-terminus head region and the C-terminal armadillo repeat (arm) regions.

We identified in our patient a novel frameshift mutation H91fsX94 on the second exon. This mutation deletes four basepairs at position 268 and inserts another 16 basepairs (268_272delACAC and 268_284InsTGGTTGTAGATGATTT). It creates a frameshift at amino acid position 91, and a stop codon at position 94, and results in a truncated PKP2 protein in the head region. Previously identified mutations on the head region (first 352 amino acids of PKP2) that would also result in a truncated PKP2 in the head region are listed in Table 1. It has been shown that this head region of PKP2 is responsible for targeting to points of cell-cell adhesion at the cell membrane, whereas the arm repeat region is responsible for interacting with other desmosomal proteins, such as plakoglobin and desmoplakin, and gap junction proteins, such as connexin 43.5,6 As a linker protein and an integral component to the formation of the desmosome complex, a truncated PKP2 would result in an abnormal desmosomal complex and affect the linking of the desmoglein/desmocollin adhesion molecules (desmosomal cadherins) at the cell membrane of the intercalated disk to desmin (intermediate filament) and cytoskeletal fibers, which lead to altered myocardial biomechanical properties especially during exercise.

GENETICS One of the most common genetic mutations found in ARVC is the plakophilin-2 mutation. The PKP2 gene is responsible for the desmosomal protein plakophilin-2, which maintains cell-cell adherence. Plakophilin-2 mutations make the cell more prone to damage specifically in areas of high mechanical stress, such as the right ventricle. Knockout of the mouse PKP2 gene induced myocardial architecture instability and proved to be fatal. Some other genes also encoding desmosomal proteins were also found in ARVC cases, such as JUP (junction plakoglobin), DSP (desmoplakin), DSG2 (desmoglein-2), and DSC2 (desmocollin-2) (Table 2).2

Table 1 Closely related mutations in the PKP2 head region


Nucleotide Change

Amino Acid Change

Type of Mutation

2 1 1 2 3 3

268_272delACAC 268_284InsTGGTTGTAGATGATTT 145_148delCAGA 216insG 235C/T 534_535insCT 983_984insGG

H91fsX94 S50fsX110 Q74fsX85 R79X C179fsX190 E329fsX352

Frameshift Frameshift Frameshift Nonsense Frameshift Frameshift

Reference Our Study 1,2 2 2–4 2 3,4



Refaat et al

Table 2 Genetic mutations found in ARVC cases

Name Plakophilin-2 (PKP2) Desmoplakin (DSP) Desmoglein-2 (DSG2) Plakoglobin (JUP) Desmocollin-2 (DSC2) Transmembrane protein 43 (TMEM43) Desmin (DES) Titin (TTN) Lamin A/C (LMNA) T-catenin (CTNNA3) Phospholamban (PLN)

Chromosomal Location 12q11 6p24 18q12 17q21 18q12 3p25 2q35 2q31 1q22 10q22.2 6q22.1

Other genes include DSC1/DSC3 (desmocollin 1 and 3), PLEC1 (plectin 1), DSG1/DSG3/DSG4 (desmoglein 1, 2 and 4), PKP4 (plakophilin 4), DMPK (dystrophia myotonica protein kinase), RPSA (ribosomal protein SA), LAMR1 (laminin receptor 1), GJA1 (gap junction alpha 1), TGFb3, RyR2, PTPLA (protein tyrosine phophatase-like, member A), DES, ZASP (Z-band alternatively spliced PDZ-motif protein), and CSN6 (COP9 signalosome subunit 6 that controls ubiquitin proteolysis).

Some nondesmosomal genes that cause ARVC include transforming growth factor-b (TGFb), transmembrane protein 43 (TMEM43), desmin (DES), titin (TTN), lamin A/C (LMNA), T-catenin (CTNNA3), and phospholamban (PLN; which was described in families with Dutch ancestry).2 The PKP2 mutations may create shorter or longer versions of the protein, depending on the mutation. Once acquired, the myocardial cells usually cannot adhere to one another, displace from one another, and die as a result. As more myocardial cells in the right ventricle die, scar and fatty tissue begin to build up, limiting the myocardial contractility because of structural changes. A recessive mutation in the C-terminus of plakoglobin leads to Naxos disease, which is a cardiocutaneous syndrome (palmoplantar keratoderma, wooly hairs, and ARVC). A recessive truncation of the C-terminus of desmoplakin leads to Carvajal syndrome, which is an overlap disease of ARVC with dilated cardiomyopathy with penetrance close to 100%.

CLINICAL PRESENTATION ARVC might remain asymptomatic or might present itself as several symptoms, such as syncope, palpations, and lightheadedness, most likely in middle life (20–40 years). The ventricular arrhythmias in patients with ARVC usually have a left

bundle branch morphology. ARVC might be the first presentation of a sudden cardiac arrest. Regarding penetrance of the disease into firstdegree relatives, probands with an identified gene mutation showed a 28.9% penetrance into first-degree relatives and those without an identified gene mutation had a 20% penetrance. The ECG usually shows a delay in the depolarization of the right ventricle, which is detected by a prolonged terminal activation (S-wave) duration in V1 to V3 ECG finding in patients with ARVC.7 Another key finding that occurred in up to 87% was the inversion of the T-wave in right precordial leads in the absence of a bundle branch block (see Fig. 1).8 Epsilon waves might be identified in the ECG leads V1 to V3 and in the right precordial leads by doubling the sensitivity of the record, and use of filter setting 40 Hz (instead of 150 Hz) to lower the noise level. The bipolar Fontaine precordial electrocardiographic leads I to III may enhance the recording of epsilon waves by applying placement of the right arm electrode on the manubrium, of the left arm electrode on the xiphoid, and of the left leg lead in V4. Other notable findings are fibrofatty replacement of myocardium, dilation and reduction in right ventricular ejection fraction (see Fig. 2), and right ventricular aneurysms as a result of dilation and progressive pathology.8 In some patients, the left ventricle is involved (left dominant arrhythmogenic cardiomyopathy) and biventricular involvement might also be seen. The left and biventricle involvements may lead to left heart failure and biventricular failure, respectively, in patients with this form of ARVC. Reduced plakoglobin (g-catenin) staining on immunohistochemical analysis of conventional endomyocardial biopsy sample has been reported in myocardial samples with ARVC (sensitivity 91%, specificity 82%, positive predictive value 83%, and negative predictive value 90%).9 The diagnosis of ARVC is also helped by signal averaged ECG in patients with right VTs, cardiac MRI with late gadolinium enhancement, and voltage mapping of the right ventricle for scar detection.

RISK CLASSIFICATION AND MANAGEMENT Patients who have had cardiac arrest, hemodynamically unstable VT, or ventricular fibrillation should have an implantable cardioverterdefibrillator (ICD) placed. Asymptomatic individuals may not benefit from ICD (regardless of family history of sudden cardiac death or inducibility at electrophysiology study) and should be evaluated on a regular basis for early identification of alarming symptoms and disease progression. In

Arrhythmogenic Right Ventricular Cardiomyopathy patients with heart failure, medical therapy for ARVC includes diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blocker and digitalis, and anticoagulants. Antiarrhythmic therapy is the first-line management in patients with ARVC with hemodynamically stable ventricular arrhythmias. Sotalol, a b receptor blocker that inhibits potassium channels, was shown to benefit patients with ARVC. Amiodarone alone or with b-blocker has been reported as an alternative approach. In patients with ARVC with VT despite medical therapy or frequent VT requiring ICD shocks, radiofrequency catheter ablation of VT should be used to control the ventricular arrhythmias and reduce appropriate ICD shocks. Recently, plasma BIN1 was shown to predict arrhythmia in patients with ARVC.10 Isthmus ablation via irrigated catheters is achieved using activation mapping (if stable) or substrate mapping (if unstable or not inducible) guided by an isolated delayed component, defined as a ventricular electrogram after the QRS separated by greater than or equal to 40 milliseconds or low-amplitude signal of less than 0.1 mV. VT can recur because of the progressive nature of the disease and the epicardial location of arrhythmogenic substrate if only an endocardial mapping is pursued. One of the more common differential diagnoses for ARVC is right VT. Other conditions that are considered in the differential diagnosis of ARVC include giant cell and lymphocytic myocarditis, dilated cardiomyopathy, Brugada syndrome, cardiac sarcoidosis with confluence of noncaseating granulomas especially in the setting of AV block, Uhl anomaly, Ebstein anomaly, atrial-septal defects, right ventricular infarctions, and pulmonary hypertension.11

SUMMARY ARVC is a rare cardiomyopathy that might be asymptomatic or symptomatic, causing palpations or syncope, and might lead to sudden cardiac death. It is recommended that physical exertion be reduced. It is also recommended that those with syncope and VT/ventricular fibrillation have an ICD placed. b-Blockers, antiarrhythmic drugs, and radiofrequency ablation should be used to control the ventricular arrhythmia burden in ARVC.

REFERENCES 1. Syrris P, Ward D, Asimaki A, et al. Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy. Circulation 2006; 113(3):356–64. 2. Gerull B, Heuser A, Wichter T, et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 2004;36(11):1162–4. 3. Christensen AH, Benn M, Tybjaerg-Hansen A, et al. Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients: diseasecausing or innocent bystanders? Cardiology 2010; 115(2):148–54. 4. Christensen AH, Benn M, Bundgaard H, et al. Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy. J Med Genet 2010;47(11):736–44. 5. Chen X, Bonne S, Hatzfeld M, et al. Protein binding and functional characterization of plakophilin 2. Evidence for its diverse roles in desmosomes and beta -catenin signaling. J Biol Chem 2002;277(12): 10512–22. 6. Joshi-Mukherjee R, Coombs W, Musa H, et al. Characterization of the molecular phenotype of two arrhythmogenic right ventricular cardiomyopathy (ARVC)-related plakophilin-2 (PKP2) mutations. Heart Rhythm 2008;5(12):1715–23. 7. Nasir K, Bomma C, Tandri H, et al. Electrocardiographic features of arrhythmogenic right ventricular dysplasia/cardiomyopathy according to disease severity: a need to broaden diagnostic criteria. Circulation 2004;110(12):1527–34. 8. Quarta G, Muir A, Pantazis A, et al. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. Circulation 2011;123(23):2701–9. 9. Asimaki A, Tandri H, Huang H, et al. A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 2009;360(11):1075–84. 10. Hong TT, Cogswell R, James CA, et al. Plasma BIN1 correlates with heart failure and predicts arrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm 2012;9(6):961–7. 11. Vasaiwala SC, Finn C, Delpriore J, et al. Prospective study of cardiac sarcoid mimicking arrhythmogenic right ventricular dysplasia. J Cardiovasc Electrophysiol 2009;20(5):473–6.


Arrhythmogenic Right Ventricular Cardiomyopathy Caused by a Novel Frameshift Mutation.

Arrhythmogenic right ventricular cardiomyopathy is a rare cardiomyopathy that might be asymptomatic or symptomatic, causing palpations or syncope, and...
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