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)

Ornithine transcarbamylase deficiency is an X-linked disease with possible manifestations in heterozygous females. Using segregation analysis in families from the literature pooled with a French series, the penetrance could be estimated to be 17% in heterozygous females (15% with severe and 2% with milder symptoms). Using these estimates, the proportion of sporadic cases among heterozygous females and hemizygous males could be derived. This proportion is 57% in females. In males, it depends on mutation rate values: assuming equal mutation rates in sperm and eggs, this proportion should be 40%. However, this value can be strongly rejected based on the proportion of isolated cases in male sibships. In both sets of data, segregation analysis provided no evidence for sporadic affected males, suggesting that there are virtually no mutations in eggs. The upper limit of the confidence interval, 0%-16%, can be taken as the maximum prior probability that an affected male occurs as the result of a new mutation in his mother's germ cells.
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PMID:A probable sex difference in mutation rates in ornithine transcarbamylase deficiency. 229 52

Ornithine carbamoyltransferase is an X-linked mitochondrial enzyme expressed in hepatocytes and enterocytes. A deficiency of this enzyme results in central nervous system dysfunction, which may be fatal in newborn boys. Milder forms are seen in older boys and girls and in adults. Establishing the carrier status of women at risk for ornithine carbamoyltransferase deficiency is important for determining reproductive and medical risks for affected women. We report a test to establish the carrier status of women at risk for ornithine carbamoyltransferase deficiency. This test relies on the allopurinol-induced accumulation of orotidine, whose synthesis is stimulated by carbamoyl phosphate, a substrate that accumulates in ornithine carbamoyltransferase deficiency. We used anion-exchange, high-performance liquid chromatography to measure urinary orotidine and orotic acid excretion after the administration of a 300-mg oral dose of allopurinol in 25 [corrected] women who were obligate heterozygotes, 13 who were probable heterozygotes, 15 mothers of affected boys from monoplex families (families with only one affected member), 12 mothers of affected girls from monoplex families, and 21 [corrected] normal, unrelated women who were not carriers. Urinary orotidine excretion was increased 3 SD or more above the mean value for the normal women in 95.8 percent of the obligate heterozygotes, 84.6 percent of the probable heterozygotes, 73.3 percent of the mothers of affected boys in monoplex families, and 33.3 percent of the mothers of affected girls in monoplex families, thus establishing that these women were carriers of a mutant ornithine carbamoyltransferase allele. The presence of allopurinol-induced orotic aciduria was not as sensitive or specific an indicator of carrier status as the presence of orotidinuria. We conclude that measurement of urinary orotidine excretion after the administration of allopurinol is a simple and reliable test for the identification of women who are heterozygous for ornithine carbamoyltransferase deficiency.
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PMID:Allopurinol-induced orotidinuria. A test for mutations at the ornithine carbamoyltransferase locus in women. 234 27

The in vivo functioning of the urea cycle in the Rett syndrome (RS) was investigated using alanine load test. The test was carried out in girls with RS and their mothers. These results were compared with those on normal females, males and obligate carriers for ornithine carbamoyltransferase deficiency. Post load hyperammonaemia was not seen in any of the RS girls who were not on medication (valproate). Increased orotate excretion was found in some of the RS girls and mothers. The pattern of urinary excretion of orotate in RS girls and their mothers after a standardised alanine load was similar to that found in female carriers of OCT deficiency. This finding can be explained by a mutant OCT, subject to the Lyon effect, and linked to the gene abnormality in RS or by the presence of an abnormal X-linked mitochondrial protein synthesised in cytoplasma and positioned in close proximity to OCT. Such a protein abnormality could also affect mitochondrial functions in other cells, e.g. in the developing brain.
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PMID:The urea cycle in the Rett syndrome. 189 21

Benzoate conjugation, represented by hippurate synthesis, was measured in hepatocytes isolated from normal and sparse-fur (spf) mutant mice, with X-linked ornithine transcarbamylase deficiency, to compare the effects of glyoxylate and piridoxylate (a hemiacetal of glyoxylate and pyridoxine), substituted for glycine. Various amino acid precursors of glycine described in the literature, including serine, threonine, glutamine, and glutamate, were studied in a similar manner. The role of glyoxylate and piridoxylate was also assessed in the renal cortex, in comparison with liver homogenates from normal and hyperammonemic mice. The results indicate the importance of glyoxylate and piridoxylate to completely substitute for glycine (96-115%) in isolated hepatocytes of spf/Y mice, as compared with 53-69% (p less than 0.05) in normal +/Y controls. The mean value of amino acid precursors to substitute for glycine in spf mice was serine 51%, threonine 29% (p less than 0.05), and glutamine 9%. In normal mice, only serine (21%) (p less than 0.01) partly substituted for glycine, whereas threonine, glutamine and glutamate gave negative values of net hippurate synthesis. The specific activity of renal cortex for hippurate synthesis from glycine, glyoxylate and piridoxylate was 3-4 times that of liver homogenates (p less than 0.01 - less than 0.001). A scheme for the transamination of glyoxylate by alanine is presented. Besides alanine, the excess of glycine, serine, and threonine is readily deaminated in the body to take part in gluconeogenic reactions, thus contributing to hyperammonemia. The cumulative effect of benzoate conjugation to drain these ammoniagenic precursors through glycine may be the basis of its therapeutic effect in hyperammonemia.
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PMID:The importance of glyoxylate and other glycine precursors in the hepatic and renal conjugation of benzoate in normal and hyperammonemic mice. 262 83

We report an anesthetic experience with ornithine transcarbamylase deficiency. The patient was 26 years of age who underwent open biopsy of the liver for a definitive diagnosis. OTC deficiency is an X-linked disorder of urea cycle. One of the anesthetic problems is how to control the blood ammonia level resulting in neurological damage which occurs following anesthesia and surgery. Recently it has been advocated that benzoate is effective to prevent hyperammonemia in patients with OTC deficiency. As patients with this disease are frequently complicated with hepatic dysfunction, anesthetics which may cause hepatic damage such as halothane should be avoided.
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PMID:[An anesthetic experience with a patient with ornithine transcarbamylase deficiency]. 270 15

Deficiency of ornithine transcarbamylase (OTC; EC 2.1.3.3), a hepatic mitochondrial enzyme involved in the detoxification of ammonia, is a severe inborn error of metabolism. It is an X-linked disorder which results characteristically in ammonia intoxication, protein intolerance and mental retardation. Early death of affected hemizygous male infants is common, while clinical manifestations in heterozygous females are variable due to random X-chromosome inactivation. Prenatal diagnosis by amniocentesis has not been feasible because OTC is not expressed in amniocytes and because no unusual metabolites can be detected in amniotic fluid. Fetal liver biopsy has been performed for some families at risk, but the dangers inherent in this procedure severely limit its usefulness. In this report, we describe the use of a nearly full-length cloned human cDNA to begin to characterize normal and mutant human OTC genes. One of 15 affected males was found to have a partial deletion of the OTC gene. Two distinct restriction fragment length polymorphisms (RFLPs) were identified at the OTC locus using the restriction endonuclease MspI; 69% of women tested were heterozygous for one or both polymorphisms. Identification of these common polymorphisms makes it possible to offer prenatal diagnosis to a large fraction of obligate carriers and to provide information on carrier status to some females at risk.
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PMID:Gene deletion and restriction fragment length polymorphisms at the human ornithine transcarbamylase locus. 298 25

Urinary orotate excretion is used as a clinical parameter to distinguish female carriers of X-linked ornithine transcarbamylase deficiency. The value of this test has been considered doubtful due to a lack of knowledge about the true variability of hepatic enzyme activity and its effect on orotate synthesis. We have used a purebred population of spf/+ heterozygous females (n = 90), with an X-linked structural mutation of ornithine transcarbamylase, to study this variability in comparison with normal +/+ females (n = 19) and hemizygous spf/Y males (n = 20). Our results show that spf/+ heterozygotes have a mean hepatic enzyme activity equal to 64% of the normal group, as compared to 44-56% reported previously. They have a very wide variability (range 28-107 mumol/h/mg protein) which overlap the normal distribution curves of +/+ and spf/Y groups. Similar overlapping is shown in the distribution of urinary orotate excretion. The correlation studies indicate that the urinary orotate level as an index of hepatic enzyme deficiency is of value only in heterozygotes having an activity less than 50% of normal. This parameter cannot, therefore, be used to screen for all heterozygotes. However, it would still be valuable in distinguishing female-children at risk of developing hyperammonemic symptoms.
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PMID:[Variability of enzyme activity and urinary orotic acid in ornithine transcarbamylase deficient spf/+ heterozygotic mice]. 380 79

We reviewed the natural history and differential diagnosis of ornithine transcarbamylase deficiency (an X-linked inborn error of urea synthesis) in 13 symptomatic female heterozygotes. The patients presented as early as the first week of life or as late as the sixth year. The most common symptoms before diagnosis were nonspecific: episodic extreme irritability (100 percent), episodic vomiting and lethargy (100 percent), protein avoidance (92 percent), ataxia (77 percent), Stage II coma (46 percent), delayed physical growth (38 percent), developmental delay (38 percent), and seizures (23 percent). Including the proband, 42 percent of the female members of the 13 families studied had symptoms. The median interval between the onset of major symptoms (vomiting and lethargy, seizures, and coma) and diagnosis was 16 months (range, 1 to 142). Five patients had IQ scores below 70 at the time of diagnosis. We suggest that careful evaluation of the family history, the dietary history, the episodic nature of the nonspecific symptoms, the response of these symptoms to the withdrawal of protein, and their frequent onset at the time of weaning from breast milk will permit early diagnosis and might thereby reduce the risk of death or neurologic impairment in female patients with partial ornithine transcarbamylase deficiency.
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PMID:Natural history of symptomatic partial ornithine transcarbamylase deficiency. 394 92

Ornithine carbamoyltransferase (OCT) is a liver-specific enzyme located in the mitochondrial matrix. OCT deficiency is an X-linked disease with a heterogeneous phenotype, even in affected males. We studied two male patients (K.M., K.G.) with early and late onset, respectively. OCT activity was zero in the autopsied liver of patient K.M. and was 6% of control in the biopsied liver of K.G. Sequencing of OCT cDNAs revealed exon 5 skipping in K.M., resulting from a T-to-C transition of the initial dinucleotide of the 5' splicing donor site of intron 5, and a G-to-T transversion at position +45 in exon 9 (L304F) in K.G., providing three OCT mRNAs of different lengths: a normally spliced transcript, 23 bp insertion of intron 8 and the first 50bp missing within exon 9. Exon 5 skipping and two other aberrant splicings produced stop codons early downstream in mature OCT mRNAs. Expression study of a missense allele, L304F, transfected to cultured Cos 1 cells revealed a 34.4% value of the control. The difference of OCT activities between the patient liver and transfected cells (6% vs. 34%) can be explained by this splicing abnormality.
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PMID:Identification of two new aberrant splicings in the ornithine carbamoyltransferase (OCT) gene in two patients with early and late onset OCT deficiency. 747 92

Ornithine transcarbamylase deficiency is an X-linked disorder of the urea cycle that can cause hyperammonemic encephalopathy in hemizygous males and heterozygous females. Affected females typically limit protein intake in their diet. This case report describes a 36-year-old woman with ulcerative colitis who went into hyperammonemic coma after administration of total parenteral nutrition. A similar episode of coma had occurred 7 years earlier after she delivered a normal boy. Heterozygous ornithine transcarbamylase deficiency was diagnosed based on a positive allopurinol tolerance test result after elevated levels of plasma glutamine and low plasma citrulline were detected. The protein load associated with parenteral alimentation resulted in symptomatic expression of this partial enzyme deficiency in this unique case. Partial ornithine transcarbamylase deficiency must always be considered in adult women and men with hyperammonemia who have normal liver function test results.
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PMID:Hyperammonemic coma due to parenteral nutrition in a woman with heterozygous ornithine transcarbamylase deficiency. 779 25


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