Orotic aciduria in lysinuric protein intolerance: dependence on the urea cycle intermediates.

Urinary excretion of orotic acid was measured in controls and in subjects homozygous and heterozygous for lysinuric protein intolerance under various conditions of amino nitrogen intake. In all situations, the controls excreted less than 28 microgram/kg/hr. Only one of the two heterozygotes studied differed from the controls, The orotic aciduria of homozygotes was normal in fasting but increased on a self-chosen low-protein diet (log mean, 80; range, 8 to 588 microgram/kg/hr in 24-hr urine), after cow's milk protein 0.5 g/kg (769; 251 to 1747 microgram/kg/hr in 4 to 6-hr urine), oral ammonium lactate, 2.5 mmoles/kg (95; 15 to 1127 microgram/kg/hr in 1.5-hr urine), and IV alanine, 6.6 mmoles/kg (519; 47 to 1831 microgram/kg/hr in 6-hr urine). Giving ornithine or citrulline IV with the infusion of alanine prevented the increase in orotic acid excretion. Given orally, citrulline was more efficient than ornithine or arginine. To prevent the hyperammonemic and orotic aciduric responses with ornithine its plasma concentrations needed to be higher than normal. Orotic aciduria is a reliable indicator of the function of the urea cycle in lysinuric protein intolerance and facilitates monitoring of the treatment of this disease.