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Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic cardiomyopathy characterized by fibrofatty replacement of right, and sometimes left, ventricular myocardium and electrical inestability associated with ventricular tachycardia. It is one of the commonest causes of sudden cardiac death in the young.
Conversely, a benign course has been observed in many patients with ARVC/D suggesting a spectrum of clinical profiles and prognoses. The classic description of the disease presents the end stage of a process where the myocardium, mainly of the right ventricle, has been substituted by fibrofatty tissue.
Thus the early stages of the disease with subtle morphologic signs and symptoms are often missed and its diagnosis is often a challenge for the clinician.
Moreover, it has been described interfamilial and intrafamilial variability, ranging from benign to malignant forms with a high risk of sudden cardiac death. The mode of inheritance is mostly autosomal dominant with incomplete penetrance, but also recessive forms, like Carvajal syndrome a Naxos disease, have been described.
Over the past decade, the understanding of the disease has increased dramatically along with delination of the genetic basis and characteristic features on diagnostic imaging of ARVC/D. With the recent publication of a proposed modification of the Task Force criteria, a new frontier is open in the ARVC/D diagnosis.
In this article a cohort of 42 consecutive index cases with a typical form of ARVC/D was investigated at the Department of Cardiothoracic and Vascular Sciences of the University of Padua, Italy.
The study protocol included: physical examination, family history, 12-lead electrocardiogram (ECG), signal-averaged ECG, 24-hour Holter ECG and 2-dimensional echocardiogram. Diagnosis was made according to the past Task Force criteria. Moreover, family members of these 42 subjects were also analyzed using the same clinical protocol. The index case patients were screened for mutations in PKP2, DSP, DSG2, DSC2, JUP, and TGF3 genes by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing.
A control group of 250 healthy and unrelated subjects (500 alleles) from the Italian population was used to exclude that the detected mutations were DNA polymorphisms. Among these 42 unrelated ARVC/D index cases, 7 (16.6%) carried a PKP2 mutation, 5 (11.9%) a DSP mutation, 4 (9.5%) a DSG2 mutation, 2 (4.8%) a DSC2 mutation, and 2 (4.8%) a TGF3 mutation. No one carried JUP mutations. A potential disease causing mutation was found in 38% of the cases.
Overall, 3 index cases (7.1%) carried multiple mutations in the same gene or in different genes. Family screening identified an additional 7 multiple-mutation carriers. Among the 7 double heterozygotes for mutations in different genes, 2 were clinically unaffected, 2 were affected, and 3 showed some clinical signs of ARVC/D even if they did not fulfill the diagnostic criteria.
Two compound heterozygotes for mutations in the same gene and 1 subject carrying 3 different mutations showed a severe form of the disease with heart failure onset at a young age. Moreover, multiple-mutation carriers showed a higher prevalence of left ventricular involvement (P=.025) than single-mutation carriers.
The authors conclude that the occurrence of compound and double heterozygotes in ARVC/D index cases is particularly relevant to mutation screening strategy and to genetic counseling. Even if multiple-mutation carriers show a wide variability in clinical expression, the extent of the disease is higher compared to that in single-mutation carriers.
Critical review of the article suggests us to focus our attention on three important aspects:
We know that in medicine no single test is able to provide a definite diagnosis in any disease. In inherited cardiomyopathies a correct diagnosis requires the integration of clinical, morphological and familial studies, together with the genetic tests.
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