Glucose-6-phosphatase mutation G188R confers an atypical glycogen storage disease type 1b phenotype

Glycogen storage disease type la (GSD la) is caused by a deficiency in microsomal glucose-6-phosphatase (G6Pase). A variant (GSD Ib) is caused by a defect in the transport of glucose-6-phosphate (G6P) into the microsome and is associated with chronic neutropenia and neutrophil dysfunction. Mutually exclusive mutations in the G6Pase gene and the G6P transport gene establish GSD la and GSD Ib as independent molecular processes and are consistent with a multicomponent translocase catalytic model. A modified translocase/catalytic unit model based on biochemical data in a G6Pase knockout mouse has also been proposed for G6Pase catalysis, This model suggests coupling of G6Pase activity and G6P transport. A 5-mo-old girl with hypoglycemia, hepatomegaly, and lactic acidemia was diagnosed with GSD la. She also developed neutropenia, neutrophil dysfunction, and recurrent infections characteristic of GSD Ib. Homozygous G188R mutations of the G6Pase gene were identified, but no mutations in the G6P translocase gene were found. We have subsequently identified a sibling and two unrelated patients with similar genotypic/phenotypic characteristics. The unusual association of neutrophil abnormalities in patients with homozygous G188R mutations in the G6Pase gene supports a modified translocase/catalytic unit model.