A 6-month-old infant has persistent fasting hypoglycemia with inappropriate hyperinsulinemia and mild hyperammonemia (80 micromol/L) that does not rise with protein load. Plasma glutamine is elevated. Molecular testing shows an activating mutation affecting allosteric regulation of an enzyme that normally catalyzes oxidative deamination of glutamate. The mutated enzyme is:

• A Glutamine synthetase
• B Carbamoyl phosphate synthetase-I
• C Glutamate dehydrogenase ✓
• D Gamma-glutamyl transpeptidase

Explanation

Hyperinsulinism-hyperammonemia syndrome results from activating mutations in GLUD1-encoded mitochondrial glutamate dehydrogenase, which loses its sensitivity to GTP inhibition. Excessive glutamate oxidation raises alpha-ketoglutarate flux through the TCA cycle, stimulating insulin secretion, while glutamate depletion increases glutamine availability and ammonia production. Glutamine synthetase works in the opposite direction, converting glutamate to glutamine, so option A is wrong. CPS-I consumes ammonia and its deficiency causes severe hyperammonemia without hypoglycemia.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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