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Background: Ornithine transcarbamylase deficiency exhibits a high degree of clinical heterogeneity, making its screening and classification challenging in some instances. In this study, we first established a simple and stable method for testing ornithine transcarbamylase activity using micro blood from newborns, rather than relying on venous blood., Methods: The activity of ornithine transcarbamylase was assessed by measuring the concentration of citrulline produced in the reaction with carbamoyl phosphate and ornithine, using serum, plasma or micro blood. Correlation analysis was evaluated using Sangerbox Tools. The Receiver Operating Characteristic curve was used in SPSS Statistics 17.0 to evaluate the diagnostic efficiency of Ornithine transcarbamylase deficiency., Results: A strong linear relationship was observed between ornithine transcarbamylase activity and both micro blood volume and reaction time (R 2  = 0.9793, 0.9922 respectively). The intra-coefficient variation and inter-coefficient variation were 11% and 12.5% with a 1-h reaction time, and 6.77% and 9.58% with a 3-h reaction time, respectively. And the inter-coefficient variation was lower than the most widely used colorimetry method (5.1-21.1%). The Limit of Blank was 0.57 nmol/mL/h. The reference interval for normal newborn population is greater than or equal to 39.6 nmol/mL/h. Notably, the method exhibited a 100% sensitivity, surpassing the sensitivity of colorimetry method (94.3%), along with and a specificity of 96.9% for diagnosing ornithine transcarbamylase deficiency., Conclusions: We pioneered a method for testing OTC activity that normally carried on venous blood can be effectively performed on microblood heel samples. Meanwhile, our method presents a simpler, more stable and reproducible approach compared to colorimetry., Competing Interests: Declarations. Ethics approval and consent to participate: The human studies were conducted following the ethical standards of the institutional and/or national research committee (Nanjing Women and Children's Healthcare Hospital + [2014]36) and the 2013 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from the patients or their guardians. Consent for publication: All authors read and approved the final manuscript. Competing interests: There are no conflicts to declare., (© 2025. The Author(s).)

We describe 10 females with ornithine transcarbamylase (OTC) deficiency and liver dysfunction, revealing a unique pattern of hepatocyte injury in which initial hyperammonemia and coagulopathy is followed by a delayed peak in aminotransferase levels. None of the patients required urgent liver transplantation, though five eventually underwent transplant for recurrent metabolic crises. We intend that this novel observation will initiate further investigations into the pathophysiology of liver dysfunction in OTC-deficient patients, and ultimately lead to the development of therapies and prevent the need for liver transplant., (© 2020 Wiley Periodicals LLC.)

Background: Ornithine transcarbamylase deficiency (OTCD) is pleomorphic congenital hyperammonemia, in which the prognosis of the patient is determined both by genotype and environmental factors. This study investigated the clinical and biochemical characteristics of OTCD patients with different prognosis., Method: Of 35 OTCD patients, six males deceased at the first disease-onset, 17 males survived and had controllable ammonia levels after treatment, and 12 females survived through the first disease-onset but had intractable hyperammonemia and high mortality. Fasting blood samples from patients collected at three disease stages were used for the analysis of amino acid (AA) profile, acylcarnitine profile, and micronutrients. Differences in profiles between patients and healthy controls and within patient groups were studied., Results: All OTCD patients had accumulation of glutamine, homocitrulline, lysine, glutamate, cystathionine, and pipecolic acid, as well as deficiency of citrulline, tryptophan, threonine, and carnitine. For male non-survivors, most other AAs and long-chain acylcarnitines were elevated at disease onset, of which the levels of creatine, N-acetylaspartic acid, and homoarginine were remarkably high. Male survivors and female patients had most other AAs at low to normal levels. Compared with male survivors, female patients had much lower protein-intolerance, as indicated by significantly lower levels of protein consumption indicators, including essential AAs, 1-methylhistidine, acylcarnitines et al., but high levels of ammonia. Female patients still had significantly higher levels of citrulline, homocitrulline, and citrulline/arginine compared to male survivors., Conclusion: Unique profiles were observed in each group of OTCD patients, indicating specific physiological changes that happened to them., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Newborn screening (NBS) programmes utilise information on a variety of clinical variables such as gestational age, sex, and birth weight to reduce false-positive screens for inborn metabolic disorders. Here we study the influence of ethnicity on metabolic marker levels in a diverse newborn population. NBS data from screen-negative singleton babies (n = 100 000) were analysed, which included blood metabolic markers measured by tandem mass spectrometry and ethnicity status reported by the parents. Metabolic marker levels were compared between major ethnic groups (Asian, Black, Hispanic, White) using effect size analysis, which controlled for group size differences and influence from clinical variables. Marker level differences found between ethnic groups were correlated to NBS data from 2532 false-positive cases for four metabolic diseases: glutaric acidemia type 1 (GA-1), methylmalonic acidemia (MMA), ornithine transcarbamylase deficiency (OTCD), and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). In the result, 79% of the metabolic markers (34 of 43) had ethnicity-related differences. Compared to the other groups, Black infants had elevated GA-1 markers (C5DC, Cohen's d = .37, P < .001), Hispanics had elevated MMA markers (C3, Cohen's d = .13, P < .001, and C3/C2, Cohen's d = .27, P < .001); and Whites had elevated VLCADD markers (C14, Cohen's d = .28, P < .001, and C14:1, Cohen's d = .22, P < .001) and decreased OTCD markers (citrulline, Cohen's d = -.26, P < .001). These findings correlated with the higher false-positive rates in Black infants for GA-1, in Hispanics for MMA, and in Whites for OTCD and for VLCADD. Web-based tools are available to analyse ethnicity-related changes in newborn metabolism and to support developing methods to identify false-positives in metabolic screening., (© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

An induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells of a 3-day-old boy with 47,XXY and ornithine transcarbamylase deficiency carrying hemizygote mutation (c.663+2T>G (sliping)) in OTC. The iPSCs had original 47,XXY, and mutation in OTC, expressing pluripotency markers and bearing differentiation potential in vitro., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Ornithine transcarbamylase deficiency is an X-linked disease with a wide range of clinical severity and manifestation age both in males and females. Here, we describe a case which is caused by a novel c.78-1G[A splice site mutation, which on mRNA level leads to a 1-bp deletion and a frameshift (c.78delG (p.C27Vfs*11)) in OTC exon 2 in a young girl. The same mutation has been detected in a mosaicstate in her asymptomatic father.

One of the X chromosome-linked disorders is ornithine transcarbamylase deficiency in the urea cycle. This disorder results in increased ammonia and glutamine in the blood. Accumulation of these metabolites without treatment causes brain edema, which often progresses to coma and death. This study describes a 5-year-old girl with ornithine transcarbamylase deficiency who presented with hyperammonemic encephalopathy that was successfully treated with an orthotropic liver transplant. Recently, liver transplant has been introduced as an alternative treatment for patients with ornithine transcarbamylase deficiency.

Rationale: Graft-derived-cell-free DNA (Gcf-DNA) in plasma was a promising biomarker to monitor graft-rejection after liver transplantation. However, little is known about the application of Gcf-DNA in living-donor-liver-transplantation (LDLT)., Patients Concern: In this study, 2 patients diagnosed with Ornithine Transcarbamylase Deficiency (OTCD) were enrolled and indicated for LDLT., Diagnoses: Two patients were genetically diagnosed with OTCD, and they suffered from recurrent and uncontrollable hyper-ammonemia and failed in accepting the normalized OTCD treatments, such as decreasing dietary nitrogen intake and increasing waste-nitrogen excretion., Interventions: LDLT was performed in the 2 patients uneventfully, and we collected circulating cell-free DNA from plasma in specific postoperative time points (day 1, day 7, day 14, day 30, day 60). Since both of the recipients were sex-mismatch with the donors, we measured Gcf-DNA through the Y-chromosome method and compared it with the routine liver function., Outcomes: The result showed that Gcf-DNA had the similar discrimination of graft injury trend while compared to routine liver function. The follow-up showed these 2 patients' status is stable., Lessons: Applying Gcf-DNA to monitor graft injury in LDLT is promising, but still long term follow-up and more samples are needed for validation.

Background: Continuous EEG studies demonstrate that neonates with seizures due to cerebral pathology, such as hypoxia ischemia, exhibit predominantly electrographic seizures (i.e. those only detected with EEG because they lack clinical features). Previous small case series demonstrate EEG changes and seizures during hyperammonemia associated with inborn errors of metabolism (IEM) but there are no reports utilizing continuous EEG in these conditions., Objective: To characterize seizures and evaluate the utility of continuous EEG recording during hyperammonemia due to inborn errors of metabolism., Methods: We retrospectively reviewed medical records and EEG tracings of neonates who presented with hyperammonemia due to inborn errors of metabolism who had continuous EEG and full medical records available for review, including follow up., Results: Eight neonates with hyperammonemia were studied, 7 had urea cycle defects: Argininosuccinate lyase deficiency [3], (ornithine transcarbamylase deficiency [3], carbomyl phosphate synthase deficiency [1] and one had an organic acidemia: Methylmalonic acidemia [1]. Most common presentations were lethargy and poor feeding at 12-72 h of life. The highest blood ammonia level was 874 μmol/L (median); range 823-1647 μmol/L (normal value <50 μmol/L in term neonates). Seven were treated with hemodialysis in addition to nitrogen scavengers. Seven neonates had seizures; six had only electrographic seizures. Seizures initially occurred within 24-36 h of clinical presentation, sometimes with normal ammonia and glutamine levels. Neonates with seizures all lacked state changes on EEG. Inter burst interval duration correlated with degree of hyperammonemia. Two cases with normal plasma ammonia but increasing interburst interval duration were proven to have stroke by MRI., Conclusions: Seizures occur frequently in neonates with hyperammonemia; most can be detected only with continuous EEG. Seizures may occur when ammonia and glutamine levels are normal. Interburst interval duration is associated with ammonia levels or cerebral dysfunction from other brain pathology. Continuous EEG can be a useful tool for managing infants with hyperammonemia and may be essential for seizure management especially for infants in deep metabolic coma., (Copyright © 2018 Elsevier Inc. All rights reserved.)

History A 19-year-old woman with no pertinent medical history was brought to the emergency department after being found unconscious on her bathroom floor by her roommate. In the preceding weeks, she had reported intractable nausea and vomiting, for which she had been taking ondansetron. No other medications had been prescribed. The day prior to presentation, she had contacted her mother and described increasing confusion. Glasgow coma scale score on arrival in the emergency department was 4. Intravenous naloxone was administered, without immediate response. Initial blood glucose level was 232 mg/dL (12.8 mmol/L) (normal range, 79-140 mg/dL [4.4- 7.7 mmol/L]), and other routine laboratory test results were normal. Urine toxicology results were negative. Cerebrospinal fluid evaluation revealed levels were within normal limits. Neurologic examination revealed dilated pupils, which showed a sluggish response to light, and left lower extremity rigidity with intermittent tremors. Initial unenhanced cranial computed tomographic (CT) findings were negative. Magnetic resonance (MR) imaging of the brain was performed. The patient's condition deteriorated, with increasing cerebral edema over the next week, and she was declared brain dead. Her liver was transplanted into an adult recipient, who subsequently developed cerebral edema and elevated plasma ammonia levels, resulting in death in the immediate postoperative period.

Purpose of Study: Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor., Methods Used: Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery., Summary of Results: Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years., Conclusion: Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Liver enzymes are released from hepatocytes into circulation and their activity can be measured in the blood. We examined whether the plasma activity of the liver enzyme ornithine carbamoyltransferase, determined by a novel liquid chromatography-mass spectrometry (LC-MS/MS) assay, could be utilized for the detection of OTC deficiency (OTCD), an X-linked inborn error of the urea cycle., Methods: The plasma ornithine carbamoyltransferase (OTC) activity was assayed in the reverse reaction using isotopically labeled citrulline-d4 as a substrate and by determination of the product, ornithine-d4, by LC-MS/MS analysis., Results: The plasma OTC activity in the controls was in the range of 111-658 pkat/L (n=49, median 272 pkat/L), and the activity increased linearly with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in patients with hepatopathy. The OTC activity was subsequently determined in 32 individuals carrying mutations in the OTC gene, and OTC/ALT and OTC/AST ratios were calculated to account for the degree of hepatopathy, which is a common finding in OTCD. The OTC/ALT ratio enabled clear differentiation of OTCD hemizygotes (n=11, range 0-69×10-6) from controls (504-3440×10-6). This ratio also enabled the detection of 11 of 12 symptomatic heterozygotes (range 38-794×10-6), while this marker did not allow for reliable differentiation of asymptomatic heterozygotes (n=9) from controls., Conclusions: LC-MS/MS assay of plasma OTC activity enabled the detection of all hemizygous and the majority of symptomatic heterozygous OTCD patients in the tested cohort. This study demonstrates that non-invasive assay of enzymes expressed predominantly in the liver could be used as an alternative approach for diagnosing inborn errors of metabolism.

Background: Acute liver failure (ALF) has been reported in ornithine transcarbamylase deficiency (OTCD) and other urea cycle disorders (UCD). The frequency of ALF in OTCD is not well-defined and the pathogenesis is not known., Aim: To evaluate the prevalence of ALF in OTCD, we analyzed the Swiss patient cohort. Laboratory data from 37 individuals, 27 females and 10 males, diagnosed between 12/1991 and 03/2015, were reviewed for evidence of ALF. In parallel, we performed cell culture studies using human primary hepatocytes from a single patient treated with ammonium chloride in order to investigate the inhibitory potential of ammonia on hepatic protein synthesis., Results: More than 50% of Swiss patients with OTCD had liver involvement with ALF at least once in the course of disease. Elevated levels of ammonia often correlated with (laboratory) coagulopathy as reflected by increased values for international normalized ratio (INR) and low levels of hepatic coagulation factors which did not respond to vitamin K. In contrast, liver transaminases remained normal in several cases despite massive hyperammonemia and liver involvement as assessed by pathological INR values. In our in vitro studies, treatment of human primary hepatocytes with ammonium chloride for 48 hours resulted in a reduction of albumin synthesis and secretion by approximately 40%., Conclusion: In conclusion, ALF is a common complication of OTCD, which may not always lead to severe symptoms and may therefore be underdiagnosed. Cell culture experiments suggest an ammonia-induced inhibition of hepatic protein synthesis, thus providing a possible pathophysiological explanation for hyperammonemia-associated ALF.

Background: The principal aim of this study was to investigate the long-term outcomes of a large cohort of patients with ornithine transcarbamylase deficiency (OTCD) who were followed up at a single medical center., Methods: We analyzed clinical, biochemical and genetic parameters of 90 patients (84 families, 48 males and 42 females) with OTCD between 1971 and 2011., Results: Twenty-seven patients (22 boys, 5 girls) had a neonatal presentation; 52 patients had an "intermediate" late-onset form of the disease (21 boys, 31 girls) that was revealed between 1 month and 16 years; and 11 patients (5 boys, 6 girls) presented in adulthood (16 to 55 years). Patients with a neonatal presentation had increased mortality (90% versus 13% in late-onset forms) and peak plasma ammonium (mean value: 960 μmol/L versus 500 μmol/L) and glutamine (mean value: 4110 μmol/L versus 1000 μmol/L) levels at diagnosis. All of the neonatal forms displayed a greater number of acute decompensations (mean value: 6.2/patient versus 2.5 and 1.4 in infants and adults, respectively). In the adult group, some patients even recently died at the time of presentation during their first episode of coma. Molecular analyses identified a deleterious mutation in 59/68 patients investigated. Single base substitutions were detected more frequently than deletions (69% and 12%, respectively), with a recurrent mutation identified in the late-onset groups (pArg40 His; 13% in infants, 57% in adults); inherited mutations represented half of the cases. The neurological score did not differ significantly between the patients who were alive in the neonatal or late-onset groups and did not correlate with the peak ammonia and plasma glutamine concentrations at diagnosis. However, in late-onset forms of the disease, ammonia levels adjusted according to the glutamine/citrulline ratio at diagnosis were borderline predictors of low IQ (p = 0.12 by logistic regression; area under the receiver operating characteristic curve of 76%, p <0.05)., Conclusions: OTCD remains a severe disease, even in adult-onset patients for whom the prevention of metabolic decompensations is crucial. The combination of biochemical markers warrants further investigations to provide additional prognostic information regarding the neurological outcomes of patients with OTCD.

A 54-year-old woman with coeliac disease was admitted to hospital electively for supplemental nutrition. Shortly after feeding started she deteriorated into a hyperammonemic coma with refeeding syndrome, requiring an extensive intensive care admission. Urea cycle disorders were investigated and a biochemical diagnosis of ornithine transcarbamylase deficiency was made. This is a rare diagnosis in the adult population. This case report summarises protein metabolism, urea cycle disorders and the challenges of management., (2015 BMJ Publishing Group Ltd.)

Background: Orotic acid (OA) is the key parameter in the detection of ornithine transcarbamylase deficiency (OTC-D). Inclusion of OA into newborn screening compatibility with existing analytical procedures is necessary., Methods: OA was eluted from dried blood spots with methanol containing deuterated [1,3-(15)N2] OA as internal standard. Quantification by tandem mass spectrometry was accomplished without chromatographic separation. Samples were measured in MRM mode for the masses m/z 155.1 → 111 for OA and 157.1 → 113 for d2 OA., Results: OA was determined in a wide range of concentrations with high precision, LOD and LOQ being 0.21 and 0.65 μmol/L, respectively. Values correlated well with those obtained after chromatography. Pretreatment of samples with HCl-butanol regularly used for acylcarnitine measurement did not significantly affect quantitative results. Inclusion of the new method into the standard newborn screening procedure did not alter the results for acylcarnitines or amino acids; the total time per analysis, however, was increased from 1.15 to 1.85 min. OA levels of 707 unaffected newborns ranged from 0.28 to 3.73 μmol/L. Five newborns with OTC-D showed concentrations of 89.7-211.1 μmol/L. In newborns with severe citrullinaemia we found values in the range of 4.99-127.7 μmol/L., Conclusions: This new method can be used as a standalone measurement of OA but it can also easily be implemented into standard newborn screening techniques as a useful supplement. In this case the method allows detection of newborns with OTC deficiency without an extra analytical run., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Ornithine transcarbamylase deficiency (OTC-D) is a urea cycle disorder caused by dysfunction of ornithine transcarbamylase, which frequently leads to hyperammonemia. Hyperammonemia represents a medical emergency requiring prompt treatment to reduce plasma ammonia levels and prevent severe neurological damage, coma, and death, particularly in patients with acute decompensation-related coma. The clinical symptoms of OTC-D can manifest themselves either at an early stage, which is often associated with severe symptoms, or in later life (late-onset OTC-D), when symptoms may be less severe. There is currently little agreement over diagnostic signs of the condition or the most appropriate therapeutic approach. Hyperammonemia is usually treated with ammonia scavengers, continuous venovenous hemodialysis, and dietary changes. N-carbamylglutamate is approved for the treatment of hyperammonemia in N-acetylglutamate synthetase deficiency and may have efficacy in other urea cycle disorders., Methods/results: Here, we report a 13-year-old girl who was diagnosed with OTC-D at the age of 3 years. On this occasion, the patient presented with vomiting, lethargy, and mental confusion. Despite biochemical parameters being within normal ranges, she was comatose within a few hours. She was promptly treated with a combined therapy of continuous venovenous hemodialysis and N-carbamylglutamate, resulting in a gradual normalization of clinical symptoms within 30 hours. No neurological damage was apparent at 18 months after treatment., Conclusions: This case demonstrates that clinical benefits can be obtained by beginning aggressive treatment of OTC-D within a few hours of the onset of severe neurological symptoms even in the absence of altered biochemical markers.

The late-onset type of ornithine transcarbamylase (OTC) deficiency is almost asymptomatic before an abrupt onset of metabolic crisis in adolescence. This study focused on coagulopathy in OTC deficiency. We collected laboratory data regarding coagulation from OTC-deficient patients in Kyushu University Hospital in Japan or from cases reported from previous articles. Five patients with late-onset OTC deficiency, admitted to Kyushu University Hospital at the first metabolic attack or who presented at the outpatient clinic in the hospital, were analyzed, and 3 additional cases of OTC deficiency with coagulopathy in previous articles were included. As a result, the blood ammonia levels in these patients were remarkably high at the time of the metabolic attack, and prothrombin times were far below the normal level. The prothrombin times remained significantly abnormal on remission, despite almost normal levels of blood ammonia, serum aspartate aminotransferase, and alanine aminotransferase. Coagulation abnormality is a previously unidentified complication of OTC deficiency in remission state. This information will aid in the identification of patients with OTC deficiency before a lethal metabolic crisis occurs during adolescence.

Urea cycle disorders (UCDs) are one of the most frequently inherited metabolic diseases in Japan, with an estimated prevalence of 1 per 50,000 live births. Here, we investigated the clinical manifestations, treatment, and prognosis of 177 patients with UCDs who were evaluated and treated from January 1999 to March 2009. These included 77 cases of neonatal-onset UCDs and 91 cases of late-onset UCDs. The most common UCD was ornithine transcarbamylase deficiency (OTCD), which accounted for 116 out of 177 patients. This result is similar to a previous study performed between 1978 and 1995 in Japan: OTCD accounted for about two-thirds of the total number of UCD cases. We studied the relationship between prognosis and the peak blood ammonia level at the onset in 151 UCD patients. Compared with a previous survey conducted in Japan, we found that a greater number of patients survived without any mental retardation despite their peak blood ammonia levels being greater than 360 μmol/l. The 5-year survival rate of patients with OTCD improved to 86% for those with the neonatal-onset type and to 92% for those with the late-onset type. We hypothesize that the increased survival rate is due to early diagnosis and better treatments that are now available in Japan. It is very important to diagnose and treat UCDs, especially OTCD, when the blood ammonia levels in patients are low. The outcome in patients with low blood ammonia levels was better than that in patients with high blood ammonia levels.

Recurrent abdominal pain remains one of the most common symptoms in pediatrics. We present the case of a 3-year-old girl who had recurrent episodes of abdominal pain requiring more than 13 visits to the emergency department. A diagnosis of ornithine transcarbamylase deficiency was eventually made. Urea cycle disorders often present beyond the neonatal period with frequent vomiting episodes; however, recurrent abdominal pain as a presenting symptom is unusual. Unnecessary invasive investigations of recurrent abdominal pain in childhood can be avoided by considering inborn errors of metabolism earlier in the differential diagnosis.

Ornithine transcarbamylase deficiency is an inborn error of metabolism that commonly presents as hyperammonemia in neonates. We present a case of a 2-year-old girl who was referred to a pediatric emergency department for evaluation of hepatitis, an uncommon presentation of ornithine transcarbamylase deficiency. Recognition of late presentations of this disease is important for survival and neurological outcome.

We demonstrate the effective use of NMR spectroscopic profiles of urine and plasma from the first successful use of hepatocyte transplantation as a bridge to auxiliary partial orthotopic liver transplantation in a child antenatally diagnosed with severe ornithine transcarbamylase deficiency. In this single-patient study, NMR profiles indicated that the disrupted urea cycle could be normalized by hepatocyte cell infusion and this was confirmed using orthogonal partial least-squares-based chemometrics. However, despite dietary manipulations and adminstration of ammonia scavengers, the desired reduction in plasma ammonia was not consistently achieved between sessions of hepatocyte transplantation due to episodes of sepsis. A subsequent liver transplant corrected the metabolic abnormalities. The use of metabolic profiling has been shown to be a promising method for evaluating the efficacy of cell infusions and has demonstrated the capability for the early detection of response to therapy in real time, an approach that may be of use in wider clinical settings.

Nitric oxide (NO) is synthesized from arginine and O(2) by nitric oxide synthase (NOS). Citrulline, which is formed as a by-product of the NOS reaction, can be recycled to arginine by the 2 enzymes acting in the urea cycle: argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL). Although the complete urea cycle is expressed only in the liver, ASS and ASL are expressed in other organs including the kidney and vascular endothelium. To examine possible alterations of the NO pathway in urea cycle defects, we measured plasma concentrations of arginine and citrulline and serum concentrations of nitrite/nitrate (NOx(-), stable NO metabolites) and asymmetric dimethylarginine (ADMA, an endogenous NOS inhibitor) in patients with congenital urea cycle disorders of 3 types: ornithine transcarbamylase (OTC) deficiency, ASS deficiency, and ASL deficiency. All were receiving oral arginine replacement at the time of this study. The same parameters were also measured in healthy subjects, who participated as controls. The OTC-deficient patients had significantly high NOx(-) and nonsignificantly high ADMA concentrations. Their NOx(-) was significantly positively correlated with arginine. The ASS-deficient patients had significantly low NOx(-) and significantly high ADMA concentrations. The ASL-deficient patients had normal NOx(-) and nonsignificantly high ADMA concentrations. In ASS-deficient and ASL-deficient patients, the NOx(-) was significantly inversely correlated with citrulline. These results suggest that NO synthesis is enhanced in OTC-deficient patients while receiving arginine but that NO synthesis remains low in ASS-deficient patients despite receiving arginine. They also suggest that endogenous NO synthesis is negatively affected by citrulline and ADMA in ASS-deficient and ASL-deficient patients. Although the molecular mechanisms remain poorly understood, we infer that the NO pathway might play a role in the pathophysiology related to congenital urea cycle disorders.

A newborn boy with family history of severe ornithine transcarbamylase (OTC) deficiency was investigated prospectively and managed aggressively at birth based on an existing protocol for at risk neonates. Undetectable citrulline levels at birth suggested that the infant was affected; however, normal plasma glutamine and urine orotic acid levels confused the diagnosis to some extent. Mutation testing confirmed that the patient did not have OTC deficiency. Thus the low plasma citrulline level did not validate our initial biochemical suspicion of OTC deficiency, and this highlights the importance of considering all available clinical, biochemical and molecular evidence in determining disease status.

Background: Hyperammonemia caused by ornithine transcarbamylase (OTC) deficiency can be properly managed by continuous arteriovenous hemodiafiltration (CAVHDF). Removal of amino acids (AA) during CAVHDF has not been thoroughly investigated. AA losses in patients with urea cycle defects due to ornithine transcarbamylase deficiency treated by CAVHDF were analyzed., Methods: Twelve neonates with elevated serum ammonia levels, confirmed through urine organic acid analysis and serum amino acid studies, were documented to have OTC deficiency. CAVHDF was administered in an attempt to lower serum ammonia concentration. Amino acid analysis of ultrafiltration and serum were performed by liquid chromatography., Results: Serum levels of leucine, isoleucine, methionine, phenylalanine, and tyrosine were significantly lower than acceptable in these patients. Glutamine was the only amino acid that increased significantly, which is clinically relevant to OTC enzyme deficiency. Although the mean serum concentrations of tyrosine and glutamine concentrations were lower in the dialysate, the serum and dialysate concentrations of other amino acids did not differ., Conclusion: CAVHDF may induce changes in amino acid metabolism and distribution as well. The requirement of aminogram monitor for amino acid supplementation in urea cycle defect patients is important.

Background: The occurrence of male patients with ornithine transcarbamylase (OTC) deficiency during adolescence or in adulthood has now been recognized. The aim of this study was to determine the prognostic factors that affect the prognosis of life, to explore a basis for therapeutic strategy., Methods: In 10 patients, nine of whom carried the R40H mutation and the other one carrying the Y55D mutation in the OTC gene, 32 demographic and laboratory data were first compared between survivors and non-survivors, using the unpaired t-test. The factors with significant difference were then subjected to multiple regression analysis., Results: The factors that exhibited significant difference were: age at onset, concentration of plasma ammonium, blood pH, and concentrations of six amino acids in plasma. The multiple regression analysis then revealed concentrations of ammonium, leucine, lysine, isoleucine, phenylalanine, glutamine and proline to be significant prognostic factors. The amino acid profile in the 10 patients showed increases in glutamine, proline, lysine, valine and methionine, and decreases in serine, ornithine and arginine. There was an inverse correlation between the age at onset and the level of the residual hepatic OTC activity., Conclusion: The results implied that: (i) the plasma amino acid profile was unique, in comparison to other liver diseases; (ii) the plasma concentration of each of the (mentioned above) six amino acids was a significant predictor of prognosis; and (iii) suppression of protein catabolism, as suggested by the higher concentrations in isoleucine and leucine in the non-survivors, prevention of glutamine-induced brain edema, correction of alkalosis, and supplementation with ornithine or arginine may improve the prognosis of life.

We report a male patient with a history of recurrent idiopathic vomiting, normal plasma ammonia and glutamine concentrations in acute phase, who died at 3 years of age. Ornithine transcarbamylase deficiency was diagnosed after detecting elevated urinary orotate concentrations in a sample collected just before death, and the diagnosis was confirmed by DNA analysis.

Women heterozygous for mutations at the ornithine transcarbamylase (OTC) locus may be at risk for hyperammonaemia and its untoward effects including coma and death in the postpartum period. We present the case of a pregnant woman heterozygous for OTC deficiency (McKusick 311250) whose past medical history was significant for two prior pregnancies complicated by postpartum hyperammonaemic coma. In the index pregnancy, increased levels of serum ammonium were noted during labour. Postpartum hyperammonaemia was averted by administration of oral sodium benzoate. Our experience demonstrates that in women at risk, perilous hyperammonaemia can be prevented through appropriate medical management.

Several recent reviews describe the management of urea cycle disorders. There is much agreement on diet, alternative pathway therapy, maintenance of arginine and ornithine levels in acute and chronic management, sick-day regimens, and some aspects of monitoring. However, differences remain in several areas, and physicians at most treatment centers have relatively little experience, because these disorders are rare. Early suspicion of the diagnosis of a urea cycle disorder, and prompt referral to a tertiary center is vital. Drug treatment using chronic administration of sodium benzoate has been abandoned by some centers, but the acceptability of phenylbutyrate is an issue for many patients. Using citrulline chronically is not always successful in recommended doses, and may result in an arginine level too low for maximum control. Appetite and nutrition problems are common. One major concern is the early identification and management of chronic catabolism, theoretically easy, but hard in practice. Biochemical measurement problems complicate monitoring, and there are disagreements about the optimum way of identifying OTC carriers. It is not always clear whom to treat. Within a kindred with an early-onset phenotype, an asymptomatic newborn girl may need treatment for some undetermined time, but target values for monitoring are not clear. In late-onset phenotypes, management of asymptomatic males identified by family screening is also difficult. Most centers do not have sufficient cases to solve these conundrums, some of which require further multicenter study. This paper examines the recommendations of a consensus conference on management, outlines some remaining problems, and incorporates in the text the points raised in open discussion during a session of a symposium held in Sydney in 2003 entitled "New Developments in Urea Cycle Disorders."

A retrospective review of the plasma ammonia and glutamine concentrations during the long-term management of 7 patients with ornithine carbamoyltransferase (OCT) deficiency and three with citrullinaemia is presented. The relationship between the plasma concentrations of ammonia and glutamine is not a simple linear one and there are significant differences between the two disorders. Patients with citrullinaemia tend to have higher plasma ammonia concentrations for a given plasma glutamine concentration compared to those with OCT deficiency. The possible reasons for these differences and the implications for management are discussed.

Ornithine transcarbamylase deficiency is a very heterogeneous urea cycle disorder resulting in hyperammonemia with various presentations from the neonatal period through adulthood. We performed a retrospective study in nine patients (four male/five female, age at diagnosis ranging from 6 days to 14 years) to evaluate the safety and efficacy of sodium phenylbutyrate (Ammonaps) in long-term treatment. All patients were diagnosed by DNA mutational analysis and/or liver enzyme measurement. They had previously been treated with sodium benzoate (median dose 248 mg/kg/day; range 106-275) and low protein diet (median 0.84 g/kg/day) and were switched to sodium phenylbutyrate (median dose of 352 mg/kg/day) at 8.9 and 4.9 years of age (median) in males and females, respectively. We analyzed clinical and biochemical data and the median follow-up duration was 26 months. During that time, there were no hyperammonemic episodes requiring hospitalization. Median plasma ammonia and glutamine levels were 30 and 902 micromol/L, respectively. Total protein intake could be increased to 0.95 g/kg/day after 18 months. No side effects related to therapy were observed. Further prospective studies should be performed to define the optimal dosage of sodium phenylbutyrate and the requirements for protein diet at different ages., (Copyright 2001 Academic Press.)

Late onset ornithine transcarbamylase deficiency (McKusick 311250) is reported in four Finnish patients, two boys and two heterozygous girls. The subtle onset and course of ornithine transcarbamylase deficiency emphasises the need for plasma ammonia and amino acid measurements in clinical situations suggesting a disorder of this nature.

A new simple, non-invasive method using ornithine transcarbamylase (OTC) mRNA isolated from peripheral blood (PBL) or lymphoblastoid cell lines has been performed. This approach based on reverse transcription and nested PCR to obtain a double strand PBL OTC cDNA allowed the identification of genetic lesions in five Italian families affected by OTC deficiency (OTCD). In the PBL OTC mRNA two new mutations, T262K and W265L, have been detected in three unrelated male OTCD patients with mild symptoms. One known mutation, T264A, has been identified in one manifesting carrier. The known mutation E310X, detected on genomic DNA of another manifesting carrier, failed to be detected in her PBL OTC mRNA because of the presence of a STOP codon. All mutations have been confirmed in the patients' and their relatives' genomic DNA. In three patients the mutations have also been confirmed in the mRNA isolated from frozen liver biopsy. The T262K amino acid substitution has been detected in a male's PBL OTC mRNA at homozygous state while a heterozygous pattern has been detected at the genomic DNA level, suggesting that the patient is a somatic mosaic for this mutation. Here we show that PBL OTC mRNA analysis is useful to detect genetic lesions in male and female OTCD patients., (Copyright 2000 Wiley-Liss, Inc.)