Urea Inborn errors

Hepatic urea synthesis takes place in part in the mitochondrial matrix and in part in the cytosol. Inborn errors of metabolism are associated with each reaction of the urea cycle. 

Brusilow, S., Tinker, J. and Batshaw, M. L. Amino acid acylation A mechanism of nitrogen excretion in inborn errors of urea synthesis. Science 207 659,1980. 

Inherited absence or mutations in enzymes involved in critical metabolic pathways—eg, the urea cycle or glycogen metabolism—are referred to as inborn errors of metabolism. If not detected soon after birth, these conditions can lead to serious metabolic derangements in infants and even death. 

Concentrations of metabolites outside the reference ranges may constitute a typical pattern indicating the presence of an inborn error of purine or pyrimidine metabolism. However, altered excretions of purine and pyrimidines may also be a secondary phenomenon due to the presence of other metabolic disorders, such as a deficiency of the urea cycle [15]. Increased concentration of a single metabolite or combinations of metabolites may also result from bacterial contamination, sample conditions, medication, or dietary compounds [6]. 

Table 18-1. Enzymes, Transporters, and Biochemical Features of Inborn Errors of Urea Synthesis... 

Several classes of inborn errors of metabolism in addition to inborn errors of urea synthesis can cause neonatal hyperammonemia. These include organic acidurias, fatty acid oxidation defects, amino acidopathies, and mitochondrial respiratory chain disorders. All of these disorders have a number of features in common. Labor and delivery tend to be normal, and there are no predisposing risk factors. Clinical features present after 24 h of life and are progressive. They are inherited, and thus a family history of previously affected children or neonatal deaths may be present. While most are inherited in an autosomally recessive manner, ornithine tran-scarbamoylase (OTC) deficiency is X linked, and a family history of affected males in the maternal pedigree is not uncommon. 

In the majority of cases, a UCD can be distinguished from other inborn errors of metabolism by routinely available clinical chemistry tests such as blood gases, acid/base balance, plasma glucose, ammonium, or lactate. Urea production, and hence serum urea nitrogen, is decreased in UCDs. Respiratory alkalosis has few causes and is an important diagnostic clue of hyperammonemia that should trigger measurement of plasma ammonium. 

Consideration of other plasma amino acids also informs the diagnosis of inborn errors of urea synthesis. The plasma concentrations of glutamine and alanine are often elevated in parallel with or prior to the ammonium concentration as they act as a nitrogen buffer. Plasma arginine concentrations are low since the only synthetic route for arginine in humans is via the urea cycle. In contrast, the arginine concentration is elevated in ARG-1 deficiency. Hyperornithinemia and homocitrullinuria are the characteristic features of the hyperammonemia, hyperornithinemia, and homocitrullinuria (HHH) syndrome caused by a defect in the ornithine transporter (ORNT-1). 

Dehydrogenase Deficiency, Biotinidase Deficiency, and Adrenoleukodystrophy. Catabolism of essential amino acid skeletons is discussed in the chapters Phenylketonuria and HMG-CoA Lyase Deficiency. The chapters Inborn Errors of Urea Synthesis and Neonatal Hyperbilirubinemia discuss the detoxification and excretion of amino acid nitrogen and of heme. The chapter Gaucher Disease provides an illustration of the range of catabolic problems that result in lysosomal storage diseases. Several additional chapters deal with key aspects of intracellular transport of enzymes and metabolic intermediates the targeting of enzymes to lysosomes (I-Cell Disease), receptor-mediated endocytosis (Low-Density Lipoprotein Receptors and Familial Hypercholesterolemia) and the role of ABC transporters in export of cholesterol from the cell (Tangier disease). 

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. 

Brusilow SW, Danney M, Waber LJ, et al. Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis. N Engl Med 1984 310 1630-1634. 

Citrulline is an endogenous amino acid involved in the urea cycle. Clinically, it can be used as an arginine substitute in the treatment of inborn errors of urea synthesis, including carbamyl phosphate synthetase and ornithine transcarbamylase. It is also a diuretic. 

The method of choice is ion exchange chromatography by automatic analysis (S14). Urine and cerebrospinal fluid can be applied directly to the column, but plasma must be first deproteinized. Since the accurate estimation of gultamine is of paramount importance in all inborn errors of the urea cycle, care must be taken to avoid the breakdown of glu-... 

Biochemical Findings in Inborn Errors of the Urea Cycle 10.1. Argininosuccinic Aciduria... 

Hyperammonemias are caused by inborn errors of ureagenesis and organic acidemias, liver immaturity (transient hyperammonemia of the newborn), and liver failure (hepatic encephalopathy). Neonatal hyperammonemias are characterized by vomiting, lethargy, lack of appetite, seizures, and coma. The underlying defects can be identified by appropriate laboratory measurements (e.g., assessment of metabolic acidosis if present and characterization of organic acids, urea cycle intermediates, and glycine). 

Inborn errors of the six enzymes of ureagenesis and NAG synthase have been described. The inheritance pattern of the last is not known, but five of the urea cycle defects are autosomal recessive and ornithine carbamoyl-transferase (OCT) deficiency is X-linked. 

M. L. Batshaw Inborn errors of urea synthesis. Annals of Neurology 35,133 (1994). 

Protein degradation and the inflammatory response (p. 664) Inherited defects of the urea cycle (hyperammonemia) (p. 664) Inborn errors of amino acid degradation (p. 672)... 

Some patients have an inborn error of metabolism that involves a defective enzyme, or enzymes of the urea cycle. This results in reduced efficiency to excrete their waste nitrogen. The patients are prescribed sodium phenylbutyrate (buphenyl) ( 30 g per day). What is the action of sodimn phenylbutyrate ... 

Other, more specific, transporter dysfunctions lead to distinct inborn errors of metabolism. Oxaluria and cystinuria, defects in oxalate and cysteine transport, respectively, manifest with renal stones. Cystinuria specifically presents with cysteine, ornithine, lysine, and arginine in the urine. The latter should not be confused with cystinosis. Lysinuric protein intolerance (LPI) is a defect in the dibasic amino acid transporter. This results in a specific amino aciduria pattern (ornithine, lysine, and arginine), which in turn results in secondary inhibition of the urea cycle. Individuals affected by LPI are at risk for hyperammonemia and also have a unique susceptibility to macrophage activation syndrome, an exaggerated systemic inflammatory response, and alveolar proteinosis. Renal damage... 

Ml Macleod, P., Mackenzie, S. and Scriver, C. R. Partial ornithine carbamyl transferase deficiency, an inborn error of the urea cycle presenting as orotic aciduria in a male infant. Can. Med. Assoc. J., 107, 405-408 (1972)... 

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). 

A basic amino acid found in many proteins. It is also involved in urea biosynthesis. In the inborn error, cystinuria, it is excreted in the urine in large amounts, along with other basic amino acids. 

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. 

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