ARVCD Linked to Mutations of Intercellular Junction Proteins

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Among the other ARVC/D causing genes, five encode for the desmosomal proteins: plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), and democollin-2 (DSC2) [1,3-5,7,8].

These proteins are localized on the cell-cell junction and are particularly abundant in epider-midis and heart muscle, where they play an important role in cell rigidity and strength. While DSP, PKP2, DSG2, and DSC2 are predominantly linked to a form of ARVC/D transmitted with an auto-somic dominant pattern, the ARVC/D form linked to JUP has a recessive inheritance and the clinical phenotype is also characterized by hair and skin disorders [19].

Pathology involving intercellular junction proteins seems to be the most frequent in ARVC/D (41% in a series of 80 unrelated ARVC/D probands) [7]. For the first time this offers the opportunity to perform genotype-phenotype correlation in a large series of patients in an attempt to assess if different genes and/or different mutations of the same gene are linked to peculiar clinical features. Studies of families carrying different ARVC/D gene mutations provide the opportunity to evaluate the entire clinical spectrum of the disease from concealed forms to overt ones.

In a study of four families carrying a DSP mutation, Bauce et al. found 26 mutations carriers [20]. Of these, 14 (54%) fulfilled the established diagnostic criteria of ARVC/D [21], while 12 patients did not, although five of them had some cardiac abnormalities (Fig. 3.4). The clinical presentation included palpitations in six cases, sudden death in three, syncope in one. Two patients had chest pain with ECG abnormalities and increased myocardial enzymes. The coronary arteries were normal by angiography in both. No skin and hair abnormalities were found at physical examination.

Abnormal 12-lead ECG's were present in 15 (58%) of the subjects, consisting of negative T waves in the precordial leads in 12 (46%), QRS complex prolongation (>110 ms) in V1-V3 in seven (27%), incomplete right bundle branch block in five (19%), qS pattern in the inferior leads in seven (27%), low QRS voltages in the peripheral leads in five (19%), ST segment elevation (<2 mm) in four (15%), and epsilon waves in two (8%). Signal-averaged ECG showed late potentials in 11 DSP mutation carriers (42%). Ventricular arrhythmias were recorded in 12 subjects (46%), ranging from ventricular fibrillation to monomorphic sustained VT with left bundle branch block morphology to nonsustained VT and isolated monomorphic premature ventricular complexes (PVCs).

Abnormal echocardiographic findings were present in 14 (54%) DSP mutations carriers, with right ventricular involvement in 13 and left ventricular involvement in seven patients. Eight patients were treated with antiarrhythmic drugs and two received an implantable cardioverter defibril-lator (ICD). During follow-up (range 1 to 24 years, median 6 years), structural progression was detected at 2D-Echo in 23% of subjects, and by ECG/SAECG in 31. Three patients died suddenly, two had aborted SD, and one died due to heart failure. The annual disease-related and SD/aborted mortality were 0.028 and 0.023 patient/year, respectively. In conclusion, this genotype-phenotype correlation study confirmed that ARVC/D is a progressive disease and that family members sharing the same mutation can show different clinical behavior as far as timing of disease onset and pro-

Family 105

Healthy male

Heatlhy female

Affected male Affected female

Status unknown

* Mutation earner

SD Sudden death (age indicated ¡n brackets)

aSD Aborted sudden death (age indicates in brackets)

PVCs Premature ventricular complexes qS qS in Inferior leads

Fig. 3.4 • Pedigree of one family carrying a mutation of the desmoplakin gene. Subjects II-1,and III-7,who carried the DSP mutation, did not fulfil the diagnostic criteria. However, the former died suddenly while the latter showed PVCs at 24-h ambulatory ECG. Reproduced from [20] with permission from Oxford University Press gression. Moreover, ARVC/D caused by DSP mutations was found to be characterized by a high occurrence of SD as the first clinical manifestation and that left ventricular involvement is not a rare feature of the disease.

Syrris et al. published a genotype-phenotype correlation study of nine families carrying PKP2 mutations [22]. Among the 34 subjects with a PKP2 mutation, 32 had clinical evaluation and 17 (53%) were found to fulfil the ARVC/D diagnostic criteria. An additional nine presented some cardiac signs of the disease. Right ventricular structural abnormalities were present in 20 (62%), mutations carriers and abnormal ECG/SAECG features in 21 (66%).

Antoniades et al. studied 22 PKP2 carriers and 26 homozygous JUP carriers and found a similar cardiac phenotype [23]. Moreover, T-wave inversion in leads V1-V3,right ventricular wall motion abnormalities and frequent ventricular complexes were the most sensitive and specific markers for identification of mutation carriers.

The desmoglein-2 gene mutation was recently identified by Pilichou et al., who found this gene in 8 probands (5 males and 3 females). The mean age at diagnosis/symptom onset was 38±20 years with a range of 11 to 63 years [7]. The clinical data showed that the first symptom consisted of sustained VT in three patients, palpitations in three, and chest pain with increased serum markers of my-ocardial necrosis in presence of angiographically normal coronary arteries in one; the remaining patient was asymptomatic. In addition, skin and hair were normal in all. There was a significant difference in the mean age at symptom onset/diagnosis between males and females (26±13 years vs. 58±4 years, respectively, p=0.001). All patients showed ECG abnormalities, and late potentials were detected in seven subjects. Ventricular arrhythmias were recorded in all probands and ranged from isolated monomorphic PVCs, nonsustained VT, and sustained VT with left bundle-branch block morphology. Abnormal echocardiographic findings were present in all probands, with right ventricular kinetic abnormalities involving only one region in one patient and >2 regions in the remaining seven. Left ventricular involvement was present in half of the patients. Family members of the two index cases were studied and five additional subjects were found to carry a DSG2 mutation; of these, two were classified as affected.

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