Plasma alpha-ketoglutarate in urea cycle enzymopathies and its role as a harbinger of hyperammonemic coma.

Metabolic observations during early stages of hyperammonemia in two infants with ornithine transcarbamylase deficiency suggest that plasma alpha-ketoglutarate concentration ([alpha-KG]) becomes subnormal before the development of hyperammonemic coma. In one case, plasma [NH4+] remained normal until 40 days of age when it rose to 58 microM. However, this hyperammonemia was preceded by a fall in plasma [alpha-KG] to 15 microM at 27 days of age. It was only after severe hyperammonemia was established at 50 days of age that coma supervened. In the second case, plasma [alpha-KG] became subnormal (14 microM) 8 days before the rise in plasma ammonium concentration [NH4+] (52 microM) and 14 days before the onset of hyperammonemic coma. In eight patients with urea cycle enzymopathies, there was a highly significant (P less than 0.01) negative linear correlation between [NH4+] and [alpha-KG]. In patients with portal-systemic encephalopathy, there was a similar relationship between [NH4+] and [alpha-KG], although the absolute [alpha-KG] levels in these patients were normal (23 +/- 4 microM) while the patients were hyperammonemic (88 +/- 25 microM).