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... 

Treatment of aminoacidurias with a low-protein diet may influence brain chemistry. It should be emphasized that the treatment of the patient with an aminoaciduria may affect brain chemistry, perhaps in an adverse manner. Nearly all patients receive a low-protein diet. Indeed, undiagnosed patients sometimes avoid consumption of protein, which they feel intuitively can cause lethargy, headache, nausea and mental confusion. As dietary protein declines, the intake of carbohydrate frequently increases. The concomitant rise of endogenous insulin secretion favors an increase in the ratio of the concentration of blood tryptophan to that of other amino acids, thereby promoting the entry of tryptophan to the brain. The latter amino acid is precursor to brain serotonin, which tends to increase. This physiology is known to be operative in patients with urea cycle defects. 

Urea cycle defects cause a variety of clinical syndromes, including a metabolic crisis in the newborn infant. 

Severe urea cycle defects become manifest in infants with a severe syndrome of coma, convulsions and vomiting during the first few days of life. Clinical confusion with septicemia is common, and many infants are treated futilely with antibiotics. Hyperammonemia is usually severe, even in excess of 1 mmol/1 (normal in term infants <100 xmol/l). 

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. 

Ornithine transcarbamylase deficiency. This is the most common of the urea cycle defects. Presentation is variable, ranging from a fulminant, fatal disorder of neonates to a schizophrenic-like illness in an otherwise healthy adult. Males characteristically fare more poorly than do females with this X-linked disorder because of random inactivation (lyonization) of the X chromosome. If inactivation affects primarily the X chromosome bearing the mutant OTC gene, then a more favorable outcome can be anticipated. Conversely, the unfavorably lyonized female has a more active disease. 

Urea cycle defects sometimes result from the congenital absence of a transporter for an enzyme or amino acid involved in the urea cycle. 

Arginine Hyperargininemia LPI Urea cycle defects, HHH syndrome Hemolytic plasma ... 

Lysine Urea cycle defects Organic acidemias Hyperornithinemia... 

Hjelm M, de Silva LV, Seakins JW, Oberholzer VG, Rolles CJ. Evidence of inherited urea cycle defect in a... 

OTC deficiency is the most common urea cycle defect.As it is X linked, affected boys typically have severe disease with neonatal presentation as described in this chapter. The disease in women who carry an OTC mutation on one X chromosome ranges from severe early-onset disease to complete absence of symptoms. Furthermore, affected women may decompensate in the context of a metabolic stress such as an infection or following parturition. OTC-deficient patients have low plasma citrulline and high urine orotic acid. Confirmation of the diagnosis requires mutation analysis or a liver biopsy for enzymology. The carrier status of women is most accurately determined by mutation analysis. 

List several metabolic fates of the amino acid arginine in the human. What is the difference between essential and non-essential amino acids How is this relevant to the treatment of urea cycle defects ... 

Patients with urea cycle defects may present at any age. In the neonatal period, a variable but usually brief interval is... 

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. 

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. 

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... 

The key to treating patients with urea cycle defects is to diagnose the disease early and then aggressively treat with compounds that can aid in nitrogen removal... 

Fig. 38.18. The metabolism of benzoic acid (A) and phenylbutyrate (B), two agents used to reduce nitrogen levels in patients with urea cycle defects.

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