Mirroring metabolic findings from a novel gene-targeted
mouse model (R299Qγ2-AMPK knock-in) bearing the equivalent
mutation, human Arg302Gln mutation carriers have been identi-
fied to exhibit increased adiposity, greater fasting glucose, and
higher levels of glycated adult hemoglobin (HbA1c), together
with reduced estimates of pancreatic isletβ-cell function [84]. Eval-
uation of R299Q γ2-AMPK knock-in mice suggests ghrelin
signalling-dependent hyperphagia and intrinsic impairment of insu-
lin secretion as major mechanisms underlying this metabolic
phenotype [84].
There are clinical reports of rarer features occurring in associa-
tion withPRKAG2mutations although, given their infrequency,
causal inference is not clearly established for all of them. These
include epilepsy presenting with generalized tonic-clonic seizures,
frequently in conjunction with myalgia [24] and, in the case of the
infantile fatal Arg531Gln mutation, a case with macroglossia,
enlarged dysmorphic kidneys, and increased number of pancreatic
islets [26].
Reflecting the presence of extracardiac features that occur in
some patients, the term PRKAG2 syndrome or PRKAG2 disease is
increasingly used.6 Prognosis
The high prevalence of arrhythmic and myocardial complications
associated withPRKAG2mutations has been highlighted in a
recent large case series of 34 patients from nine families, with a
survival rate of 67% at age 60 years [67]. While specific indications
for ICD implantation inPRKAG2mutation carriers are unclear,
given the high incidence of progression to complete heart block
and its often abrupt onset, timely permanent pacemaker implanta-
tion—e.g., in the setting of unexplained syncope—is critical and,
arguably, represents the most important prognostic therapeutic
intervention for the disease. Given that fasciculoventricular path-
ways have been shown to represent the substrate for ventricular pre-
excitation in many patients, catheter ablation in these circumstances
carries a high risk of inducing iatrogenic AV conduction block and
precipitating the requirement for permanent pacing.7 Management
A key initial step in the clinical management ofPRKAG2disease is
its prompt identification, facilitated by a high index of clinical
suspicion in cases of unexplained familial LVH. While the pattern
of LVH evident on echocardiographic and/or CMR imaging isPRKAG2 syndrome 609