The PRKAG2 cardiac syndrome is an inherited metabolic disease of the heart characterized by excessive myocardial glycogen deposition. The biochemical alterations associated with this condition remain controversial and have not previously been studied in affected humans. Positron emission tomography (PET) imaging was used to quantitatively assess myocardial glucose uptake (MGU) in 6 adult subjects with the PRKAG2 cardiac syndrome and 6 healthy, matched control subjects using the glucose analogue (18)F-Fluoro-2-deoxyglucose (FDG). Studies were performed under a euglycemic hyperinsulinemic clamp to ensure stable blood glucose levels. Rubidium-82 perfusion scans were performed to ensure that myocardial differences in myocardial glucose uptake were not the result of significant myocardial scar. In adult patients with phenotypic expression of disease, the median myocardial glucose uptake of the left ventricle was 0.18 mumol/min/g (interquartile range, 0.14, 0.24), compared with 0.40 mumol/min/g (interquartile range, 0.30 to 0.45) in the control group (P=0.01). The median blood glucose during FDG-PET imaging was 4.72 mmol/L (interquartile range, 4.32 to 4.97) in the PRKAG2 group and 4.38 mmol/L (interquartile range, 3.90, 4.79) in the control group (P=NS). The significant decrease observed in myocardial glucose uptake in affected patients occurred in the absence of significant myocardial scar. The PRKAG2 cardiac syndrome is associated with a reduction of glucose uptake in adult patients affected with this genetic condition. In this pilot study, (18)F-FDG-PET imaging is a useful tool to assess alterations in myocardial glucose transport in this inherited metabolic disease and provide insight into the biochemical pathophysiology of the diseased state.