PRKAG2 Cardiac Syndrome: A Comprehensive Review of Clinical Manifestations, Pathophysiological Mechanisms, and Precision Medicine Frontiers

PRKAG2 cardiac syndrome (PCS) is a metabolic storage cardiomyopathy caused by pathogenic variants in the PRKAG2 gene encoding the γ2-subunit of AMP-activated protein kinase (AMPK). It is defined by left ventricular hypertrophy, ventricular preexcitation and progressive conduction system disease accompanied by early-onset atrial arrhythmias. This review systematically evaluates PCS, outlining its clinical manifestations, genotype-phenotype spectrum, and diagnostic clues that distinguish it from sarcomeric hypertrophy. It explores underlying pathophysiological mechanisms, detailing how chronic AMPK activation drives glycogen accumulation via allosteric G6P activation of glycogen synthase, following a biphasic temporal model from early GLUT4-mediated glucose flooding to late metabolic feedback suppression. It further examines how Akt–mTOR hyperactivation fosters hypertrophy and how activated fasciculoventricular pathways mediate preexcitation. Finally, it reviews current supportive clinical management and highlights emerging precision medicine frontiers—including RNA-based silencing, pharmacological pathway inhibitors, and CRISPR-Cas9 gene editing—that aim to shift PCS care toward targeted disease modification.