Hyperammonemia urea cycle enzymes

Hyperammonemia Urea Cycle Enzyme Levels in Liver"... 

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). 

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. 

Given the following information about five newborn infants (identified as I to V) who appeared normal at birth but developed hyperammonemia after 24 hours, determine which urea cycle enzyme might be defective in each case (for each infant, choose from the same five answers, lettered A through E). All infants had low levels of blood urea nitrogen (BUN). (Normal citrulline levels are 10-20 p,M.)... 

There is evidence of a pathogenetic link between hyperammonemia and the phenomenon of Alzheimer type II astrocytosis this astrocytic phenotype has been described in a wide range of hyperammonemic syndromes associated with congenital urea cycle enzyme defects, as well as in experimental animals with urease-induced hyperammonemia and in primary cultures of astrocytes exposed to anunonia (Butterworth et al., 1987). 

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... 

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. 

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. 

Hyperammonemia in Conditions Affecting the Urea Cycle Other Than Primary Enzyme Errors of Urea Synthesis... 

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. 

Explain how deficiencies in several different enzymes of the urea cycle give rise to hyperammonemia. 

Valproate may contribute to hyperammonemia by inhibiting carbamoylphosphate synthetase-I, the enzyme that begins the urea cycle. Phenobarbital may potentiate the toxic effect of valproate. The electroencephalogram in severe hyperammonemic encephalopathy exhibits continuous generalized slowing, a predominance of theta and delta waves, bursts of frontal intermittent rhythmic delta activity, and triphasic waves (Segura-Bruna et al., 2006). 

Hyperammonemia may also result from congenital or acquired causes that are not related to inherited metabolic diseases. Examples of congenital causes include malformations such as portosystemic shunts, extrahepatic portal vein obstructions, and cirrhosis with portal hypertension. Transient hyperammonemia of the newborn (THAN) is typically identified in premature infants and does not appear to have a neurologic effect on those asymptomatic preterm infants [11]. Liver failure may also result in fulminant hyperammonemia. In severe liver failure, all of the enzymes expressed in the liver are deficient, resulting in complete impairment of the urea cycle as well as a deficiency of other important liver-specific enzymes snch as the glycine cleavage enzyme. 

Three inborn errors of metabolism involving enzymes of the urea cycle have been demonstrated. These diseases are observed in children less than a year old. They all cause hyperammonemia and have a characteristic neurological and gastrointestinal symptomatology nausea, vomiting, agitation, convulsions, stupor, coma, and general mental retardation (see Fig. 9-14). 

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