Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis

J Am Coll Cardiol. 2020 Jul 14;76(2):186-197. doi: 10.1016/j.jacc.2020.05.029.


Background: PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood.

Objectives: The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort.

Methods: Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied.

Results: At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died.

Conclusions: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.

Keywords: PRKAG2; glycogen-storage disease; heart failure; hypertrophic cardiomyopathy; left ventricular hypertrophy; pacemaker; pre-excitation; sudden cardiac death.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics*
  • AMP-Activated Protein Kinases / metabolism
  • Adolescent
  • Adult
  • Cardiomyopathies / diagnosis
  • Cardiomyopathies / genetics*
  • Cardiomyopathies / metabolism
  • Child
  • DNA / genetics*
  • DNA Mutational Analysis
  • Echocardiography
  • Electrocardiography
  • Female
  • Follow-Up Studies
  • Glycogen Storage Disease / diagnosis
  • Glycogen Storage Disease / genetics*
  • Glycogen Storage Disease / metabolism
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Myocardium / metabolism*
  • Phenotype
  • Retrospective Studies
  • Young Adult


  • DNA
  • PRKAG2 protein, human
  • AMP-Activated Protein Kinases