PRKAG2 – Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and risk of sudden cardiac death. PRKAG2 encodes the γ2 regulatory subunit of AMP-activated protein kinase (AMPK) and is implicated in a glycogen storage cardiomyopathy that phenocopies HCM. Heterozygous PRKAG2 variants lead to cardiac glycogen deposition, ventricular preexcitation, and conduction defects, distinguishing PRKAG2 syndrome from sarcomere-protein HCM (PMID:15673802).

PRKAG2 syndrome follows autosomal dominant inheritance with full penetrance of cardiac phenotypes across infancy to adulthood. Segregation analyses in ≥12 unrelated kindreds demonstrate cosegregation of heterozygous variants with HCM and ventricular preexcitation in ≥25 affected relatives, with complete clinical penetrance of LVH and arrhythmia (PMID:32259713).

Case series identified infantile-onset HCM with de novo c.1516G>A (p.Glu506Gln) and recurrent c.905G>A (p.Arg302Gln) variants in infants requiring septal myectomy or presenting prenatally (PMID:19787389; PMID:28550180). Multi-patient cohorts found PRKAG2 mutations in 7 of 24 patients with massive LVH and preexcitation, and five distinct variants in 12 kindreds with 100% penetrance of cardiac glycogen storage disease (PMID:15673802; PMID:32259713).

Functional studies show that PRKAG2 missense variants (Arg302Gln, Thr400Asn, Asn488Ile) confer constitutive AMPK activation, promote glycogen accumulation, and induce cardiomyocyte hypertrophy reversible by rapamycin in cellular models (PMID:11827995; PMID:28550180). Transgenic mice expressing mutant PRKAG2 display ventricular preexcitation, conduction defects, and LVH, with reduced AMPK activity and excessive glycogen deposition (PMID:15611370).

No studies dispute the PRKAG2–HCM association. Large gene screens found no alternative metabolic gene defects in patients with LVH and preexcitation without sarcomeric mutations, and absence of significant glycogen in some infantile cases suggests variant-specific effects on AMPK regulation (PMID:16267253; PMID:19787389).

Collectively, definitive genetic and functional data establish PRKAG2 as a causative gene for an autosomal dominant glycogen storage cardiomyopathy overlapping HCM. Genetic testing for PRKAG2 variants should be considered in unexplained LVH with arrhythmic features to guide surveillance and potential targeted therapies. Key Take-home: PRKAG2 variants cause a distinct, diagnosable form of cardiac glycogen storage disease manifesting as HCM with arrhythmic risk.

References

• The New England journal of medicine • 2005 • Glycogen storage diseases presenting as hypertrophic cardiomyopathy. PMID:15673802
• The Journal of clinical investigation • 2002 • Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. PMID:11827995
• Circulation • 2005 • Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome. PMID:15611370
• Pediatric cardiology • 2009 • Severe hypertrophic cardiomyopathy in an infant with a novel PRKAG2 gene mutation: potential differences between infantile and adult onset presentation. PMID:19787389
• American journal of physiology. Heart and circulatory physiology • 2017 • A novel, de novo mutation in the PRKAG2 gene: infantile-onset phenotype and the signaling pathway involved. PMID:28550180
• EBioMedicine • 2020 • Identification, clinical manifestation and structural mechanisms of mutations in AMPK associated cardiac glycogen storage disease. PMID:32259713

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