Infant with Severe Cerebral Damage

The biosynthesis of urea from ammonia and carbon dioxide requires five enzymes. One enzyme, carbamylphosphate synthetase converts ammonia and bicarbonate to carbamyl phosphate, which subsequently condenses with ornithine to form citrulline, a reaction catalysed by ornithine transcarbamylase. Citrulline is then converted by argininosuccinic acid synthetase to argininosuccinic acid, which is cleaved to form arginine and fumaric acid. The enzyme arginase finally converts arginine to ornithine and urea. All of these enzymes, with the exception of arginase, have been associated with an inborn error of metabolism: hyperammonaemia with a defective ornithine transcarbamylase (Russell et al., 1962; Levin and Russell, 1967), citrullinaemia with a defective argininosuccinate synthetase (McMurray et al., 1962), and argininosuccinic aciduria with a defective argininosuccinic acid cleavage enzyme (Allen et al., 1958). Mental retardation is a common feature of these enzymatic defects, but it is uncertain whether the cerebral defect is due to accumulation of ammonia. There is increasing evidence that the urea cycle proceeds in the brain cells (Sporn et al., 1959; Kemp and Woodbury, 1965), so that brain damage may be due to toxic effects of accumulated urea cycle intermediates and not necessarily to a high ammonia level. Five cases with a high blood ammonia level (postprandial ammonaemia) due to enzymatic defects have been described. In 4 of these cases enzyme activity determinations have been carried out (Freeman et al., 1964; Russell et al., 1962; Levin and Russell, 1967). In the case described by Freeman et al. (1964) a reduced activity of carbamylphosphate synthetase with normal activities of the other enzymes of the urea cycle was found. The other 3 cases showed a very low activity of liver ornithine transcarbamylase, though the activity of carbamylphosphate synthetase was also below the normal value (see Addendum).