Citrullinaemia type I (ASS1 deficiency — argininosuccinate synthetase) causes hyperammonaemia. Why does hyperammonaemia impair brain function at the biochemical level?
- A Elevated ammonia drives reductive amination of alpha-ketoglutarate (αKG) to glutamate, depleting αKG and impairing TCA cycle flux in astrocytes; excess glutamate is converted to glutamine (osmotic swelling of astrocytes) ✓
- B Ammonia directly inhibits the electron transport chain complex I in neurons
- C Ammonia alkalinises intracellular pH, inhibiting glycolysis and ATP production
- D Ammonia activates NMDA receptors constitutively, causing excitotoxicity
Explanation
Excess ammonia in the CNS is detoxified primarily in astrocytes by glutamine synthetase (glutamate + NH3 + ATP → glutamine). This depletes glutamate and α-ketoglutarate (TCA cycle intermediate), impairing Krebs cycle flux and energy production. Glutamine accumulation in astrocytes causes osmotic swelling (Alzheimer type II astrocytes) — the primary mechanism of hepatic encephalopathy and ammonia-induced cerebral oedema. Additionally, glutamine accumulation may impair mitochondrial function (glutamine enters mitochondria where glutaminase regenerates ammonia locally — the 'trojan horse' hypothesis). Elevated ammonia also disrupts neurotransmitter balance (GABA-A receptor sensitisation).
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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