Partial Ornithine Transcarbamylase Deficiency Research Articles

Restoration of nitrogen homeostasis in a man with ornithine transcarbamylase deficiency

We evaluated the hypothesis that sodium phenylbutyrate-induced phenylacetylglutamine biosynthesis in a man with partial ornithine transcarbamylase (OTC) deficiency has a dual effect; it provides an additional vehicle for waste nitrogen excretion, and in the process it suppresses the patient's residual urea N synthesis, which then may be available for N homeostasis if the need arises. A 38-year-old man was studied over three periods. Period I was a control period during which he received a fixed caloric and N intake plus l-citrulline. Phenylbutyrate was added in period II and was maintained during period III, during which his N intake was increased. Plasma levels of ammonium and glutamine and net urea N synthesis were measured in each period; phenylacetylglutamine N synthesis was measured in periods II and III. These studies demonstrated that phenylbutyrate administration led to a 73% decrease in net de novo urea N synthesis during period II, which subsequently increased threefold in period III in response to the increased N intake. Phenylacetylglutamine N synthesis was 2.27 g/d, similar to his estimated maximum net urea N synthesis of 2.65 g/d. During periods II and III, his plasma levels of ammonium and glutamine improved as compared with period I when they were abnormally high. We conclude that sodium phenylbutyrate treatment of patients with urea cycle disorders who have significant residual enzyme activity results in both an improvement in waste N excretion and improved N homeostasis as a result of the generation of a reserve urea N synthetic capacity. This therapeutic approach may be useful in other nitrogen accumulation decreases, eg, portal-systemic encephalopathy.

Urea cycle defect: a case with MR and CT findings resembling infarct

A 2 1/2 year old girl was admitted to the hospital because of recurrent vomitting, impaired consciousness, and hyperammonemia. MR and CT findings resembled an infarct, but she was found to have a defect in the urea cycle, partial ornithine transcarbamylase deficiency.

Fatal hyperammonemia resulting from a C-to-T mutation at a MspI site of the ornithine transcarbamylase gene

Ornithine transcarbamylase (OTC) deficiency is the most common inborn error of the urea cycle in humans and is responsible for lethal neonatal hyperammonemia in males. Partial OTC deficiency also occurs in females and can be responsible for life-threatening hyperammonemic comas in heterozygotes. The cosegregation of the trait with a 5.8-kb abnormal MspI fragment in an affected family led us to hypothesize that this unexpected migration pattern was related to the mutation event in this particular family. Using polymerase chain reaction amplification of the specific mRNA derived from a post-mortem biopsy of the liver, we found that the MspI site located in the seventh exon of the gene was abolished and we finally identified a C-to-T transition at codon 225 of the cDNA, changing a proline to a leucine in the protein. Subsequent digestion of amplified exon 7 using the restriction enzyme MspI allowed direct screening for the mutant genotype during the next pregnancy. The present study supports the view that direct detection of the mutant genotype using either Southern blotting or digestion of amplified exons of the gene can contribute to genetic counselling in noninformative families. Finally, since MspI digestions are routinely performed for restriction fragment length polymorphism-based family studies in OTC deficiency, we suggest that the possible presence of the 5.8-kb abnormal fragment should be investigated on Southern blots of affected individuals.

Automated determination of orotic acid, uracil and pseudouridine in urine by high-performance liquid chromatography with column switching

A column-switching high-performance liquid chromatographic method, requiring no sample preparation apart from filtration, is described for quantification of urinary orotic acid, uracil and pseudouridine. The analyses were carried out using a reversed-phase octadecylsilane-bonded column for sample clean-up and a cation-exchange column for separation; 5–20 ]sml samples of urine were directly analysed, and more than 100 samples could be analysed consecutively. Each sample required only 30 min. Detection limits of these compounds were 5 pmol. Creatinine-related urinary uracil excretion was lowest in the newborn period (17.3 ± 14.4 μmol/g of creatinine). A patient with partial ornithine transcarbamylase deficiency and his mother usually excreted a high level of uracil during the period of normal orotic acid excretion and normal serum ammonia level.

Carrier detection in a partially dominant X-linked disease: ornithine transcarbamylase deficiency

Ornithine transcarbamylase (OTC) deficiency is an X-linked disease responsible for lethal neonatal hyperammonemia in males. Partial OTC deficiency also occurs in females and can be responsible for life-threatening hyperammonemic comas in heterozygotes (15%). Increased orotic acid excretion occurs in both symptomatic and asymptomatic carriers, especially under protein loading tests. The disease is therefore partially dominant with neonatal lethality in the hemizygous male; the fraction of new mutations has previously been estimated to be low in males (point estimation = 0, upper bound of the confidence interval = 0.16) and 57% in females. Genetic counseling in this disease is difficult because it is not clear whether a negative protein loading test rules out carrier status. In an attempt to determine how reliable the test is for carrier detection, we investigated ten obligate carriers for orotic acid excretion; considering all data available, we concluded that the test is rarely negative in obligate carriers (8%). Consequently, a negative test in a mother decreases the minimum risk of being a carrier from 84% a priori to 30% if she had an affected son and from 43% a priori to 5% if she had a heterozygous daughter. Finally, the diagnosis of a new mutation in the germ cells of the maternal grandfather in one particular family could be ascertained by extensive DNA analysis.

Secondary carnitine deficiency in the newborn period in twins of a mother with partial ornithine transcarbamylase deficiency

Secondary carnitine deficiency in the newborn period in twins of a mother with partial ornithine transcarbamylase deficiency

The spfash mouse: a missense mutation in the ornithine transcarbamylase gene also causes aberrant mRNA splicing.

Ornithine transcarbamylase (ornithine carbamoyltransferase; carbamoyl-phosphate:L-ornithine carbamoyltransferase, EC 2.1.3.3) is a mitochondrial matrix enzyme of the mammalian urea cycle. The X chromosome-linked spfash mutation in the mouse causes partial ornithine transcarbamylase deficiency and has served as a model for the human disease. We show here that the spfash mutation is a guanine to adenine transition of the last nucleotide of the fourth exon of the ornithine transcarbamylase gene. This nucleotide change produces two remarkably different effects. First, this transition causes ornithine transcarbamylase mRNA deficiency because the involved exon nucleotide plays a part in the recognition of the adjacent splice donor site. As a result of the mutation, ornithine transcarbamylase pre-mRNA is spliced inefficiently both at this site and at a cryptic splice donor site 48 bases into the adjacent intron. Second, two mutant proteins are translated from these mRNAs. From the correctly spliced mRNA, the transition results in a change of amino acid 129 from arginine to histidine. This missense substitution has no discernable effect on mitochondrial import, subunit assembly, or enzyme activity. On the other hand, the elongated mRNA resulting from mis-splicing is translated into a dysfunctional ornithine transcarbamylase subunit elongated by the insertion of 16 amino acid residues.

Hyperammonemia related to carnitine metabolism with particular emphasis on ornithine transcarbamylase deficiency.

Carnitine status was evaluated in 8 patients with partial ornithine transcarbamylase (OTC) deficiency and 19 patients with secondary carnitine deficiency, who were used as positive references. Laboratory findings indicated that all patients with OTC deficiency had secondary carnitine deficiency especially in hyperammonemic attack. After L-carnitine administration in 2 patients with OTC deficiency, the number of attacks was significantly reduced in both cases.

Chronic benzoate therapy in a boy with partial ornithine transcarbamylase deficiency

Resultats du traitement a long terme d'un garcon de 7 ans dont l'activite ornithine transcarbamylase hepatique n'est que de 5% et que l'administration de benzoate de sodium durant les 3 dernieres annees a protege contre des episodes recidivants d'hyperammoniemie. L'excretion d'azote par des voies metaboliques alternes a aide au maintien d'un apport proteinique convenable pour assurer la croissance physique et maintenir une intelligence limite. La necessite ou non de poursuivre le traitement sera reevaluee quand les besoins en proteines pour la croissance seront moindres

Ornithine transcarbamylase deficiency: a cause of lethal neonatal hyperammonemia in males.

Three successive male infants in one family became comatose and died at less than 10 days of age. No cause for death was identified in the first boy, but striking hyperammonemia, which was due to almost complete absence of hepatic ornithine transcarbamylase activity, was found in the second and third boys. All attempts to control the hyperammonemia, including total dietary protein restriction, exchange transfusion and peritoneal dialysis, proved futile, suggesting that ornithine transcarbamylase deficiency of this magnitude is incompatible with survival. These findings are in sharp contrast to previous reports of partial ornithine transcarbamylase deficiency, noted to occur almost exclusively in females and to be compatible with long-term survival on a diet restricted in protein. Hyperammonemia resulting from almost complete ornithine transcarbamylase deficiency must now be included in the differential diagnosis of neonatal lethargy and coma.