(asymmetric septal hypertrophy) (Fig.12) and can vary within
families [24, 25, 56]. Massive septal hypertrophy (44 mm thick-
ness) has been associated with myocardial infarction of the septum
in the setting of unobstructed coronary arteries and speculated to
reflect extreme blood supply-demand mismatch [78]. The use of
cardiovascular magnetic resonance in a cohort of six patients has
revealed other patterns of LVH, including asymmetric hypertrophy
involving the mid-inferolateral left ventricle [76].
Reflecting the complexity of thePRKAG2mutation-associated
phenotype, multiple reports also document the existence of other-
wise phenotypically positive mutation carriers who do not have
LVH [27, 29, 30, 65]. Whether some of these individuals with
reported normal overall LV mass may in fact express more subtle
manifestations of LVH, such as wall thickening affecting only one
or a few isolated LV segments and more reliably identified by
segmental analysis by CMR [76], or represent the impact of
genetic, epigenetic, or environmental modifiers [79] is unclear.5.6 Reported
Extracardiac Features
5.6.1 Skeletal Myopathy
Notwithstanding systemic expression ofPRKAG2across tissues
and in marked contrast to other disorders associated with cardiac
glycogen storage (e.g., Pompe or Danon disease), cardiomyopathy
is frequently the sole clinical manifestation of aPRKAG2mutation.
Initial reports of extracardiac disease involving skeletal muscle
[24, 80]—resulting in myalgia (muscle pain) or stiffness during or
after exercise and sometimes associated with proximal muscle weak-
ness, elevation in serum creatine kinase level or progression in
weakness—highlighted the potential deleterious impact of mutant
PRKAG2expression on other organ systems. Underlining their
rarity, skeletal muscle manifestations have only been described in
carriers of the Asn488Ile mutation [24] and one carrier with the
Ser548Pro variant [80]. This paucity may reflect the relatively
modest contribution ofγ2-containing complexes to total AMPK
activity in the skeletal muscle [81]. It may also indicate a lack of
systematic evaluation for skeletal muscle-related pathology (includ-
ing subclinical involvement) or an attribution of symptoms of effort
intolerance primarily to cardiac disease. Where undertaken in symp-
tomatic cases, histopathology and ultrastructural assessment of the
skeletal muscle have revealed subsarcolemmal vacuolation of some
muscle fibers with associated non-lysosomal glycogen accumula-
tion [80], although reports differ on the presence of mitochondrial
changes such as ragged red fibers [24].5.6.2 Other Features Early onset of systemic arterial hypertension has been reported in
Arg531Gly and Lys485Gln mutation carriers, the latter presenting
with hypertension at age 15 years [30, 74]. Assuming a direct link,
the mechanism(s) underlying hypertension inPRKAG2mutation
carriers are unclear but may conceivably involve perturbed AMPK-
related signalling in vascular endothelial and/or smooth muscle
cells [82] and/or reflect a renal contribution [83].
608 Arash Yavari et al.