allopurinol and Ornithine-Carbamoyltransferase-Deficiency-Disease

The diagnosis of heterozygosity for X-linked ornithine carbamoyltransferase (OCT) deficiency has usually been based on measurement of the increase of orotate and orotidine excretion after an allopurinol load. We examined the choices of analyte, cutoff, and test conditions to obtain maximal test accuracy.. Urine orotate/orotidine responses to allopurinol load in 37 children (13 OCT-deficient and 24 non-OCT-deficient) and 24 women (7 at risk for carrier status and 17 not related to OCT-deficient children) were analyzed by liquid chromatography after sample purification by anion-exchange chromatography. Diagnostic accuracy was evaluated by nonparametric ROC curves.. Sample purification was necessary to prevent interferences. Orotate and orotidine excretion increased with increased protein intake during the test. At a cutoff of 8 mmol orotidine/mol creatinine, sensitivity was 1.0 and specificity was 0. 92 in mild forms of OCT deficiency. Results in monoplex carrier women may differ greatly from those expected because of the genetics of this deficiency.. Standardization of protein intake is required in the allopurinol loading test. A negative response in the face of clinical suspicion should be followed with a repeat test during a protein intake not <2.5 g x kg-1 x day-1. Measurements of orotidine provide better clinical sensitivity than measurements of orotate.

Topics: Adolescent; Adult; Allopurinol; Child; Child, Preschool; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Female; Humans; Male; Middle Aged; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Proteins; ROC Curve; Sensitivity and Specificity; Uridine

Topics: Allopurinol; Child; Child, Preschool; Female; Gas Chromatography-Mass Spectrometry; Gout Suppressants; Humans; Infant; Infant, Newborn; Male; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Proteinuria; Purine-Pyrimidine Metabolism, Inborn Errors

Topics: Acids; Adolescent; Allopurinol; Amino Acids; Child; Citrulline; Female; Humans; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Quaternary Ammonium Compounds; Rett Syndrome

One-fifth of the gene mutations causing ornithine transcarbamylase deficiency cannot be detected. In such cases carrier risk estimation must refer to biochemical data-such as increased plasma glutamine concentration or increased orotidine excretion after allopurinol load -although these parameters do not yield a definite diagnosis. Here, I derive odds for carrier risk estimation from published data, i.e. from mean and standard deviation of glutamine concentrations in carriers and noncarriers, assuming normal distributions, and from allopurinol test results in individual carriers and noncarriers using logistic regression. I show how such biochemical information may be combined with genetic information, thus demonstrating the usefulness of biochemical data. The necessity to assess individual results in larger proband groups and to consider possible correlations between different parameters is indicated.

Topics: Allopurinol; Genetic Carrier Screening; Glutamine; Humans; Logistic Models; Ornithine Carbamoyltransferase Deficiency Disease; Risk Factors

Topics: Allopurinol; Carrier State; Data Interpretation, Statistical; Genetic Carrier Screening; Heterozygote; Humans; Models, Statistical; Ornithine Carbamoyltransferase Deficiency Disease; Reproducibility of Results; Sensitivity and Specificity

The allopurinol test aims to distinguish carriers and noncarriers for ornithine transcarbamylase (OTC) deficiency. We have evaluated the reliability of the test in at-risk females of known genotype. Results based on urine orotidine and/or orotic acid measurement were compared in terms of sensitivity and specificity. Retrospectively, we analysed the results of allopurinol tests in 42 women (22 confirmed heterozygotes and 20 noncarriers) from 23 pedigrees at risk of being carriers for OTC deficiency. Using a cut-off of 2 standard deviations above the mean of controls, the highest sensitivity (91%) was given by orotidine alone or in combination with orotic acid, but specificity was only 70% and 65%, respectively. We conclude that the value of the allopurinol test for detecting OTC carriers in at-risk females is limited. This needs to be recognized when counselling families. The test still has a role as a safe, quick, noninvasive screen of individuals at risk, but test results in possible carriers should be interpreted with caution. In the absence of other supportive evidence, confirmation by mutation analysis is required.

Topics: Adult; Allopurinol; Female; Genetic Carrier Screening; Genotype; Humans; Infant, Newborn; Male; Mass Screening; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Pedigree; Reproducibility of Results; Retrospective Studies; Risk Factors

Carriers of X-linked ornithine transcarbamylase deficiency (OTCD) are themselves mildly affected. The allopurinol test is quite sensitive (92.7%) and very specific in detecting these carriers. Consequently, it has also been recommended for the diagnosis of mild OTCD in the general population. However, there is a controversy on its utility since OTCD could not be demonstrated in several patients with positive test results but negative family histories. We show that this controversy is due to an improper use of statistical concepts, i.e., to the postulate of a specificity of "100%," and to the confusion of specificity with type I error rate. Spontaneous orotic aciduria implies a positive allopurinol test and limits the specificity of the test to a maximum of 99.7%. Therefore, according to Bayes' theorem, almost all positive test results in the general population must turn out to be type I errors, due to the minute prevalence (1/32,000) of mild OTCD (i.e., asymptomatic carriers and male patients with inapparent disease). Family history seems to be the only preselective parameter that can sufficiently raise the prevalence in the group to be tested. Bayesian analysis also yields the rate of type II errors (OTCD inspite of a negative test) which is high in closely related at-risk females (22.6% in mothers of male patients) but minimal in the general population. Conclusion. The allopurinol test is useful for the exclusion but not for the diagnosis of inapparent OTCD in sporadic individuals. Test results in possible carriers should be interpreted with caution.

Topics: Allopurinol; Bayes Theorem; Biological Assay; False Negative Reactions; False Positive Reactions; Female; Humans; Male; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease

Topics: Allopurinol; Child; False Negative Reactions; Female; Genetic Carrier Screening; Humans; Mutation; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Uracil

Measurement of urinary orotidine and orotic acid after an oral allopurinol challenge is an important diagnostic test for ornithine carbamoyltransferase deficiency that is sometimes used in infants (< 1 year of age), although there is little information on normal test results in this age group. We found higher orotidine excretion in normal infants than in older children given the test, whereas orotate excretion was similar in both groups. The increased orotidine excretion appears to be due to the use in the infants of higher allopurinol doses per kilogram of body weight than in the children. The normalized-dose dependency of the orotidine response extends even to adult age. Thus, dose-normalized responses should be used in the test and there is no need for careful age-matching of the controls.

Topics: Adolescent; Adult; Age Factors; Allopurinol; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Male; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Uridine

A deletion of at least 11.5 cM in the paternal X chromosome mapping between microsatellites DXS989 and DXS1003 and encompassing the genes for ornithine transcarbamylase (OTC), retinitis pigmentosa GTPase regulator (RPGR) and dystrophin, was associated with the loss of band Xp21 in a female patient with OTC deficiency. Another four female patients were heterozygous for point mutations in the OTC gene: the nonsense mutation Q69X or the missense mutations I172F, G188V and G197R. In the OTC amino acid sequence, I172 and G197 are proximate to residues involved in catalysis, and G188 is within a loop joining helix 5 and strand 6 in the core of the ornithine-bindingdomain. Therefore, the mutations of these residues may cause structural changes affecting catalysis and/or the architecture of the ornithine domain. The mutation appeared "de novo" in the patients or, in one case, in the mother of the patient, in agreement with the predominance of "de novo" mutations in female patients of OTC deficiency. There was full agreement between the results of mutational analysis and of allopurinol testing in the patients and their female relatives, supporting the value of the allopurinol test in the detection of carriers of OTC deficiency. This deficiency is a genetically heterogeneous X-linked condition.

Topics: Allopurinol; Amino Acid Metabolism, Inborn Errors; Ammonia; Child, Preschool; Female; Gene Deletion; Humans; Infant; Microsatellite Repeats; Mutation; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Polymorphism, Single-Stranded Conformational; X Chromosome

We describe a 4-generation family in which a previously healthy 10-year-old boy died of late-onset ornithine transcarbamylase (OTC) deficiency. Pedigree analysis and allopurinol loading tests in female relatives were not informative. A missense mutation (A208T) in the OTC gene was detected in the deceased patient and in several clinically healthy male and female relatives, the oldest male being 97 years old. OTC deficiency was established in autopsy liver tissue of the propositus and liver biopsy samples of his sister, mother, and a maternal uncle. The males had 4% and 6% residual activity, respectively, the females 58% and 67%, respectively. The observed relation between the mutation and the decreased OTC activity in liver tissue of these subjects suggests that the mutation is a deleterious one. Late-onset, "mild" OTC deficiency can have a fatal or a favorable outcome. The disease can segregate undetected in families.

Topics: Adult; Aged; Allopurinol; Autopsy; Biopsy; Child; Child, Preschool; Female; Glutamine; Heterozygote; Humans; Liver; Male; Mutation; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Pedigree; X Chromosome

A large family with ornithine transcarbamylase deficiency due to mutation R141Q was ascertained through a propositus who presented with acute neonatal hyperammonemic coma. Of 13 females at risk, 11 were evaluated clinically and had laboratory studies performed. Seven were found to be heterozygous for the mutation. Of these seven, five had chronic clinical symptoms and two were asymptomatic. None of the heterozygotes had elevated plasma ammonia on random testing. Of the five symptomatic females, three had markedly elevated plasma glutamine levels on random testing, while two had levels in the upper range of normal. Plasma citrulline and arginine levels were somewhat lower in the symptomatic individuals but still within the normal range. Five heterozygotes who were tested had either spontaneous orotic aciduria or elevated orotic acid following ingestion of allopurinol, whereas one unaffected female and one unaffected male had normal allopurinol tests. A higher than expected proportion of female heterozygous for the R141Q mutation were clinically and biochemically symptomatic but remained undiagnosed for many years. Plasma glutamine determination and allopurinol testing should be performed in females who present with a combination of relatively non-specific symptoms detailed in this report.

Topics: Allopurinol; Amino Acid Metabolism, Inborn Errors; Ammonia; Arginine; Citrulline; Female; Glutamine; Heterozygote; Humans; Infant, Newborn; Male; Mutation; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Pedigree

Recurrent episodes of bizarre behavior were the only clinical symptoms that finally led to the diagnosis of ornithine transcarbamylase deficiency in an 8-year-old boy. The suspected diagnosis could not be confirmed with the use of current challenge tests. The response to a high-protein diet for 24 hours appeared to be a helpful diagnostic aid.

Topics: Allopurinol; Amino Acid Metabolism, Inborn Errors; Child Behavior Disorders; Child, Preschool; Diagnostic Errors; Dietary Proteins; Heterozygote; Humans; Male; Ornithine Carbamoyltransferase Deficiency Disease

Topics: Adolescent; Adult; Allopurinol; Chromatography, High Pressure Liquid; Female; Genetic Carrier Screening; Humans; Middle Aged; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Uridine

The increase in orotidine excretion following a 300 mg allopurinol dose has been used for carrier detection in ornithine carbamoyl transferase (OCT) deficiency. This test was evaluated, using three collection periods, in 23 healthy women, 4 obligate heterozygotes and 32 other women at risk of being carriers of OCT deficiency. Four methods for the analysis of orotidine and orotic acid were compared. Using the most reproducible method, the excretion of orotic acid in controls was found to be consistently higher than that of orotidine in all three periods. The distribution of both orotic acid and orotidine excretion of controls was skewed so that standard deviations (S.D.) were calculated after logarithmic transformation. All four obligate heterozygotes showed orotic acid and orotidine excretion in excess of 3 S.D. above the control mean and a further 7 women had one or more excretion values in excess of 3 S.D., while 16 gave a value of less than 2 S.D. for both metabolites. We conclude that the predictive value of the test is good, that both orotic acid and orotidine should be measured to reduce the risk of misclassification and that values greater than 2 S.D. for both in one or more periods should be used as the cut-off point to identify carriers.

Topics: Adolescent; Adult; Allopurinol; Child; Female; Heterozygote; Humans; Middle Aged; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Predictive Value of Tests; Risk; Spectrophotometry, Ultraviolet; Uridine

Allopurinol loading test is based on the inhibition of pyrimidine biosynthesis and the subsequent increase in orotic acid excretion caused by a single dose of allopurinol. Abnormally elevated amounts of orotic acid excretion are demonstrated in ornithine carbamoyl transferase (OCT) deficiency patients and heterozygotes as well as in other disorders of urea cycle. Biochemical studies performed for the diagnosis of one patient and carrier detection in her family are presented.. Amino acids: ion exchange chromatography; ammonium: method of Van Anken and Shiphorst; orotic acid: modification of Adachi et al, and allopurinol test following Brusilow et al.. The characteristic amino acid profile of the patient together with her clinical history suggested the diagnosis of OCT deficiency, which was confirmed with protein and allopurinol loading test. The heterozygote condition became evident only by means of allopurinol test in 2/5 female relatives.. Allopurinol test is a useful tool for the preliminary investigation of urea cycle function, avoiding the possible hyperammonemia caused by other test, and permitting extensive familial studies without hospitalization. It results more informative than the protein loading test.

Topics: Allopurinol; Amino Acid Metabolism, Inborn Errors; Child; Female; Genetic Carrier Screening; Humans; Ornithine Carbamoyltransferase Deficiency Disease; Pedigree

The allopurinol challenge test was performed on 44 healthy subjects (28 children and 16 adolescents) in order to establish normal values of urinary orotic acid excretion following allopurinol ingestion in the paediatric population. The subjects were divided into three groups according to their age: 6 months to 6 years; 6 years to 10 years; and 10 years to 17 years. They were given 100 mg, 200 mg, or 300 mg of allopurinol, respectively (based on age) in a single oral dose. Maximum peak urinary orotic acid levels following ingestion of allopurinol were 13.0 (n = 14), 9.3 (n = 14), and 10.2 (n = 16) mumol/mmol creatinine in the three groups, respectively. In all children tested the peak orotic acid level was 3.1 +/- 2.7 mumol/mmol creatinine (mean +/- SD, n = 44). This allopurinol challenge test was also performed in six children with urea-cycle disorders, including five females with ornithine transcarbamylase (OTC) deficiency, all of whom demonstrated abnormally elevated levels of urinary orotic acid (peak levels of 26-134 mumol/mmol creatinine) following allopurinol ingestion.

Topics: Adolescent; Aging; Allopurinol; Child; Child, Preschool; Citrulline; Female; Humans; Infant; Male; Metabolism, Inborn Errors; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Urea; Uridine

Topics: Allopurinol; Amino Acid Metabolism, Inborn Errors; Female; Genetic Carrier Screening; Humans; Ornithine Carbamoyltransferase Deficiency Disease; Uridine

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.

Topics: Adult; Allopurinol; Chromatography, High Pressure Liquid; Female; Genetic Carrier Screening; Heterozygote; Humans; Middle Aged; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Uridine

Topics: Allopurinol; Ammonia; Coma; Female; Genetic Carrier Screening; Heterozygote; Humans; Nitrogen; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Pregnancy; Puerperal Disorders; Uridine

Topics: Adult; Alanine; Allopurinol; Ammonia; False Positive Reactions; Female; Genetic Carrier Screening; Humans; Infant, Newborn; Male; Ornithine Carbamoyltransferase Deficiency Disease; Pedigree; Uridine

Urinary orotidine and orotic acid have been determined in a patient with purine nucleoside phosphorylase (PNP) deficiency under various dietary therapeutic conditions. For this purpose a new procedure for the analysis of both compounds has been developed, consisting of prefractionation with Dowex 1X8, followed by two HPLC steps on a micro Bondapak NH2 and a micro Bondapak C18 column. With this method normal as well as slightly elevated excretions of orotic acid have been found in our patient. No evidence was obtained for inhibition of OPRT by purine (deoxy)nucleosides as a cause of pyrimidine starvation. A significant increase of urinary orotidine was found after loading with allopurinol. For comparison excretory values in a patient with ornithine transcarbamylase deficiency and also in a patient with orotic aciduria type I are shown. The possible cause of the slight increase in urinary orotic acid in our patient has been discussed.

Topics: Allopurinol; Child; Child, Preschool; Chromatography, High Pressure Liquid; Deoxycytidine; Humans; Infant; Ornithine Carbamoyltransferase Deficiency Disease; Orotate Phosphoribosyltransferase; Orotic Acid; Orotidine-5'-Phosphate Decarboxylase; Pentosyltransferases; Purine-Nucleoside Phosphorylase; Purine-Pyrimidine Metabolism, Inborn Errors; Respiratory Tract Infections; Uracil; Uridine

A method is presented for the two-dimensional thin-layer chromatographic screening of purines, pyrimidines and their nucleosides in the urine. Prior to chromatography, isolation of these substances from the urine is performed by anion-exchange column chromatography. Purines and pyramidines are quantitatively eluted with formic acid 0.01 M and 4 M respectively. The results of recovery and stability experiments are given. Normal excretory patterns are presented. Also results in patients with various diseases are shown: ornithine transcarbamylase deficiency, adenosine deaminase deficiency, purine nucleoside phosphorylase deficiency, adenine phosphoribosyltransferase deficiency, xanthine oxidase deficiency and hypoxanthine-guanine phosphoribosyltransferase deficiency. Finally the pattern of a patient on treatment with allopurinol is given.

Topics: Adenosine Deaminase; Allopurinol; ATP Phosphoribosyltransferase; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Chromatography, Thin Layer; Humans; Lesch-Nyhan Syndrome; Ornithine Carbamoyltransferase Deficiency Disease; Purine-Nucleoside Phosphorylase; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Pyrimidines; Xanthine Oxidase