Transgenic Mice Overexpressing Mutant PRKAG2 Define the Cause of Wolff-Parkinson-White Syndrome in Glycogen Storage Cardiomyopathy

Abstract

Background-Mutations in the ␥ 2 subunit (PRKAG2) of AMP-activated protein kinase produce an unusual human cardiomyopathy characterized by ventricular hypertrophy and electrophysiological abnormalities: Wolff-ParkinsonWhite syndrome (WPW) and progressive degenerative conduction system disease. Pathological examinations of affected human hearts reveal vacuoles containing amylopectin, a glycogen-related substance. Methods and Results-To elucidate the mechanism by which PRKAG2 mutations produce hypertrophy with electrophysiological abnormalities, we constructed transgenic mice overexpressing the PRKAG2 cDNA with or without a missense N488I human mutation. Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction. Electrophysiological testing demonstrated alternative atrioventricular conduction pathways consistent with WPW. Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes. These anomalous microscopic atrioventricular connections, rather than morphologically distinct bypass tracts, appeared to provide the anatomic substrate for ventricular preexcitation. Conclusions-Our data establish PRKAG2 mutations as a glycogen storage cardiomyopathy, provide an anatomic explanation for electrophysiological findings, and implicate disruption of the annulus fibrosis by glycogen-engorged myocytes as the cause of preexcitation in Pompe, Danon, and other glycogen storage diseases.

Pompe disease diagnosis and management guideline

“…The mechanism of accelerated atrioventricular conduction in Pompe disease may be related to the insulator effect of glycogen in conduction tissue40,41 however glycogen accumulation can also result in a short PR in association with other models of glycogen storage 42. True Wolf-Parkinson-White syndrome has been reported to occur in Pompe disease43 as well, though a coincidental occurrence can not be ruled out.…”

Postmortem Findings and Clinical Correlates in Individuals with Infantile-Onset Pompe Disease

“…Several longterm survivors have experienced arrhythmias (McDowell et al 2008;Prater et al 2012), and we propose that cardiac conduction is affected by glycogen accumulation within the conduction system. Glycogen accumulation in the cardiac conduction system is present in glycogen storage disease type III and in the mouse model for PRKAG2-caused hypertrophic cardiomyopathy (Austin et al 2012;Arad et al 2003). Persistence of glycogen in cardiac conduction tissue, despite ERT, suggests poor penetration and a potential cardiac cause for sudden death in cases 1 and 3.…”

Danon disease presenting with dilated cardiomyopathy and a complex phenotype

“…WPW appears rare in cardiomyopathies due to mutations in cytoskeletal or sarcomeric genes. The origin of pre-excitation in Danon disease is unknown, but the analogy with PRKAG2 may implicate disruption of the annulus fibrosus by glycogen-engorged myocytes, as observed in mouse models (Arad et al 2003).…”