A 9-month-old infant presents with severe hypoglycemia, vomiting, and hepatomegaly after introduction of fruit juice. Genetic testing confirms autosomal recessive deficiency of the enzyme marked **B** in the fructose metabolism diagram. Which of the following best explains the pathophysiology of this infant's acute presentation?

Question

Accepted Answer

A. Accumulation of fructose-1-phosphate traps inorganic phosphate, depleting ATP and inhibiting both gluconeogenesis and glycogenolysis, causing severe hypoglycemia. ## Why option 1 is correct

Hereditary fructose intolerance (HFI) results from autosomal recessive deficiency of **aldolase B** (marked **B**). When fructose is ingested, fructokinase (A) still phosphorylates it to fructose-1-phosphate, but the deficient aldolase B cannot cleave it further. Fructose-1-phosphate accumulates and traps inorganic phosphate (Pi), depleting the free phosphate pool. This causes ATP depletion and simultaneous inhibition of both gluconeogenesis and glycogenolysis, resulting in severe hypoglycemia—the hallmark acute presentation. The clinical history of symptom onset after introduction of fruit juice is pathognomonic. (Harper 32e Ch 20; Nelson 21e)

## Why each distractor is wrong

- **Option 2**: This describes essential fructosuria, caused by fructokinase (A) deficiency, not aldolase B deficiency. Essential fructosuria is benign and asymptomatic, with no hypoglycemia or hepatomegaly. It is an incidental finding.
- **Option 3**: Aldolase B deficiency does not prevent entry into glycolysis; rather, it causes toxic accumulation of the upstream substrate (fructose-1-phosphate). Hyperglycemia is not a feature of HFI; hypoglycemia is.
- **Option 4**: This describes aldolase A deficiency, which affects glycolysis of glucose-derived fructose-1,6-bisphosphate and causes lactic acidosis. Aldolase A deficiency is extremely rare and presents differently; it is not the enzyme marked **B** in hepatic fructose metabolism.

**High-Yield:** HFI = aldolase B deficiency → fructose-1-P accumulation → phosphate trapping → ATP depletion → hypoglycemia + aversion to sweets (self-protective). Lifelong fructose/sucrose/sorbitol avoidance is curative.

[cite: Harper 32e Ch 20; Nelson 21e]

Answer

B. Deficiency of fructokinase prevents phosphorylation of fructose, leading to fructose accumulation in blood and benign fructosuria

Answer

C. Impaired conversion of fructose-1-phosphate to glyceraldehyde prevents entry of fructose into glycolysis, causing hyperglycemia and osmotic diuresis

Answer

D. Aldolase A deficiency prevents cleavage of fructose-1,6-bisphosphate, blocking glycolysis and causing lactic acidosis

Explanation

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