Publication

Abstract : Abnormalities of desmosomes, more specifically mutations in the desmoplakin (DSP) gene, have been shown to cause not only arrhythmogenic right ventricular cardiomyopathy (ARVC) but also sick sinus syndrome (SSS) as well. Although various ARVC overlap syndromes have been described, its association with sinus node dysfunction is not documented. In this report, we describe an autosomal dominant missense mutation in the DSP gene in a proband with sick sinus syndrome and features of ARVC on cardiac MRI. Clinical case – A 70 year old man presented with a recurrent episodes of syncope, that were historically suggestive of an arrhythmic etiology. He had a history of systemic hypertension which was under adequate control with ACE inhibitors. His 2D Echocardiogram (ECHO) revealed a structurally normal heart. During his evaluation of syncope, his baseline electrocardiogram (ECG), head up tilt test, brain imaging, and electroencephalography were non-contributory. Cardiac MRI(CMR) examination was performed with 1.5-T MR Imager using a dedicated cardiac phase array coil. It revealed focal out-pouching in the right ventricular free wall that did not satisfy the major ARVD Task Force Criteria. The LV wall morphology and function was normal. No obvious late enhancement was noted. As extended 24 hour and 7 day ECG Holter monitoring also did not reveal any abnormalities, an implantable loop recorder was implanted. This revealed multiple sinus pauses (longest pause of 3.2 seconds) suggestive of sick sinus syndrome. The patient underwent a dual chamber implantable cardioverter defibrillator, and is doing well on follow up. In view of CMR findings suggestive of ARVC ,whole exome sequencing was done and it revealed a missense substitution affecting desmoplakin (DSP) gene on chromosome 6p24.3, previously described as ARVD8. Family screening – As shown in Figure 1, the entire family of the proband (I,1) was screened for both features of ARVD and sinus node dysfunction. All children of the proband were asymptomatic at the time of screening. An ECG, 2D ECHO, Exercise testing, CMR , as well as genetic screening was performed. All children were carriers for the same missense mutation (ARVD8) on the DSP gene. In one of the sons (II,1) of the proband, CMR revealed RV dilation and dyskinesia of the anterior right ventricular free wall, suggestive of ARVD. There were no features of sinus node dysfunction in any of the children of the proband. Conclusion – Autosomal dominant missense mutations on the desmoplakin (DSP) gene can cause a potential overlap syndrome of ARVC and sick sinus syndrome. Patients with this mutation are may be at higher risk for both cardiac conduction abnormalities and life-threatening ventricular arrhythmias, and hence both CMR and genetic screening are crucial in their risk stratification