Ammonia urea cycle disorders

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. 

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. 

Evaluate for urea cycle disorders, as hyperammonemic encephalopathy, sometimes fatal, has been associated with valproate administration in these uncommon disorders urea cycle disorders, such as ormithine transcarbamylase deficiency, are associated with unexplained encephalopathy, mental retardation, elevated plasma ammonia, cyclical vomiting, and lethargy... 

Bachmann C, Colombo JP. Acid-base status and plasma glutamine in patients with hereditary urea cycle disorders. In Soeters PB, Wilson )HP, Meijer AJ, eds. Advances in ammonia metabolism and hepatic encephalopathy, 1st ed. Amsterdam Elsevier, 1988 72-8. 

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. 

Persons who suffer from severe liver or kidney disease may be susceptible to ammonia intoxication, as it is chiefly by the actions of these organs that NH/ is biotransformed and excreted (Cordoba et al. 1998 Gilbert 1988 Jeffers et al 1988) individuals with hereditary urea cycle disorders are also at risk (Schubiger et al. 1991). In these individuals, the levels produced endogenously are sufficient to produce toxicity. Levels that are likely to be encountered in the environment, with the exception of those resulting from high-level accidental exposures, are insignificant, due to the low absorption rate, in comparison with levels produced within the body (WHO 1986). 

After an asymptomatic period, typical signs of intoxication or poisoning as a result of the accumulation of harmful metabolites begin. The length of time of the apparent health can vary across the spectrum of disorders and is shorter if the accumulating metabolite is particularly toxic. For example, ammonia can accumulate to toxic concentrations within hours in cases of severe urea cycle disorders or can manifest over a few days in organic acidurias. At times, the relationship between feeding (breast milk or infant... 

Diaz GA, et al. Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate. Hepatology. 2013 57(6) 2171-9. 

While ammonia, derived mainly from the a-amino nitrogen of amino acids, is highly toxic, tissues convert ammonia to the amide nitrogen of nontoxic glutamine. Subsequent deamination of glutamine in the liver releases ammonia, which is then converted to nontoxic urea. If liver function is compromised, as in cirrhosis or hepatitis, elevated blood ammonia levels generate clinical signs and symptoms. Rare metabolic disorders involve each of the five urea cycle enzymes. 

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). 

The determination of plasma ammonia is of great importance both for the diagnosis and for the treatment of hereditary metabolic disorders of the urea cycle. The level is always raised in these conditions since the other mechanisms for regulating blood ammonia mentioned above are not able by themselves to keep the ammonia level within normal limits. 

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. 

The primary function of the urea cycle is to rid the body of waste nitrogen. Deficiency in the activity of any of the six enzymes in the urea cycle may result in the accumulation of ammonia, often to toxic concentrations. Treatment involves restricting protein, preventing catabolism, supplementing amino acids that are normally produced by the urea cycle, and promoting the excretion of nitrogen via alternative pathways. Outcomes are guarded and appear to be better for patients identified by NBS compared to patients identified clinically. Liver transplantation is a treatment option, especially for patients with a severe form of the disorder. 

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. 

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