A 4-month-old White male infant with a temperature of 38.4°C is examined by his pediatrician. His mother indicates that he has had the fever for the past 4 days, been listless, vomiting, and has watery stools. Blood work indicates the infant is hypoglycemic but this condition does not respond to either epinephrine or glucose administration. In addition, his blood pH is slightly acidic and shows reduced bicarbonate. Other untoward blood chemistry includes elevated triglycerides, cholesterol, and liver enzymes. The child has a protuberant abdomen, thin extremities, and a doll-like face. The pediatrician suspects a specific condition and orders a liver biopsy to test for the activity of which of the following enzyme activities?

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The symptoms and biochemical findings suggest Von Gierke's disease (Glycogen storage disease type I), which is caused by a deficiency in glucose 6-phosphatase. This enzyme deficiency leads to hypoglycemia, lactic acidosis, hyperlipidemia, and hepatomegaly.  This child is manifesting the classic signs and symptoms of von Gierke disease (GSDI) which results from the absence of glucose-6-phosphatase activity. Patients with von Gierke disease can present during the neonatal period with lactic acidosis and hypoglycemia. The hallmark features of this disease are hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. The severity of the hypoglycemia and lactic acidosis can be such that in the past the affected individuals died in infancy. Infants often have a dolllike facial appearance due to excess adipose tissue in the cheeks. The metabolic consequences of the hepatic glucose-6-phosphate deficiency of von Gierke disease extend well beyond just the obvious hypoglycemia that results from the deficiency in liver being able to deliver free glucose to the blood. The inability to release the phosphate from glucose 6-phopsphate results in diversion into glycolysis and production of pyruvate as well as increased diversion onto the pentose phosphate pathway. The production of excess pyruvate, at levels above of the capacity of the TCA cycle to completely oxidize it, results in its reduction to lactate leading to lactic acidemia. In addition, some of the pyruvate is transaminated to alanine leading to hyperalaninemia. Some of the pyruvate will be oxidized to acetyl-CoA, which cannot be fully oxidized in the TCA cycle and so the acetyl-CoA will end up in the cytosol where it will serve as a substrate for triglyceride and cholesterol synthesis resulting in hyperlipidemia. The oxidation of glucose 6-phosphate via the pentose phosphate pathway leads to increased production of ribose-5-phosphate which then activates the de novo synthesis of the purine nucleotides. In excess of the need, these purine nucleotides will ultimately be catabolized to uric acid, resulting in hyperuricemia and consequent symptoms of gout.

A 4-Month-Old White Male Infant with a Temperature of 38