Elsevier

Heart Rhythm

Volume 6, Issue 11, November 2009, Pages 1574-1583
Heart Rhythm

Clinical
Genetic
Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene

https://doi.org/10.1016/j.hrthm.2009.07.041Get rights and content

Background

Desmin-related myopathy is a clinically heterogenous group of disorders encompassing myopathies, cardiomyopathies, conduction disease, and combinations of these disorders. Mutations in the gene encoding desmin (DES), a major intermediate filament protein, can underlie this phenotype.

Objective

The purpose of this study was to investigate the clinical and pathologic characteristics of 27 patients from five families with an identical mutation in the head domain region (p.S13F) of desmin.

Methods/Results

All 27 carriers or obligate carriers of a p.S13F DES founder mutation demonstrated a fully penetrant yet variable phenotype. All patients demonstrated cardiac involvement characterized by high-grade AV block at young ages and important right ventricular (RV) involvement. RV predominance was demonstrated by the presence of right bundle branch block in 10 patients (sometimes as a first manifestation) and by RV heart failure in 6 patients, including 2 patients who fulfilled the diagnostic criteria for arrhythmogenic RV cardiomyopathy. Because of this clinical overlap with desmosome cardiomyopathies, we also studied the organization of the intercalated disks, particularly the distribution of desmosomal proteins. Normal amounts of the major desmosomal proteins were found, but the intercalated disks were more convoluted and elongated and had a zigzag appearance.

Conclusion

In this largest series to date of individuals with a single head domain DES mutation, patients show a variable yet predominantly cardiologic phenotype characterized by conduction disease at an early age and RV involvement including right bundle branch block and/or RV tachycardias and arrhythmogenic RV cardiomyopathy phenocopies. A localized effect of desmin on the structure of the cardiac intercalated disks might contribute to disease pathogenesis.

Introduction

The DES gene encodes desmin, which is a major intermediate filament protein of skeletal and cardiac muscle that provides structural and functional integrity by coordinating mechanical stress transmission, organelle positioning, organization and assembly of sarcomeres, signal transduction, and apoptosis.1 Mutations in the DES gene are associated with a variable clinical phenotype referred to as desmin-related myopathy (OMIM #601419). The clinical phenotype encompasses “isolated” myopathies, pure cardiac phenotypes (including dilated cardiomyopathy [DCM] and restrictive cardiomyopathy [RCM]), cardiac conduction disease, and combinations of these disorders.2, 3, 4, 5, 6, 7, 8, 9, 10 If both cardiologic and neurologic features occur, they can manifest in any order, as cardiologic features can precede, occur simultaneously with, or follow manifestation of generalized neuromuscular disease.

More than 40 DES mutations have been identified in 53 different index patients. The majority of mutations are located in the α-helical rod domains of the gene. Potential genotype–phenotype relationships are emerging. It has recently been suggested that mutations in the 2B segment of desmin are mainly involved in skeletal muscle disease, whereas mutations in the 1B and tail domain cause more serious cardiac disease.11

We have identified five Dutch families, two of which have recently been partially described, with a variable yet predominantly cardiologic phenotype among individuals carrying an identical missense mutation in the head domain of the DES gene.12

The aim of this study was to investigate (1) the impressive phenotypic variability in the largest series of patients with a single DES mutation that is located in the head domain (p.S13F); (2) the occurrence of right-sided myocardial involvement including arrhythmogenic right ventricular cardiomyopathy (ARVC)-like phenotypes; and (3) the effect of the p.S13F mutation on cell–junction organization.

Section snippets

Clinical evaluation

The five index patients were referred to our cardiogenetics outpatient clinic, UMC Groningen, with either a primary cardiologic phenotype (two index patients) or a neurologic phenotype associated with cardiac manifestations (three index patients). Two of the index patients were recently described.12 The index patients and their relatives underwent a regular clinical genetic counseling procedure. Patients who gave informed consent were evaluated for cardiologic and/or neurologic and genetic

Phenotypic description

Detailed clinical data of all individual DES 38C>T mutation or obligate carrier patients and those likely to be affected, including outcomes and results of previous histology, are given in Table 1. The pedigrees are shown in Figure 1. The clinical criteria for two patients who met the criteria for ARVC are given in Table 2. Results of clinical evaluation were available for 22 individuals from the five families, and limited information was available for another five patients who were obligate

Discussion

Disease-associated DES mutations are generally located in the α-helical domain of desmin, and only five mutations in the N-terminal head domain have been described to date.2, 10, 24, 25 The head domain is believed to be important for aggregation of tetramers to fibers (assembly) and for stability of the protein. Interaction with the outer cellular membrane occurs through the desmosome where desmin interacts with several proteins such as desmoplakin.1, 26 The assembly state of desmin seems to

Conclusion

This report describes the largest series to date of 27 patients with a single head domain desmin mutation. The associated phenotype is fully penetrant. Patients demonstrated a highly variable yet predominantly cardiologic clinical picture of right-sided myocardial involvement (including the diagnosis of ARVC), RBBB, and/or ventricular tachycardias originating from the RV during the early phases of the disease. Males manifested disease at an earlier age than did females. Some of the families

Acknowledgements

We thank the patients who participated in this study and our colleagues who referred patients and supplied additional information. We thank Jackie Senior (editing), Eric Hennekam (genealogy), and Marian Claessens (haplotyping) for assistance.

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