Background: The classification of hypoglycemia into ketHG and non-ketHG is important for the diagnostic approach. Among ketHG are disorders of glycogen formation, clinically recognizable by supranormal postprandial rise of plasma glucose and lactate concentration. In addition to hepatic glycogen synthase (encoded by GYS2), other proteins play a role in glycogen formation. In liver, glycogenin-2 (GYG2), glycogenin-1 (GYG1), shown to interact with glycogenin-2, and a glycogen synthase kinase are important. Defects of GYS2, GYG2 and GYG1 might result in ketHG, although GYG1 mutations have recently been associated with myopathic symptoms (Moslemi et al, NEJM 2010). Methods/Results: Nineteen consecutive patients with ketHG and typical laboratory findings were investigated (the majority without liver biopsy and/or enzymatic studies). When GYS2, GYG1 und GYG2 were systematically sequenced, only one patient with GYS2 deficiency was diagnosed. Defects of glycogenins were not detected. Conclusion: Glycogen synthase deficiency is a rare cause of ketHG even if the presentation is typical. In contrast to muscle glycogenin deficiency, recently reported for the first time, a deficiency of the most important hepatic glycogenin, GYG2, has not yet been diagnosed. We continue to offer GYG2 sequencing in suspicious patients, particularly those with low hepatic glycogen content and normal liver glycogen synthase activity.