Studies on the Etiology of Hyperammonemia Associated with Inborn Errors of Amino Acid Metabolism. I. Etiology of Hyperammonemia Associated with Disorder of Lysine Metabolism

The purpose of this study is to investigate the etiology of hyperammonemia associated with hyperlysinemia and massive homocitrullinuria. An 18-year-old mentally and physically retarded male with periodic hyperammonemia is described. Levels of lysine and citrulline in his serum and those of blood ammonia were elevated and daily excretions of homocitrulline in his urine were strikingly high on an ordinary diet. With a decrease in protein intake to 1.5 g/kg of body weight/day, only urinary homocitrulline excretion remained about ten times higher than the normal values while the other amino acids in his serum and urine appeared to be within the normal range. After an oral load of lysine on a normal protein intake, several abnormal findings were observed. That is, clinically he had episodes of irritability, vomiting, and coma caused by ammonia intoxication. Biochemically, levels of citrulline and arginine in his serum and the urinary homocitrulline excretion rate went on increasing and arginase in the blood cells was markedly depressed. Blood cell arginase, which showed lower activity than controls peculiary on a normal protein intake, was extremely inhibited by lysine in the vitro experiment. The blood cells contained much higher concentrations of lysine and homocitrulline than those of control subjects. Citrulline tolerance curve after the load of L-citrulline was found to be normal. Lysine : NAD-oxido-reductase activity in the liver was near the lower limits of the control values. The activity of argininosuccinate synthetase was reduced to 22% of the control values. Arginase activity was also reduced. The partial defect of argininosuccinate synthetase as well as reduced arginase in the liver of the patient may be due to disorder of lysine metabolism and may play an important role in the etiology of hyperammonemia