Arginase defect

The clinical symptomatology, which is almost the same in all enzymatic disturbances of the urea cycle, is caused by hyperammonaemia. An arginase defect results in enhanced excretion of lysine, ornithine and cystine. Neurological symptoms such as hyperreactivity and athetosis followed by paresis and tetraplegia predominate. 

Hyperargininemia. This defect is characterized by elevated blood and cerebrospinal fluid arginine levels, low erythrocyte levels of arginase (reaction 5, Figure 29-9), and a urinary amino acid pattern resembling that of lysine-cystinuria. This pattern may reflect competition by arginine with lysine and cystine for reabsorption in the renal tubule. A low-protein diet lowers plasma ammonia levels and abolishes lysine-cystinuria. 

Figure 47-SO The major metabolic pathways for the use of ammonia by the hepatocyte. Solid bars indicate the sites of primary enzyme defects in various metabolic disorders associated with hyperammonemia /) carbamyl phosphate synthetase I, (2) ornithine transcarbamylase, (3) argininosuccinate synthetase, (4) argininosuccinate lyase, (5) arginase, (6) mitochondrial ornithine transport, (7) propionyi CoA carboxylase, (fi) methylmalonyl CoA mutase, (9) L-lysine dehydrogenase, and (10) N-acetyl glutamine synthetase. Dotted lines indicate the site of pathway activation (+) or inhibition ( ). (From Flannery OB, Hsia YE, Wolf 6. Current status of /lyperommofiemjo syndromes. Hepatology 1982 2 495-506,)...

A number of inherited diseases are associated with the urea cycle. The mutations result in changes in either Vm or Km as defective proteins are produced. These include disruptions of N- acety 1 gl utam ate synthase, carbamoyl phosphate synthetase, ornithine transcarbamoylase (the most prevalent of the urea cycle deficiencies), argininosuccinate synthetase, argininosuccinate lyase, and arginase. In these diseases, when applicable, treatments are low-protein diets, to put less strain on urea cycle flux and, when appropriate, addition of amino acids as required, such as ornithine and/or arginine. 

Fig. 12.1. Position of ornithine in the urea cycle and in biosynthetic pathways for proline, polyamines and creatine. 12.1, defect in hyperornithinemia i, ornithine-5-amino-transferase (mitochondrial) 2, ornithine transcarbamylase (mitochondrial) 3, arginase (cytosolic) 4, glycine transaminidase 5, ornithine decarboxylase (cytosolic) 6, guanidi-noacetate methyltransferase (cytosolic)...

Small amounts of urea are secreted in sweat but most is excreted in the urine following filtration by the kidney glomeruli although significant quantities of urea may be passively reabsorbed with water by the proximal tubules on each occasion. Urea is the major nitrogenous constituent of urine when the diet contains normal quantities of protein. Where the diet contains low levels or lacks protein, the decline in urinary urea concentrations reflects the control exercised on carbamoyl-phosphate synthase levels. Defects in the function of carbamoyl-phosphate synthase, ornithine carbamoyltransferase, argininosuccinate synthase and arginase result in hyperammonaemia (elevated blood ammonia concentrations) with concomitant effects on the brain. 

---