association with atrial fibrillation has also been reported in one case
series as the most frequent cause of death [24].
The prevalence of atrial tachyarrhythmia (specifically atrial
fibrillation and/or atrial flutter) progressively increases with age
and, based on some patient series, may exceed 80% by ~50 years
of age [57]. The incidence of atrial fibrillation is much higher in
PRKAG2mutation carriers than in patients with otherwise spo-
radic isolated Wolff-Parkinson-White syndrome [58]. It has been
suggested that in the absence of significant atrial fibrosis, atrial
hypertrophy in conjunction with ion channel dysfunction [59]—
either through a direct modulatory effect on channel function or
due to an acidic pH resulting from substantial intracellular glyco-
gen accumulation—may in part explain the strong susceptibility to
atrial fibrillation (Fig.10)[ 60].5.2.2 Sinus Bradycardia
and Chronotropic
Incompetence
Individuals bearing a mutantPRKAG2gene, particularly those
with the Arg302Gln variant, may develop progressive, symptomatic
sinus bradycardia, often with resting heart rates below 40 beats per
minute. Bradycardia during infancy or fetal development appears to
be rare but has been reported prenatally with both the Arg531Gln
and Arg384Thr mutations and may prompt urgent Caesarean sec-
tion [25, 26]. In adult mutation carriers, the true incidence of sinus
node disease may be underestimated given the large proportion
who develop concomitant AV conduction block and undergo pace-
maker implantation before potential symptoms arising from sinus
bradycardia become manifest [17]. A further manifestation of sinus
node disease inPRKAG2cardiomyopathy is an inadequate heart
rate increment on exercise (chronotropic incompetence). The latter
can be associated with exercise limitation and may symptomati-
cally benefit from pacemaker implantation [12, 24].5.2.3 Atrioventricular
Conduction Abnormalities
AV conduction disturbances of primary genetic origin, despite
being increasingly recognized in a number of conditions, are still
considered rare. Atrioventricular conduction block may occur as a
single abnormality, such as in Lene`gre’s disease caused by a muta-
tion in the sodium channelSCN5A[61], or in association withFig. 9Atrial fibrillation with extremely rapid ventricular conduction associated withPRKAG2cardiomyopathy.
Rhythm strip of the same patient as in Fig.8 demonstrating atrial fibrillation with a very rapid ventricular rate
of ~280 beats/min. The patient died suddenly several months after this ECG was obtained
602 Arash Yavari et al.