Ammonia urea cycle defects

The urea cycle is essential for the detoxification of ammonia 678 Urea cycle defects cause a variety of clinical syndromes, including a metabolic crisis in the newborn infant 679 Urea cycle defects sometimes result from the congenital absence of a transporter for an enzyme or amino acid involved in the urea cycle 680 Successful management of urea cycle defects involves a low-protein diet to minimize ammonia production as well as medications that enable the excretion of ammonia nitrogen in forms other than urea 680... 

Urea cycle defects Failure to convert ammonia to urea via urea cycle (Fig. 40-5). Coma, convulsions, vomiting, respiratoryfailure in neonate. Often mistaken for sepsis of the newborn. Mental retardation, failure to thrive, lethargy, ataxia and coma in the older child. Associated with hyperammonemia and abnormalities of blood aminogram Low protein diet Acylation therapy (sodium benzoate, sodium phenylacetate) Arginine therapy in selected syndromes Hepatic transplantation... 

Diagnosis of a urea cycle defect in the older child can be elusive. Patients may present with psychomotor retardation, growth failure, vomiting, behavioral abnormalities, perceptual difficulties, recurrent cerebellar ataxia and headache. It is therefore essential to monitor the blood ammonia in any patient with unexplained neurological symptoms, but hyperammonemia is inconstant with partial enzymatic defects. Measurement of blood amino acids and urinary orotic acid is indicated. 

Hyperammonemia resulting from any of the enzymatic disorders of the biosynthesis of urea, must be distinguished from other conditions in which plasma ammonia is raised, sometimes sufficiently so to cause clinical manifestation. Severe liver disease as a primary cause of acquired hyperammonemia may be excluded from consideration since it is readily distinguishable from urea cycle defects. However, there are a number of other conditions described with hyperammonia as a prime manifestation, which because they show some clinical and biochemical similarity to hereditary enzyme defects of the urea cycle, have been claimed to be urea cycle disorders. 

This condition has been described by Rett (RIO, Rll) and Rett and Stockl (R12) in 22 children, all girls, the oldest of them 13 years of age, from a survey of 6000 mentally subnormal children. In all 22, the blood ammonia was raised from 2 to 5 times the normal the highest being 165 /ig/100 ml. The blood urea was said to be normal in all cases, as was the plasma amino acids. Where liver biopsy was obtained, this was also normal. The brain was examined in 5 children who died. They showed cerebral atrophy but no Alzheimer Type II cells. A relationship between hyperammonemia and the cerebral changes of the syndrome was postulated and attention drawn to the similarity with some of the neurological manifestations of children with urea cycle defects. However, the cause of the hyperammonemia was unexplained, and it seems unlikely that these were examples of primary urea cycle disorders. 

Urea cycle defects Deficiency of enzymes of the urea cycle results in a build up of ammonia in the blood. Severe cases are often fatal in the first few days after birth... 

Primary urea cycle defects are caused by a deficiency of any of the six urea cycle enzymes (Chap. 15) and result in insufficient disposal of waste nitrogen. As a result, nitrogen accumulates in the form of ammonia and as its precursors, as glutamine and glycine. Primary defects in an enzyme of the urea cycle typically result in higher ammonia levels than secondary impairments of the urea cycle, although exceptions occur. 

In healthy people the rate of ketogenesis, and therefore the concentration of acetoacetate and 3-hydroxybutyrate in the blood, will decrease after meals, but may increase in mitochondrial disorders [15, 20]. Increased serum ammonia, creatine kinase or CSF protein concentration is not indicative for a mitochondrial disturbance. If found, urea cycle defects, liver cirrhosis, muscle dystrophy or brain necrosis must be considered. Patients with Kearns-Sayre syndrome and Leigh syndrome, however, often have increased protein concentrations in the CSF. 

All defects in urea synthesis result in ammonia intoxication. Intoxication is more severe when the metabolic block occurs at reactions 1 or 2 since some covalent linking of ammonia to carbon has already occurred if citrulline can be synthesized. Clinical symptoms common to all urea cycle disorders include vomiting, avoidance of high-protein foods, intermittent ataxia, irritability, lethargy, and mental retardation. The clinical features and treatment of all five disorders discussed below are similar. Significant improvement and minimization of brain damage accompany a low-protein diet ingested as frequent small meals to avoid sudden increases in blood ammonia levels. 

The urea cycle is essential for the detoxification of ammonia. The urea cycle (Fig. 40-5) converts ammonia to urea (10-20g/day in the healthy adult). A urea cycle enzymopathy, whether associated with cirrhosis or an inherited metabolic defect, often causes a hyperammone-mic encephalopathy and irreversible brain injury (see also Ch. 34). 

Causes and symptoms When liver function is compromised, as a result of genetic defects in one of the urea cycle of hyperammonemia enzymes or to liver disease, hyperammonemia (ammonia intoxication) can occur. 

Hyperammonemia is an increase in the levels of ammonia in the blood caused by a defect in an enzyme of the urea cycle. The excess ammonia is channeled into glutamate and glutamine with a deleterious effect on brain function. 

Since one of the most important, if not the most important, result of a defect of the biosynthesis of urea is an increased level of blood ammonia, it is essential to consider other conditions that might affect indirectly the urea cycle or in some other way raise the blood ammonia. For example, it has been suggested that since lysine can act as a competitive inhibitor of the conversion of arginine to ornithine and urea, an increased level of plasma lysine may therefore inhibit the urea cycle (B12). 

The fact that relatively large amounts of urea can be produced by subjects in whom an enzyme defect of the urea cycle has been proved has perplexed many investigators. Despite the fact that the activity of the rate-limiting enzyme has been reduced even to zero as measured by a sophisticated method, urea production still continues. It must therefore be concluded that, in all these cases, urea production is only impaired, not abolished. In all normal circumstances, all but a small fraction of the nitrogen in excess of tissue protein requirements is still excreted as urea and/or as the amino acid whose further metabolism is blocked. The impairment shows itself in the elevated levels of blood ammonia and consequently of glutamine, which vary according to the stress placed upon the urea cycle by varying the rates of protein intake. 

E. The patient exhibits signs of a defect in the urea cycle. The presence of elevated uracil in addition to ammonia and glutamine points to an accumulation of carbamoyl phosphate. If ornithine transcar-bamoylase is deficient, carbamoyl phosphate will accumulate in the mitochondria and leak into the cytosol, providing the starting compound for the synthesis of uracil. 

Explain how a defective enzyme in the urea cycle can produce high levels of ammonia. 

If any of the urea cycle enzymes is missing, ammonia (the nitrogen-containing substrate of the cycle) cannot be metabolized. If any of the enzymes is defective (i.e., it does not catalyze its reaction at an appropriate rate), ammonia is metabolized slowly. Under both circumstances the body s ammonia concentration is excessively high. 

---