DSP-Related Cardiomyopathy as a Distinct Clinical Entity? Emerging Evidence from an Italian Cohort
Francesca Di Lorenzo1, Enrica Marchionni2, Valentina Ferradini1
1Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Insights
Desmoplakin gene (DSP) variants are linked to a distinct cardiomyopathy. This condition presents with arrhythmias, left ventricular enlargement, and myocardial fibrosis, sometimes mimicking myocarditis.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Desmoplakin gene (DSP) variants are typically associated with Arrhythmogenic Cardiomyopathy (ACM) and Dilated Cardiomyopathy (DCM).
- These conditions are inherited in an autosomal dominant pattern.
- Understanding DSP variant impact is crucial for diagnosing and managing inherited cardiomyopathies.
Purpose of the Study:
- To analyze clinical, genetic, and imaging features of patients with DSP variants.
- To characterize the phenotype of DSP-related cardiomyopathy.
- To identify distinct clinical patterns associated with DSP gene mutations.
Main Methods:
- Retrospective analysis of 18 probands with DSP variants identified via Next Generation Sequencing (NGS).
- Collection and review of cardiological, genetic, and imaging data.
- Cardiac Magnetic Resonance Imaging (CMRI) to assess myocardial fibrosis (Late Gadolinium Enhancement).
Main Results:
- 16 heterozygous pathogenic/likely pathogenic DSP variants were identified, predominantly truncating.
- Patients presented with a mean age of 40.61 years, often asymptomatic or mildly symptomatic.
- A significant proportion experienced presumed myocarditis episodes, left ventricular enlargement, and myocardial fibrosis on CMRI.
- 61% received implantable cardioverter defibrillator (ICD) implantation.
Conclusions:
- DSP-related cardiomyopathy is a distinct clinical entity.
- Characterized by high arrhythmic burden, variable left ventricular enlargement, and myocardial fibrosis.
- Often presents with recurrent myocarditis-like episodes and subepicardial fibrosis on CMRI.
Abstract:
Variants in desmoplakin gene (DSP MIM *125647) have been usually associated with Arrhythmogenic Cardiomyopathy (ACM), or Dilated Cardiomyopathy (DCM) inherited in an autosomal dominant manner. A cohort of 18 probands, characterized as heterozygotes for DSP variants by a target Next Generation Sequencing (NGS) cardiomyopathy panel, was analyzed. Cardiological, genetic data, and imaging features were retrospectively collected. A total of 16 DSP heterozygous pathogenic or likely pathogenic variants were identified, 75% (n = 12) truncating variants, n = 2 missense variants, n = 1 splicing variant, and n = 1 duplication variant. The mean age at diagnosis was 40.61 years (IQR 31-47.25), 61% of patients being asymptomatic (n = 11, New York Heart Association (NYHA) class I) and 39% mildly symptomatic (n = 7, NYHA class II). Notably, 39% of patients (n = 7) presented with a clinical history of presumed myocarditis episodes, characterized by chest pain, myocardial enzyme release, 12-lead electrocardiogram abnormalities with normal coronary arteries, which were recurrent in 57% of cases (n = 4). About half of the patients (55%, n = 10) presented with a varied degree of left ventricular enlargement (LVE), four showing biventricular involvement. Eleven patients (61%) underwent implantable cardioverter defibrillator (ICD) implantation, with a mean age of 46.81 years (IQR 36.00-64.00). Cardiac magnetic resonance imaging (CMRI) identified in all 18 patients a delayed enhancement (DE) area consistent with left ventricular (LV) myocardial fibrosis, with a larger localization and extent in patients presenting with recurrent episodes of myocardial injury. These clinical and genetic data confirm that DSP-related cardiomyopathy may represent a distinct clinical entity characterized by a high arrhythmic burden, variable degrees of LVE, Late Gadolinium Enhancement (LGE) with subepicardial distribution and episodes of myocarditis-like picture.
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