Dataset Information

Left-dominant arrhythmogenic cardiomyopathy: an association with desmoglein-2 gene mutation-a case report.

ABSTRACT:

Background

Desmosomes are specialized intercellular adhesive junctions of cardiac and epithelial cells that provide intercellular mechanical coupling through glycoproteins, one of which is desmoglein (DSG). DSG-2 mutations are frequently associated with biventricular arrhythmogenic cardiomyopathy (ACM). We report a case of left-dominant ACM in a patient who initially was misclassified as dilated cardiomyopathy (DCM).

Case summary

A 28-year-old-woman was found to have a moderately reduced left ventricular (LV) systolic function and frequent premature ventricular contractions (PVCs). Targeted genetic testing revealed a heterozygous likely pathogenic variant associated with ACM in exon 15 of the DSG-2 gene (c.3059_3062del; p.Glu1020Alafs*18). Subsequent cardiac magnetic resonance (CMR) imaging showed epicardial and mid-myocardial fatty infiltration involving multiple LV wall segments, multiple areas of mid-myocardial fibrosis/scar, regional dyskinesis involving both ventricles, and an overall reduced left ventricular ejection fraction. The patient's right ventricular (RV) cavity size and overall RV systolic function were normal. Based on the patient's frequent PVCs, family history, fibrofatty myocardial replacement in multiple LV segments, and dyskinetic motion of multiple ventricular wall segments (predominantly affecting the LV), the patient was diagnosed with left-dominant ACM.

Discussion

Identifying a likely pathogenic mutation associated with ACM in a patient with ventricular arrhythmias and a family history of sudden cardiac death increased the possibility of ACM. Subsequent CMR imaging confirmed the diagnosis of left-dominant ACM by demonstrating regional biventricular dyskinesia and a characteristic pattern of fibrofatty myocardial replacement. Our case highlights the importance of targeted genetic testing and advanced cardiac imaging in distinguishing left-dominant ACM from DCM.

SUBMITTER: Lao N

PROVIDER: S-EPMC8274644 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by fibro-fatty myocardial replacement and is clinically associated with malignant ventricular arrhythmias and sudden cardiac death. It presents a major diagnostic and therapeutic challenge due to its complex clinical presentation and multiparametric diagnostic scoring system that includes structural, histological, and electrocardiographic data. A 57-year-old man with a history of palpitation and premature ventricular contractions (PVC) experienced syncope and sustained ventricular tachycardia at a rate of 213 bpm, which was successfully rescued by synchronized cardioversion. Multiple ventricular aneurysms were found in the right ventricular free wall and the left ventricular apical regions, as well as mild biventricular systolic dysfunction, according to echocardiography and high-frequency ultrasound. The genetic analysis revealed the following desmoplakin genes, chr6-7585274-7585275, NM_004415, exon24, and c.7780delT (p.S2594Pfs*9), a heterozygous and likely pathogenic mutation, as the mutation sites in the patient and his 24-year-old daughter. During the 21-month follow-up, the patient did not experience syncope or pre-syncope symptoms while on β-blocker (bisoprolol) therapy. Among the multimodality imaging techniques of the ACM, late gadolinium enhancement on cardiac magnetic resonance (CMR) is accepted as a more objective indicator of myocardial fibrosis. Left ventricular systolic dysfunction, fibrosis on CMR, and frequent PVC are the primary and most sensitive clinical signs of desmoplakin cardiomyopathy. However, echocardiography continues to be the most commonly used imaging modality for assessing focal ventricular movement and structural abnormalities. The pathological characteristics of arrhythmogenic cardiomyopathy of the right ventricular anterior free wall and apical regions near the transducer can be better shown using high-frequency linear ultrasound with a higher resolution.

Project description:BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable heart muscle disorder that predominantly affects the right ventricle. Mutations in genes that encode components of desmosomes, the adhesive junctions that connect cardiomyocytes, are the predominant cause of ARVC. A case with novel heterozygous mutation in the LAMA2 gene is reported here. The protein encoded by LAMA2 gene is the α2 chain of laminin-211 protein, which establishes a stable relationship between the muscle fiber membrane and the extracellular matrix. We explored the potential mechanism and the relationship between the mutation and ARVC.Case presentationAt the age of 8, the patient developed syncope and palpitation after exercise. Dynamic electrocardiogram recorded continuous premature ventricular beats, and MRI showed the right ventricle was significantly enlarged and there were many localized distensions at the edge of the right ventricular wall. The patient was diagnosed with ARVC and received heart transplantation at the age of 14 due to severe heart dysfunction. The myocardial histological pathological staining revealed a large amount of fibrosis and adipose migration. Whole exome sequencing (WES) identified the heterozygous mutation in the LAMA2 gene [NM_000426.3: c.8842G > A (p.G2948S)]. This is the first report of these variants. Analysis was performed on genetic disorders to reveal splice site changes and damage to protein structure. LAMA2 p.G2948S predicted unstable protein structure and impaired function. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were established. RNA-seq and the western blot were performed on IPSC-CMs to explore the ARVC-related signaling pathway.ConclusionThis is the first case report to describe an ARVC phenotype in patients possessing a novel LAMA2 c.8842G > A (p.G2948S) mutation. Our results aid in understanding of the pathogenesis of ARVC. The molecular mechanism of LAMA2 leading to ARVC disease still needs further study.