indistinguishable from that of the more common familial sarco-
meric HCM, the identification of an isolated short PR interval
and/or frank ventricular pre-excitation pattern on ECG is a strong
diagnostic clue. However, the occurrence of shortened PR interval
on ECG in conjunction with a phenotype of HCM is not uniquely
associated with PRKAG2 syndrome. Its differential diagnosis
includes, but is not limited to, other inherited disorders including
lysosomal and/or other storage disorders. The latter include
Pompe, Anderson-Fabry, or Danon disease, in addition to primary
mitochondrial diseases with cardiac involvement (e.g., MERRF,
myoclonic epilepsy with ragged red fibers, syndrome or
MELAS—mitochondrial myopathy, encephalopathy, lactic acidosis,
and stroke-like episodes), although these frequently co-feature a
variety of prominent extracardiac symptoms and signs that aid in
their identification [17]. Ultimately, PRKAG2 genotyping is
required for a definitive diagnosis [17]. In addition to facilitating
clinical management and prognostication of the index case, positive
genetic identification enables cascade screening of at-risk family
members, both to identify (potentially subclinical) carriers for fur-
ther assessment and long-term follow-up and to provide reassur-
ance and discharge, as appropriate [85].
In certain clinical scenarios, endomyocardial biopsy (EMB) has
been used as part of the investigative workup [56, 74], typically
revealing the presence of characteristic histological features (cardi-
omyocyte hypertrophy with prominent cytosolic vacuolation, vac-
uolar and intracellular glycogen excess, and absence of significant
myocyte disarray) [13, 24]. However, given its invasive nature with
attendant procedural risks, current international guidelines on the
use of EMB recommend it to be considered in a minority of cases
where careful noninvasive assessment (including clinical assess-
ment, pedigree analysis, noninvasive cardiac imaging, and labora-
tory and molecular genetic testing) has failed to reveal the cause,
particularly if storage or infiltrative disorders are suspected or in
cases of acute unexplained heart failure [1, 86]. Notably, rare
reports describe symptomatic, genotype-positive patients without
histological evidence of cardiac glycogen excess [28, 55]. Such
observations may reflect true heterogeneity in phenotypic expres-
sion (and, by inference, the existence of glycogen-independent
disease mechanisms), allelic differences, sampling differences in
the setting of nonuniform cardiac disease involvement (as in the
case of EMB where the right interventricular septum is typically
sampled, as opposed to postmortem evaluation of the whole heart),
or variations in tissue extraction times and processing techniques.
Given the rarity ofPRKAG2mutations and the associated
challenges of conducting clinical trials for such disorders, there
are at present no evidence-based consensus statements to guide its
specific treatment; however, a recent summary of published cases
has outlined broad treatment guidelines, including suggestions on610 Arash Yavari et al.