A 5-month-old infant has recurrent fasting hypoglycemia precipitated by protein-rich feeds, with hypoketosis and persistently elevated ammonia (100 to 200 micromol/L) without elevation of any urea cycle intermediate. Hypoglycemia worsens after leucine challenge. Which molecular defect is most likely?
- A Activating mutation of glutamate dehydrogenase (GLUD1) ✓
- B Deficiency of carbamoyl phosphate synthetase-I
- C Inactivating mutation of glutamine synthetase
- D Deficiency of branched-chain alpha-keto acid dehydrogenase
Explanation
Hyperinsulinism-hyperammonemia syndrome stems from activating mutations of mitochondrial glutamate dehydrogenase, making the enzyme insensitive to GTP inhibition and hypersensitive to its activator leucine. Constitutive flux converts glutamate to alpha-ketoglutarate plus ammonia, raising ammonia mildly, while leucine-stimulated insulin release causes protein-sensitive hypoketotic hypoglycemia. Normal urea cycle intermediates exclude CPS-I deficiency, ketosis-prone encephalopathy excludes MSUD, and glutamine synthetase loss causes severe neonatal hyperammonemia without hypoglycemia.
Reference: Nelson Textbook of Pediatrics, 21st ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.