Von Gierke disease (Type I glycogen storage disease) is due to deficiency of which enzyme?

• A. Glucose-6-phosphatase
• B. Lysosomal acid alpha-glucosidase
• C. Glycogen phosphorylase
• D. Debranching enzyme

Answer: (A)

Blocking the final step of hepatic glucose production defines Von Gierke disease. The deficiency is glucose-6-phosphatase, the enzyme that converts glucose-6-phosphate into free glucose that can be released into the bloodstream. Without this step, the liver cannot provide glucose during fasting, causing severe hypoglycemia, and the accumulation of glucose-6-phosphate drives glycogen storage and other metabolic issues like lactic acidosis, hyperuricemia, and hyperlipidemia with hepatomegaly from glycogen buildup. The other enzymes listed are involved in different glycogen storage diseases: lysosomal acid alpha-glucosidase deficiency causes Pompe disease with lysosomal glycogen accumulation; glycogen phosphorylase deficiency leads to a different hepatic form of hypoglycemia; debranching enzyme deficiency causes Cori disease with abnormal limit dextrin and milder hypoglycemia. Thus, the enzyme deficient in Von Gierke disease is glucose-6-phosphatase.