Ornithine deficiency

Citrulline is exchanged for ornithine across the inner mitochondrial membrane by ORNT-1. Ornithine is produced in the cytosol as the final step in the urea cycle and must be returned to the mitochondrial matrix for transcarbamoyla-tion by OTC. A second ornithine-citrulline antiporter (ORNT-2) is also expressed in the liver mitochondria and may attenuate the severity of disease in patients with HHH (Hyperammonemia, Hyperornithinemia, Homocitrullinuria) disease due to ORNT-1 deficiency. This disorder typically manifests later in life with intermittent hyperammonemic encephalopathy and protein aversion. Intramitochondrial ornithine deficiency causes both hyperammonemia and hyperornithinemia due to a lack of substrate for OTC. Homocitrullinuria occurs due to the use of lysine by OTC as an alternate substrate. The diagnosis is confirmed by mutation analysis. 

Hyperammonemia Type 2. A deficiency of ornithine transcarbamoylase (reaction 2, Figure 29-9) produces this X chromosome-linked deficiency. The mothers also exhibit hyperammonemia and an aversion to high-protein foods. Levels of glutamine are elevated in blood, cerebrospinal fluid, and urine, probably due to enhanced glutamine synthesis in response to elevated levels of tissue ammonia. 

Tuchman M et al The biochemical and molecular spectrum of ornithine transcarbamoylase deficiency. J Inherit Metab Dis 1998 21 40. 

Since pyrimidine catabolites are water-soluble, their overproduction does not result in clinical abnormalities. Excretion of pyrimidine precursors can, however, result from a deficiency of ornithine transcar-bamoylase because excess carbamoyl phosphate is available for pyrimidine biosynthesis. 

Diagnosis of CPS or OTC deficiency may not be apparent from the blood aminogram. Ornithine levels typically are normal. The presence of hyperammonemia, hyperglu-taminemia, hyperalaninemia and orotic aciduria in a critically ill infant affords presumptive evidence for OTC deficiency. The presence of this blood aminogram without orotic aciduria suggests carbamyl phosphate synthetase deficiency. 

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. 

The cause is defective transport of dibasic amino acids by the proximal tubule and intestine. The transport defect occurs at the basolateral rather than the luminal membrane. Hyperammonemia reflects a deficiency of intra-mitochondrial ornithine. An effective treatment is oral citrulline supplementation, which corrects the hyperammonemia by allowing replenishment of the mitochondrial pool of ornithine. 

Yudkoff, M., Daikhin,Y., Nissim, I., Jawad,A.,Wilson, J. and Batshaw, M. B. In vivo nitrogen metabolism in ornithine transcarbamylase deficiency. /. Clin. Invest. 98 2167-2173, 1996. 

Ye, X., Robinson, M. B., Batshaw, M. L., Furth, E. E., Smith, I. and Wilson, J. M. Prolonged metabolic correction in adult ornithine transcarbamylase-deficient mice with adenoviral vectors. / Biol. Chem. 271 3639-3646,1996. 

The two conditions can be distinguished by an increase in orotic add and uracil, which occurs in ornithine transcarbamoylase deficiency, but not in the defldency of carbamoyl phosphate synthetase. Orotic acid and uracil are intermediates in pyrimidine synthrais (see Chapter 18). This pathway is stimulated by the accumulation of carbamoyl phosphate, the substrate for ornithine transcarbamoylase in the urea cycle and for aspartate transcarbamoylase in pyrimidine synthesis. 

Answer E. Given these symptoms, the defect is in the urea cycle and the elevated orotate suggests deficiency of ornithine transcarbamoylase. 

In view of the toxicity of ammonia, complete absence of any one of the enzymes of the cycle is fatal. Nonetheless, disorders of the cycle do occur, which are caused by a low activity of one of the enzymes or carbamoyl phosphate synthetase. In addition, defects in N-acetylglutamate synthase have been reported, but they are very rare. With the exception of ornithine transcarbamoylase, the deficiencies have an autosomal recessive mode of inheritance. The transcarbamoylase deficiency is inherited as an X-linked dominant trait, usually lethal in male patients. A deficiency of carbamoyl phosphate synthetase, ornithine transcarbamoylase or argininosuccinate synthetase results in accumulation and excretion of citrulline. A deficiency of argininosuccinate lyase results in the accumulation and excretion of argininosuccinate and arginine (Table 10.5). The abbreviations CPSD, OTCD, ASD, ALD and AD stand, respectively, for the deficiencies of these enzymes, where D stands for deficiency. 

Lactobacillus delbrueckii. In 1953, Rodwell suggested that the histidine decarboxylase of Lactobacillus 30a was not dependent upon pyridoxal phosphate (11). Rodwell based his suggestion upon the fact that the organism lost its ability to decarboxylate ornithine but retained high histidine decarboxylase activity when grown in media deficient in pyridoxine. It was not until 1965 that E. E. Snell and coworkers (12) isolated the enzyme and showed that it was, indeed, free of pyridoxal phosphate. Further advances in characterization of the enzyme were made by Riley and Snell (13) and Recsei and Snell (14) who demonstrated the existence of a pyruvoyl residue and the participation of the pyruvoyl residue in histidine catalysis by forming a Schiff base intermediate in a manner similar to pyridoxal phosphate dependent enzymes. Recent studies by Hackert et al. (15) established the subunit structure of the enzyme which is similar to the subunit structure of a pyruvoyl decarboxylase of a Micrococcus species (16). 

Urea cycle disorders (UCDs) Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with UCDs, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders (see Precautions). 

The answer is D. The patient s symptoms are consistent with a kidney stone, which is confirmed by the radiographic finding. The etiology of the stone is indicated by the urinalysis data, which suggest cystinuria. The cells of this patient s renal proximal tubules would be deficient in a transporter responsible for the reabsorptive uptake of cystine and the basic amino acids, arginine, lysine, and ornithine. Failure of the tubules to reabsorb these amino acids from the ultrafiltrate causes them to be excreted at high concentration in the urine. 

Ornithine transcarbamoyiase deficiency, an X-iinked condition and the most common of these disorders. -CPS-i deficiency. 

A patient with ornithine transcarbamylase (OTC) deficiency is being treated in a gene therapy clinical trial. The gene therapy approach for this disease is primarily designed to... 

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. 

Morsy, M.A., Alford, E.L., Bett, A., Graham, F.L., Caskey, C.T. (1993). Efficient adenoviral-mediated ornithine transcarmylase expression in deficient mouse and human hepatocytes. J. Clin. Invest., 92, 1580-1586. 

Ornithine carbamoyltransferase deficiency p Glnf, Citf, Alaj, Lysj, ArgJ,... 

Supplementing the diet with arginine is useful in treating deficiencies of ornithine transcarbamoylase, argini-nosuccinate synthetase, and argininosuccinase. Many... 

Kay JD, Hilton-Jones D, Hyman N. Valproate toxicity and ornithine carbamoyltransferase deficiency. Lancet 1986 2(8518) 1283 1. 

Raper, S. E., Chirmule, N., Lee, F. S., Wivel, N. A., Bagg, A., Gao, G. P., Wilson, J. M. and Batshaw, M. L. (2003). Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol. Genet. Metab. 80, 148-158. 

A number of inherited disorders of urea cycle metabolism are known. Hy per-ammonemia I and II are associated with CPS I and ornithine transcarbamylase deficiencies, respectively. Citrullinemia, arginosuccinic aciduria, and argininemia are associated with low levels of arginosuccinic acid synthetase, arginosuccinase, and arginase, respectively. All such disorders are associated with mental retardation, convulsions, and failure to thrive if not treated. Treatment involves the feeding of low-protein diets or, experimentally, the administration of a-keto analogs of essential amino acids instead of protein. 

The clinical syndrome of acute neonatal hyper-ammonemic encephalopathy described in the case report represents the classical presentation of a patient with a urea cycle disorder (UCD). It is important to note that this neonatal course represents only the most common and severe presentation of a UCD. This holds true for all the diseases listed in Table 18-1, with the exceptions of arginase (ARG-1) deficiency, which results in progressive spasticity of the lower limbs, and of the mitochondrial membrane transporters citrin and ornithine transporter 1 (ORNT-1). Deficiency of citrin results in adult-onset encephalopathy deficiency of... 

Ornithine transcarbamoylase OTC deficiency OTC Xp21.1 Liver Citrulline i Orotic acid TT... 

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