In human metabolism, patients with Von Gierke's disease (Glycogen Storage Disease Type I) cannot perform effective gluconeogenesis to maintain fasting blood glucose because which enzyme is defective?

Introduction / Context:
Von Gierke's disease (GSD I) is a classic inborn error of carbohydrate metabolism. A key clinical hallmark is severe fasting hypoglycemia because the liver cannot release free glucose into the bloodstream despite active glycogenolysis and gluconeogenesis. Understanding the blocked step pinpoints the responsible enzyme.

Given Data / Assumptions:

• GSD I involves the terminal step of hepatic glucose release.
• Gluconeogenesis generates glucose-6-phosphate (G6P) in the cytosol.
• Free glucose export to blood requires dephosphorylation of G6P in the endoplasmic reticulum lumen.

Concept / Approach:
Glucose-6-phosphatase hydrolyzes G6P to glucose + inorganic phosphate. Without this enzyme (or its transporter G6PT in Type Ib), both glycogenolysis and gluconeogenesis fail to deliver free glucose, causing hypoglycemia and lactic acidosis due to shunting of G6P into glycolysis and lactate production.

Step-by-Step Solution:

Verification / Alternative check:
Biochemical profiles show elevated lactate, triglycerides, and uric acid; hepatomegaly results from glycogen and fat accumulation—findings consistent with a G6Pase pathway defect.

Why Other Options Are Wrong:

• Lactate dehydrogenase: affects lactate/pyruvate interconversion, not final glucose release.
• Pyruvate carboxylase: its deficiency impairs gluconeogenesis upstream but does not define Von Gierke's disease.
• Fructose-1,6-bisphosphatase: another gluconeogenic defect (FBPase deficiency) with different presentation.
• None of these: incorrect because G6Pase is the known culprit in GSD I.

Common Pitfalls:
Assuming glycogen breakdown alone raises blood glucose; the terminal dephosphorylation step is indispensable for hepatic glucose export.

Final Answer:
Glucose-6-phosphatase