Abstract
The hyperammonemia which occurs in patients with enzyme deficiencies of the urea cycle, apart from carbamyl phosphate synthetase (CPS) deficiency, is unexplained. In CPS deficiency, ammonium (NH4 +) is a substrate for the reaction and thus it accumulates. In argininosuccinic acid synthetase deficiency accumulation of citrulline (cit) is readily explained but accumulation of NH4 + is not because although the ornithine transcarbamylase reaction is reversible the CPS reaction is irreversible and not product inhibited. The relationship between plasma levels of NH4+ and other urea precursors was explored in a case of neonatal onset citrullinemia during 2-1/2 months of management with protein restriction and dietary supplements of nitrogen free analogues of essential amino acids. When plasma cit was 2 mM or less, hyperammonemia was not observed. At higher cit levels, NH4+ rose with cit (r=.65, p<.01). Significant positive correlations were also seen between plasma NH4+ and glutamine (gln) (r=.71, p<.01), NH4+ and glutamate (r=.58, p<.01), and NH4+ and alanine (r=.37, p<.01). The two amino adds giving the best prediction of NH4+ concentration were gln and cit: [NH4]=-20+(.327±.52) [gln]+ (.012±.001) [cit]; (r=.71, F=85.47, d.f.=71). Orotic aciduria occurred only when hyperammonemia was present. These findings suggest that hyperammonemia is a consequence of accumulation of cit, leading in turn to accumulation of carbamyl phosphate which constantly decomposes, releasing ammonium.
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Brusilow, S., Batshaw, M., Robinson, B. et al. THE MECHANISM OF HYPERAMMONEMIA IN CITRULLINEMIA. Pediatr Res 11, 453 (1977). https://doi.org/10.1203/00006450-197704000-00500
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DOI: https://doi.org/10.1203/00006450-197704000-00500