progressive cardiac conduction system disease, cardiomyocyte gly-
cogen excess, and propensity to SCD.
Individuals bearing aPRKAG2mutation typically present with
palpitations, pre-syncope, syncope, chest pain, features of heart
failure (e.g., exertional dyspnea), or sudden death. They may also
be identified after identification of an abnormal ECG (Fig.8),
unexplained LVH or, rarely (contrasting with sarcomeric HCM)
through the presence of a cardiac murmur [55, 56]. The age of
presentation, severity of symptoms, and natural history may be
influenced by the specific mutation inherited. It has been suggested
that the course of the disease for the same mutation may have
interfamilial variability and, occasionally, even intrafamilial hetero-
geneity [24]. The overall mean age at diagnosis for all reported
mutations is ~30 years [17]. For the two most commonly reported
mutations, mean age at diagnosis ranges from 19 years (Asn488Ile
variant) to 36 years (Arg302Gln variant) [17]. Pediatric or even
antenatal (de novo) presentation has been reported in association
with a number of variants, including His383Arg [10], Arg384Thr
[25], Arg531Gly [30], and Arg531Gln [26], and has been linked
to a more severe clinical phenotype.(^1000) normal ATP LOW ATP
800
600
400
p-AMPK (% of WT baseline) 200
0
WT
Normal ATP Low ATP
γ2-mutant
∗ ∗
∗
WT γ2-mutant
WT γ2-mutant WT γ2-mutant
P-AMPK
a-AMPK
Fig. 7Ambient ATP concentration influences the impact of mutantPRKAG2on AMPK Thr172α-AMPK
phosphorylation. Panα-Thr172 phosphorylation immunoblots (upper row) and associated densitometry
(lower row) from freeze-clamped WT and TGN488Iex vivo perfused hearts under conditions of normal and
depleted ATP (Reproduced from ref.54 with permission from Wolters Kluwer Health, Inc.)
600 Arash Yavari et al.