Ammonia metabolism in a family affected by hyperargininemia.

A French-Canadian family, with a 14-year old mentally retarded girl, was investigated for hyperargininemia. The girl showed a fasting plasma ammonia N concentration of 100 micrograms/dl (normal : 50.5 +/- 13 micrograms/dl), and a two-hour post protein load level of 183 micrograms/dl (normal : 51.6 +/- 17.6 micrograms/dl). Plasma urea N was lower than normal in the post-load sample. Arginine concentrations were 11 times normal in the plasma, 47 times normal in the urine and 4 times normal in erythrocytes. Measurement of erythrocyte arginase showed only 1% activity in the propositus, and 52-54% in the parents and a sibling as compared to controls. In heterozygous members of the family, the Km (arginine) was similar to controls. Column chromatography of serum amino acids in the propositus showed arginine to be 17.6 S.D. higher than the normal mean. A characteristic cystine-lysinuria pattern of urinary amino acids was also seen. Measurement of other urinary nitrogenous metabolites showed low urinary urea and excessive orotic aciduria. On "normal" food intake, the patient excreted 122 mg of orotic acid/24 h, as against 3.7 mg by the sibling and 3.9 mg by the mother. It is postulated that the level of ornithine in hepatocyte mitochondria is critical to the disposal of carbamyl phosphate. The lack of normal regeneration of ornithine by liver arginase, and an excessive urinary excretion may be responsible for its low mitochondrial concentration. This would cause diversion of unmetabolised carbamyl phosphate towards orotic acid synthesis or ammonia production.