Type Ic, a novel glycogenosis. Underlying mechanism

Area of Science:

• Biochemistry
• Molecular Biology
• Metabolic Disorders

Background:

• Glycogen storage disease type I (GSD I) presents with classic clinical symptoms.
• Hepatic D-glucose-6-phosphate phosphohydrolase (EC 3.1.3.9) activity is typically deficient in GSD I.
• A unique case presented with GSD I symptoms but normal enzyme levels in detergent-activated homogenates.

Purpose of the Study:

• To characterize a unique form of glycogen storage disease.
• To investigate the underlying molecular mechanism of the disease using intact and disrupted microsomes.
• To elucidate the role of translocases T1 and T2 in the glucose-6-phosphatase system.

Main Methods:

• Analysis of liver biopsy specimen from an 11-year-old female.
• Enzyme activity assays of glucose-6-phosphate phosphohydrolase using intact and detergent-disrupted microsomes.
• Investigated latency and inhibition patterns with D-glucose and inorganic phosphate (Pi).

Main Results:

• Glucose-6-P phosphohydrolase showed 75% latency in intact microsomes, significantly higher than normal controls (25%).
• Activities of inorganic pyrophosphatase, PPi:glucose phosphotransferase, and carbamyl-P:glucose phosphotransferase were totally latent in intact microsomes but manifested upon disruption.
• Exogenous Pi inhibited activity only in detergent-disrupted microsomes, suggesting a defect in the Pi translocase (T2).

Conclusions:

• The findings are consistent with a defect in T2, the translocase for Pi, PPi, and carbamyl-P.
• Endogenous Pi did not inhibit, suggesting an independent egress pathway for Pi or unidirectional T2 function.
• This unique glycogenosis likely involves defects in both T1 (glucose-6-P translocase) and T2.