cardiomyopathies, such as dilated cardiomyopathy due to muta-
tions of theLMNAgene, or cardiomyopathies associated with
hypertrophy such as that due to mutations in LAMP2 or
PRKAG2[62–64]. InPRKAG2cardiomyopathy, progression to
symptomatic AV block is a common event between the third and
fourth decades. Concurrent with AV block is loss of ventricular pre-
excitation. This is an expected event in the setting of a fasciculo-
ventricular pathway since its proximal end connects to the AV
conduction axis, usually in the bundle branches (Fig. 11).
Advanced AV block can present abruptly and represents an impor-
tant cause of SCD in patients withPRKAG2mutations. The inci-
dence of heart block and pacemaker implantation can vary
dependent upon the mutation carried. Thus, a 55% pacemaker
implantation rate has been reported for patients with the
Arg302Gln mutation, as compared to 30% of those with the
Asn488Ile mutation [17]. Notably conduction system distur-
bances—reflecting conduction delay—can occur at multiple levels,
including intra-atrial, intrahisian, infrahisian, and intraventricular.
Reflecting the latter, reports of bundle branch block, most fre-
quently complete or incomplete right bundle branch block but
also left bundle branch block or left anterior hemiblock, have been
made in association withPRKAG2mutations [27, 57, 65, 66].Fig. 10Cardiac histological findings in an individual with the Arg302GlnPRKAG2mutation. Cardiac histology
from a 52-year-old male with the Arg302Gln mutation, permanent atrial fibrillation, and LVH. Upper row
illustrates right atrial appendage sections stained with PAS (a), hematoxylin and eosin (b), and Masson
trichrome staining (c), illustrating severe cardiomyocyte vacuolization and granular inclusions consistent with
glycogen (arrows) but no significant fibrosis. Lower row demonstrates similar findings in the same patient
from the RV septum, including transmission electron microscopy (d), with ventricular cardiomyocyte vacuo-
lization, abundant glycogen accumulation (e), and, in contrast to familial HCM, a conspicuous absence of
myocardial disarray (f) (Reproduced from ref.60 with permission from Wolters Kluwer Health, Inc.)
PRKAG2 syndrome 603