Ornithine methyl ester. An unusual metabolite encountered in the urine of patients with a urea cycle disorder characterized by hyperammonemia, hyperornithinemia and homocitrullinuria.

In the urine of six subjects with a urea cycle disorder characterized by hyperammonemia, hyperornithinemia and homocitrullinuria, an unusual ninhydrin-reaction compound was encountered. This unknown on hydrolysis yielded ornithine as the only amino acid and, on dansylation studied, yielded didansyl ornithine. The metabolite from urine has been shown to have the same chromatographic mobility as ornithine methyl ester on paper cellulose thin layer, and ion exchange chromatography. When trimethylsily derivatives were prepared the unknown and the ornithine methyl ester standard had similar mobility on gas chromatography. Identification of the unknown as the ornithine methyl ester was confirmed by gas chromatography-mass spectrometric analysis. In the patients' urines the concentration of methyl ornithine ranged from 70 to 368 microne moles/g creatinine.

Hyperornithinemia, hyperammonemia, and homocitrullinuria associated with decreased carbamyl phosphate synthetase I activity.

Six subjects from three sibships with hyperornithinemia, homocitrullinuria, and hyperammonemia are described. Assays of liver biopsy in one showed decreased CPS I and leukocyte assays indicate a similar defect in all six. Loading studies with ornithine and citrulline are consistent with a block early in the urea cycle between ornithine and citrulline. They thus support the results of the enzymatic assays. Similar studies with lysine and homocitrulline indicate there is excessive homocitrulline biosynthesis that is related to lysine intake, but there is no evidence of a block in the main lysine catabolic pathway. The younger more severely affected patients require protein restriction to 1.2 and 1.5 g/kg/24 hr to control hyperammonemia; hyperornithinemia remains unaffected. Adult subjects avoid large protein meals but tolerate a diet that is almost normal. The mode of inheritance of this disorder appears to be autosomal recessive. The fine structure of liver shows the presence of large and abnormally configurated mitochondria. There is a peculiar periodic structure situated closely to the inner mitochondrial membrane, and it is possible that the presence of this may be related to the impairment of transport of ornithine into the mitochondria; this in turn may give rise to hyperornithinemia. This disorder adds to the metabolic errors that suggest that there are close links of lysine metabolism to the urea cycle but the details are yet to be defined.