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

van Tintelen, J. Peter; Van Gelder, Isabelle C.; Asimaki, Angeliki; Suurmeijer, Albert J.H.; Wiesfeld, Ans C.P.; Jongbloed, Jan D.H.; van den Wijngaard, Arthur; Kuks, Jan B.M.; van Spaendonck-Zwarts, Karin Y.; Notermans, Nicolette; Boven, Ludolf; van den Heuvel, Freek; Veenstra-Knol, Hermine E.; Saffitz, Jeffrey E.; Hofstra, Robert M.W.; van den Berg, Maarten P.

doi:10.1016/j.hrthm.2009.07.041

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

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

J. Peter van Tintelen, MD, PhD
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Address reprint requests and correspondence: Dr. J. Peter van Tintelen, Department of Genetics, University Medical Center Groningen, University of Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands
Isabelle C. Van Gelder, MD, PhD
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
Angeliki Asimaki, PhD
- Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Albert J.H. Suurmeijer, MD, PhD
- Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Ans C.P. Wiesfeld, MD, PhD
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Jan D.H. Jongbloed, PhD
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Arthur van den Wijngaard, PhD
- Department of Clinical Genetics, University Hospital Maastricht, Maastricht, The Netherlands
Jan B.M. Kuks, MD, PhD
- Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Karin Y. van Spaendonck-Zwarts, MD
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Nicolette Notermans, MD, PhD
- Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands
Ludolf Boven, BS
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Freek van den Heuvel, MD, PhD
- Department of Pediatric Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Hermine E. Veenstra-Knol, MD
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Jeffrey E. Saffitz, MD, PhD
- Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Robert M.W. Hofstra, PhD
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Maarten P. van den Berg, MD, PhD
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Received 6 March 2009; accepted 23 July 2009. published online 29 July 2009.

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.

Keywords: Cardiomyopathy, Genetics, Heart block, Bundle branch block

Abbreviations: ARVC, arrhythmogenic right ventricular cardiomyopathy, CK, creatine phosphokinase, Cx43, connexin43, DCM, dilated cardiomyopathy, DES, desmin, PCR, polymerase chain reaction, RBBB, right bundle branch block, RCM, restrictive cardiomyopathy, RV, right ventricular