Urea cycle enzymes deficiencies

Christmann R. Valproate-induced coma in a patient with urea cycle enzyme deficiency. Epilepsia 1990 31 228. 

Todo, S., Starzl, T.E., Tzakis, A., Benkov, K.J., Kalousek, F., Saheki, T., Tanikawa, K., Fenton, W.A. Orthotopic liver transplantation for urea cycle enzyme deficiency. Hepatology 1992 15 419—422... 

Sucrase-isomaltase deficiency Urea cycle enzyme deficiencies Phenylketonuria... 

Deficiency of a Urea Cycle Enzyme Results in Excretion of Pyrimidine Precursors... 

Figure 10.10 The use of benzoate and phenylacetate to lower the concentration of ammonia in patients with a deficiency of a urea cycle enzyme.

FIGURE 18-14 Treatment for deficiencies in urea cycle enzymes. The aromatic acids benzoate and phenylbutyrate, administered in the diet, are metabolized and combine with glycine and glutamine, respectively. The products are excreted in the urine. Subsequent synthesis of glycine and glutamine to replenish the pool of these intermediates removes ammonia from the bloodstream. 

Metabolism of nitrogen in a patient with a deficiency in the urea cycle enzyme carbamoyl phosphate synthetase I. Treatment with phenylbutyrate converts nitrogenous waste to a form that can be excreted. 

Symptoms include tremors, slurring of speech, somnolence, vomiting, cerebral edema, and blurring of vision. All inherited deficiencies of urea cycle enzymes cause mental retardation. 

Hyperammonemia occurs in biotin deficiency and the functional deficiency associated with lack of holocarboxylase synthetase (Section 11.2.2.1) and bio-tinidase (Section 11.2.3.1). In deficient rats, the activity of ornithine carbamyl-transferase is two - thirds of that in control animals, as a result of decreased gene expression, although the activities of other urea cycle enzymes are unaffected (Maeda etal., 1996). 

Cause deficiencies of urea cycle enzymes, almost exclusively seen in children. 

Animal and human studies have shown that an elevated concentration of ammonia (hyperammonemia) exerts toxic effects on the central nervous system. There are several causes, both inherited and acquired, of hyperammonemia. The inherited deficiencies of urea cycle enzymes are the major cause of hyperammonemia in infants. The two major inherited disorders are those involving the metabolism of the dibasic amino acids lysine and ornithine and those involving the metabolism of organic acids, such as propionic acid, methylmalonic acid, isovaleric acid, and others (see Chapter 55). 

None of these cases can be considered as established examples of an isolated carbamyl phosphate synthetase deficiency. Although in the first the clinical history and the presence of severe hyperammonemia support the diagnosis of a defect of urea synthesis, the normal finding of levels of plasma amino acids, apart from glycine, is against it. No actual numerical data on the level of activity of the urea cycle enzymes are given. 

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... 

Elevated levels of ammonia in the blood can be caused by a deficiency of mitochondrial carbamoyl phosphate synthetase or a deficiency of any of the urea cycle enzymes. These two types of disorders can be distinguished by the presence of orotic acid or related metabolites in the urine. 

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. 

Elevated concentrations of orotic acid and uracil may be found in the urine of heterozygote carriers for urea cycle disorders, most commonly ornithine carbamoyltransferase (OCT) deficiency. This is due to the increased flux through the pyrimidine pathway which occurs, especially where the relevant enzymes are expressed only in liver tissue, as is the case when urea cycle enzymes are defective. A protein load was used previously to stress this route and the elevation in orotic acid excretion used as a diagnostic marker. However, the test frequently failed to detect known carriers. The al-lopurinol loading test (measurement of the increment in urinary orotic acid and orotidine in three separate 8 hour urine collections over the 24 hours following a 300 mg allopurinol tablet) is the most reliable test so far for carrier detection for such disorders [17]. 

An inborn error of metabolism which is due to a deficiency of the urea cycle enzyme argininosuccinase. Argininosuccinic acid and ammonia accumulate and the symptoms include mental retardation and hepatomegaly. 

A rare inborn error of metabolism in which there is a deficiency of this urea cycle enzyme. Hyperammonaemia is a feature of the disease. 

A urea cycle enzyme found mainly in the liver and kidney. High serum levels are found in conditions where there is hepatocellular damage such as hepatitis. A congenital deflciency of the enzyme has also been described (ornithine carbamyl transferase deficiency). 

The toxicity of ammonia was dramatically demonstrated by experiments carried out as early as 1931 injection of the enzyme urease, which catalyses the conversion of urea to ammonia, into rabbits rapidly caused their death. The normal concentration of ammonia in blood is about 0.02 mmol/L toxicity becomes apparent at a concentration of abont 0.2 mmol/L or above (see Table 10.1). Ammonia toxicity in very young children is usually associated with vomiting and eventually coma. It is almost invariably due to the deficiency of an enzyme of the urea cycle (see below). In adults, ammonia accnmulation, and hence toxicity, usually results from damage to the liver caused by poisons, alcohol or viral infection. 

CH 10 METABOLISM OF AMMONIA AND NUCLEIC ACIDS Table 10.5 Changes in the concentration of various intermediates of the urea cycle or their metabolites in plasma or urine in various enzyme deficiency diseases in humans ... 

The answer is B. All the findings are consistent with a diagnosis of hyperammonemia. A clue to its hereditary etiology is provided by the family history suggesting that the patient s sibling may have died of a similar condition. It is likely that the patient is suffering from a deficiency of one of the enzymes of the urea cycle the most common... 

In the urea cycle, two molecules of ammonia combine with a molecule of carbon dioxide to produce a molecule of urea and water. The overall cycle involves a series of biochemical reactions dependent on enzymes and carrier molecules. During the urea cycle the amino acid ornithine (C5H12N202) is produced, so the urea cycle is also called the ornithine cycle. A number of urea cycle disorders exist. These are genetic disorders that result in deficiencies in enzymes needed in one of the steps in the urea cycle. When a urea cycle deficiency occurs, ammonia cannot be eliminated from the body and death ensues. 

The final step of the urea cycle is the cleavage of arginine to release urea and regenerate ornithine. Ornithine then reenters the mitochondria via the ORNT-1 ornithine-citrulline antiporter. ARG-1 is a cytosolic homotrimeric enzyme of 35-kd monomers that is expressed in fiver and red blood cells. A second mitochondrial arginase (ARG-2) most likely plays a role in nitric oxide synthesis and is most abundant in brain, kidney, and prostate. ARG-1 deficiency is unique among the urea cycle deficiencies as patients do not present with hyperammonemia and encephalopathy but rather develop progressive spasticity of the lower limbs. Biochem-... 

The accumulation of any of these amino acids could be due to reduced activity of their respective enzymes in the urea cycle (Sec. 15.5), resulting in decreased overall activity of the cycle. Inborn errors of metabolism are known for deficiencies in these enzymes. Decreased activity of the urea cycle results in elevated levels of ammonia in the blood, a condition known as hyperammonemia that causes nausea, vomiting and even coma. 

---