Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

X-linked ornithine transcarbamylase deficiency (OTCD) often leads to fatal neonatal hyperammonemia in affected males (hemizygotes). In prenatal management of subsequent pregnancies, families carrying female fetuses are often reassured of the low risk of clinically overt disease. We suggest that such reassurance may be misleading. While OTCD heterozygotes may show no symptoms or only mild protein intolerance, the clinical course in a fraction of children can include manifestations similar to those in affected males. We present three cases of symptomatic and previously undiagnosed OTCD heterozygotes to illustrate the potential severity of this condition. Significant improvement in function and growth followed diagnosis and treatment; however, two of the three children remain significantly developmentally delayed. While a quantitative risk estimate cannot be derived from these data, the cases are indicative of an adverse outcome in manifesting heterozygotes. Accordingly, OTCD carrier families should be counseled regarding the possibility of significant hyperammonemia, neurologic deficit, and the need for pharmacologic and dietary intervention in their heterozygote daughters.
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PMID:Prenatal counseling in heterozygotes for ornithine transcarbamylase deficiency. 800 20

Sparse-fur (spf) mutant mice with X-linked ornithine transcarbamylase deficiency were used to study the effect of L-carnitine on energy metabolites in congenital hyperammonemia. L-Carnitine was used at doses of 2, 4, 8, or 16 mmol/kg body weight (BW), and levels of ammonia, glutamine, glutamate, and some intermediates of energy metabolism were measured in brain and liver of spf/Y mice. Cerebral and hepatic levels of ammonia were decreased with 4 mmol L-carnitine (P < .001), whereas other doses did not seem to have any effect on this metabolite. Cerebral levels of glutamine were decreased following administration of L-carnitine at doses of up to 4 mmol/kg BW, whereas hepatic glutamine levels remained unaltered at all doses of L-carnitine. Both cerebral and hepatic levels of pyruvate, lactate, and alpha-ketoglutarate were decreased at doses of up to 8 mmol L-carnitine/kg BW. L-Carnitine treatment elevated adenosine triphosphate (ATP), free coenzyme A (CoA), and acetyl CoA levels in both brain and liver of spf/Y mice. Cytosolic and mitochondrial redox ratios of spf/Y mice, which were altered by congenital chronic hyperammonemia, were partially corrected by L-carnitine administration. L-Carnitine supplementation to spf/Y mice during sodium benzoate therapy also restored the availability of free CoA and ATP, thus counteracting the adverse effects of higher doses of sodium benzoate. These changes in free CoA and acetyl CoA levels could be due to the deinhibition of pantothenate kinase and stimulation of fatty acid oxidation by L-carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of L-carnitine on cerebral and hepatic energy metabolites in congenitally hyperammonemic sparse-fur mice and its role during benzoate therapy. 810 93

Ornithine transcarbamylase deficiency (OTC), the most common inborn error of the urea cycle, shows an X-linked inheritance with frequent new mutations. Southern blots reveal only a small percent of the mutation, but amplification of cDNA or genomic DNA using the polymerase chain reaction (PCR) followed by DNA sequencing, has contributed greatly to overcoming this difficulty. Problems remaining are the limited availability of fresh liver samples for preparation of intact mRNA in the former case, and there are primer sequences for PCR for only some exons in the latter case. Here, we report the structures of intron sequences which are long enough to analyze all exons and adjacent introns of the OTC gene using PCR and PCR single-strand conformation polymorphisms (PCR-SSCP). We carried out a DNA analysis of findings in five Japanese male patients with neonatal or late onset form. Five patients had mutations in the protein coding region. C to G (S192R), A to T (D196V), A to G (T264A), T to C (M268T), and C to T (R277W) substitutions. The first four of these were novel missense mutations and the presence of the mutation was confirmed in the corresponding families.
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PMID:Four novel gene mutations in five Japanese male patients with neonatal or late onset OTC deficiency: application of PCR-single-strand conformation polymorphisms for all exons and adjacent introns [corrected]. 836 26

Breeding experiments were conducted to combine the X-linked sparse-fur (spf) mutation with ornithine transcarbamylase deficiency and the autosomal recessive deficiency of short-chain acyl CoA dehydrogenase (SCAD) in BALB/cByJ mice. We obtained spf/Y (scad/scad), spf/+ (scad/scad) and spf/spf (scad/scad) double mutants amongst the F2 progeny, which were tested and separated on the basis of urinary orotate and the GC/MS analysis of urinary butyrylglycine, methylsuccinate and ethylmalonate. The testing of the biochemical type was feasible both on the basis of a 24-h urine collection form adult mice kept in metabolic cages and on the basis of urine spots collected on filter paper from younger progeny. It is postulated that the spf/Y (scad/scad) double-mutant may serve as a useful animal model to study the ammonia: fatty acyl CoA synergism.
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PMID:Breeding experiments to combine the X-linked sparse-fur (spf) mutation with the autosomal recessive BALB/cByJ strain: testing the biochemical phenotype of double-mutant mice as a model for ammonia: fatty acyl CoA synergism. 846 Oct 26

Ornithine carbamoyltransferase deficiency (OCTD) is the most common inborn error of urea synthesis. An X-linked disorder, OCTD males commonly present with hyperammonemic coma in the newborn period. There is a high rate of mortality and morbidity, with most survivors sustaining severe brain damage and resultant developmental disabilities. Although ammonia is presumed to be the principal neurotoxin, there is evidence that other neurochemical alterations may also be involved. The OCTD sparse fur (spf/Y) mouse has proven to be a useful model of this disease with similar metabolic and neurochemical alterations to those found in the human disease. In this study, the levels of the tryptophan derived excitotoxin quinolinic acid were examined in the brains of spf/Y mice. In addition, the neuropathology was examined using both light and electron microscopic approaches. Consistent with reports in children with urea cycle disorders, the levels of tryptophan and quinolinic acid were increased two-fold in various brain regions of the spf/Y mouse. Quinolinic acid, an agonist at the N-methyl-D-aspartate (NMDA) receptors, is known to produce selective cell loss in the striatum. We found a significant loss of medium spiny neurons and increased numbers of reactive oligodendroglia and microglia in the striatum of spf/Y mice. These neurochemical and neuropathological observations are consistent with an excitotoxic influence on brain injury in OCTD. It leads us to suggest that administration of NMDA receptor antagonists may ameliorate brain damage in children with inborn errors of urea synthesis.
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PMID:Evidence of excitotoxicity in the brain of the ornithine carbamoyltransferase deficient sparse fur mouse. 877 76

Ornithine Transcarbamylase Deficiency, an X-linked disorder, is the most common cause of inherited urea cycle disorders. Approx. 90 mutations that produce reduced levels of ornithine transcarbamylase (OTCase) activity have been identified in patients [Tuchman (1993) Hum. Mutat. 2, 174-178; Tuchman and Plante (1995) Hum. Mutat. 5, 293-295]. A model of the three-dimensional structure of OTCase, developed on the basis of its homology to the catalytic subunit of Escherichia coli aspartate transcarbamylase (ATCase) [Tuchman, Morizono, Reish, Yuan and Allewell (1995) J. Med. Genet. 32, 680-688], and in good agreement with the crystal structure of Pseudomonas aeruginosa OTCase [Villeret, Tricot, Stalon and Dideberg (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 10762-10766], indicates that many mutations that produce severe clinical symptoms are at the active site or buried in the interior of the protein. However, one of the few recurrent mutations, R277W, an alteration that produces a milder phenotype of ornithine transcarbamylase deficiency, is located in the model in a loop remote from the active site that is analogous to a similar loop (the 240's loop, a flexible loop of the catalytic chain of Escherichia coli aspartate transcarbamylase, comprised of residues 230-250) of ATCase. Human wild-type OTCase and the R277W mutant have been cloned and overexpressed in E. coli and a rapid and efficient purification method utilizing the bisubstrate analogue, Ndelta-(phosphonacetyl)-L-ornithine, has been developed and used to purify both proteins. Gel chromatography indicates both are trimeric. The pH dependence of the kinetic parameters of the wild-type enzyme is similar to that of E. coli OTCase [Kuo, Herzberg and Lipscomb (1985) Biochemistry 24, 4754-4761], suggesting that its catalytic mechanism is similar, although its maximal activity is approx. 10-fold less. Compared with the wild-type, the R277W mutant has nearly 70-fold lower affinity for L-ornithine, shows no substrate inhibition, and its thermal stability is reduced by 5 degrees C. Its reduced affinity for L-ornithine, which in turn results in lower activity at physiological concentrations of ornithine, as well as its reduced stability, may contribute to the clinical effects that it produces.
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PMID:Expression, purification and kinetic characterization of wild-type human ornithine transcarbamylase and a recurrent mutant that produces 'late onset' hyperammonaemia. 906 86

Ornithine transcarbamylase deficiency (OTCD) is an inborn error of urea synthesis inherited as an X-linked trait, a clinical manifestation of which is a repeated episodes of hyperammonemic coma. Recently, liver transplantations have been performed in these patients in the USA and Europe. We experienced the anesthetic managements of liver transplantations in two OTCD patients, who had been suffering from several episodes of hyperammonemic decompensation despite a restricted protein diet with administration of sodium benzoate. Anesthesia was induced and maintained with a combination of fentanyl and midazolam in both cases. Their postoperative courses were good without any neurological damages, though one patient had hyperammonemic attack during the operation.
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PMID:[Living related liver transplantation for patients with ornithine transcarbamylase deficiency]. 922 81

Ornithine transcarbamylase deficiency shows X-linked inheritance with partial dominant expression in carrier females. We studied a girl with intermittent severe orotic aciduria and mild hyperammonaemia despite apparently normal enzyme activity in the liver. Sequence analysis of all 10 exons of the ornithine transcarbamylase gene revealed a novel A-->G exchange (A502G) in exon 5 which changes His-136 to arginine in the ornithine transcarbamylase protein. Km values for carbamyl phosphate and ornithine determined in the patient's liver were comparable to those of wild-type enzyme but, unlike the wild-type enzyme, the mutant enzyme was unstable upon freezing and thawing. Electron microscopy revealed several giant mitochondria with paracrystalline inclusions. The results are compatible with the assumption that the mutant enzyme cannot form a functional complex with carbamyl phosphate synthetase and the ornithine carrier, resulting in decreased availability of substrates and diminished enzyme activity in vivo.
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PMID:Mutation of ornithine transcarbamylase (H136R) in a girl with severe intermittent orotic aciduria but normal enzyme activity. 926 87

Ornithine carbamoyltransferase deficiency, an X-linked trait, leads to toxic hyperammonemia in sparse fur (spf/Y) mice. Quantitative analysis of the basilar dendritic tree of layer V pyramidal cells in frontoparietal cortex stained by the Golgi Kopsch method revealed a significant decrease in both the complexity of the dendritic arbor and in dendritic terminal spine density (60%) in spf/Y mice compared with controls. Such reductions may contribute to behavioral dysfunction observed in spf/Y mice.
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PMID:Dendritic alterations in cortical pyramidal cells in the sparse fur mouse. 963 Jun 7

The N-methyl-d-aspartate (NMDA) receptor, a glutamate receptor subtype, is a ligand-gated ion channel. Overstimulation of NMDA receptors may increase intracellular Ca2+ concentrations to lethal levels in neurodegenerative disorders affecting the basal ganglia. Such excitotoxicity may also contribute to the loss of medium spiny neurons in the striata of the hyperammonemic sparse fur (spf/Y) mouse, a model of the X-linked disorder of the urea cycle, ornithine carbamoyltransferase deficiency (OCTD). Levels of quinolinic acid (QA), a potent NMDA agonist, are elevated in the brains of spf/Y mice. Further, direct injection of QA into the striatum produces selective degeneration of medium spiny neurons. Microglia, an endogenous source of QA in the brain, are abundant in spf/Y mice during the period of neuronal degeneration. The location and density of NMDA receptors was visualized by gold labelled immunocytochemistry with a polyclonal antibody to the NMDAR1 receptor subtype and their distribution quantified. A 58% reduction was found in the median density value in the layer V pyramidal neurons in fronto-parietal cortex (p<0.001), but no significant change was observed in the striatum. NMDA receptor binding was examined using [3H]dizocilpine ([3H]MK-801). Receptor density (Bmax) in the striata of clinically stable spf/Y mice and +/Y littermates was unchanged, but was decreased 15% (p<0.01) in the fronto-parietal cortices in clinically stable spf/Y mice compared with +/Y littermate controls.
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PMID:Characterization of N-methyl-d-aspartate receptors in the hyperammonemic sparse fur mouse. 966 30


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