• Normal intracranial ammonia physiology
  • Glutamate and ammonia exist in a chemical equilibrium with glutamine, mediated by the enzyme glutamine synthetase.
  • Glutamate serves as a substrate for glutamate decarboxylase to form GABA.
• Pathophysiology
  • Elevated serum ammonia levels disrupt the balance between glutamine, glutamate, α-ketoglutarate, and GABA through the actions of glutamate dehydrogenase and glutamine synthetase, resulting in increased glutamine and decreased glutamate levels → low GABA synthesis and GABAergic tone → typical features of hyperammonemic encephalopathy:
    • Excess glutamine → osmotic damage to astrocytes → cellular swelling and dysfunction → cerebral edema
    • Imbalance of the neurotransmitters → Inhibition of excitatory neurotransmission and activation of inhibitory neurotransmission
  • Low α-ketoglutarate → inhibition of TCA cycle
• Etiology
  • Hereditary: most often in children but heterozygotes can present as older children or adults
    • Urea cycle disorders, especially ornithine transcarbamylase deficiency
    • Organic acidemias: most commonly methylmalonic acidemia