Multiple transport protein defects in a patient with glycogen storage disease type 1: GSD 1b/1c_β

Abstract

A male child presented at 5 months of age with vomiting, diarrhoea, hypoglycaemia and hepatomegaly. Histology on a frozen liver biopsy suggested glycogen storage disease (GSD), while biochemical analyses confirmed an elevated glycogen content and normal activities of the GSD enzymes with the proviso that a variant of GSD 1 should be considered. The patient presented at 9 months of age with severe lactic acidosis and hypoglycaemia. A glucagon tolerance test and galactose load test on the patient produced no glycaemic response. A second biopsy was obtained and appropriately handled for the investigation of variants of the glucose-6-phosphatase enzyme (G6Pase) complex. Results showed that the patient had a deficiency of two transport proteins of the G6Pase complex, namely glucose-6-phosphate translocase and pyrophosphate translocase, i.e. GSD 1b/1c beta. These results were confirmed by additional kinetic analyses which provided confirmation of the double translocase deficiency. Evidence for inhibitors to these translocases was not found. The patient's treatment has resulted in the hypoglycaemia now being well controlled; however, at 3 years of age, height and weight are markedly lagging and he is moderately developmentally delayed. Neutropenia has not been found and neutrophil function is normal. Double enzyme deficiencies are very rare and possible explanations which might lead to this phenotype are considered. This, to the authors' knowledge, is the first report of a double translocase deficiency causing GSD type 1.

A Gene on Chromosome 11q23 Coding for a Putative Glucose- 6-Phosphate Translocase Is Mutated in Glycogen-Storage Disease Types Ib and Ic

“…Their argument was that they did not observe the time-dependent inhibition of glucose-6-phosphatase that they would have expected to find if the decrease in glucose-6-phosphatase activity had been due only to accumulation of inorganic phosphate in the microsomes. Evidence for simultaneous defects in the transport of inorganic phosphate and glucose-6-phosphate was also reported for another case (Hawkins et al 1995), though one patient recently studied by Marcolongo et al (1998), in whom Pi and glucose-6-phosphate transport were measured by light scattering, was reported to have an isolated Pi-transport defect. Now that the gene encoding the putative glucose-6-phosphate translocase has been identified, it will be possible to determine whether all "non-a" forms of GSD type I are due to mutations in this gene.…”

Mice Lacking Thioredoxin-interacting Protein Provide Evidence Linking Cellular Redox State to Appropriate Response to Nutritional Signals

“…This process requires an intact function of the G6Pase complex. Thus, the increase in plasma glucose after a bolus of galactose provides an estimation of the relative flux of substrate through G6Pase (28). As shown in Fig.…”

Glucose-6-Phosphatase Mutation G188R Confers an Atypical Glycogen Storage Disease Type 1b Phenotype

“…Since the cloning of T1 and definition of mutations at this locus, it appears likely that the T1 translocase performs both transport functions, the import of G6P into and transport of phosphate out of the microsome (15)(16)(17)(18)(19). In either event, mutations in the G6Pase gene have not been associated with abnormalities of PMN.…”