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1/31. Correction of ureagenesis after gene transfer in an animal model and after liver transplantation in humans with ornithine transcarbamylase deficiency.

    We report effects of gene transfer and liver transplantation on urea synthesis in ornithine transcarbamylase deficiency (OTCD). We measured the formation of [15N] urea after oral administration of 15NH4Cl in two girls with partial OTCD before and after liver transplantation. Ureagenesis was less than 20% of that observed in controls before transplantation, and was normalized afterward. Studies performed on the OTCD sparse fur (spf/Y) mouse showed discordance between OTC enzyme activity and ureagenesis with modest increases in OTC enzyme activity after gene transfer resulting in significant improvement in ureagenesis. This study suggests that both liver transplantation and gene therapy may be effective in improving ureagenesis in OTCD.
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ranking = 1
keywords = ornithine transcarbamylase deficiency, transcarbamylase deficiency, ornithine transcarbamylase, transcarbamylase, ornithine, deficiency
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2/31. Lymphocyte mRNA analysis of the ornithine transcarbamylase gene in Italian OTCD male patients and manifesting carriers: identification of novel mutations.

    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.
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ranking = 0.31259915948769
keywords = ornithine transcarbamylase, transcarbamylase, ornithine, deficiency
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3/31. Under recognition of late onset ornithine transcarbamylase deficiency.

    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.
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ranking = 1.2
keywords = ornithine transcarbamylase deficiency, transcarbamylase deficiency, ornithine transcarbamylase, transcarbamylase, ornithine, deficiency
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4/31. Late onset heterozygous ornithine transcarbamylase deficiency mimicking complex partial status epilepticus.

    A 57 year old woman with post-traumatic complex partial seizures was admitted because of recurrent episodes of altered mental state over the preceding 4 years, each lasting up to 5 days. There was a history of dietary protein intolerance since childhood and two of her daughters had died in the neonatal period from unexplained encephalopathies. In hospital she developed fluctuating confusion, amnesia, and sudden episodes of unresponsiveness. An EEG was consistent with complex partial status epilepticus but there was no response to benzodiazepines. Nasogastric feeding and sodium valproate were given and shortly afterwards she lapsed into a deep coma. blood ammonia and urinary orotate were raised, and genetic testing confirmed that she was a carrier of a mutation in exon 3 of the ornithine transcarbamylase gene (C to T at position 92). Treatment with protein restriction, carnitine, and sodium phenylbutyrate led to a full recovery over a period of 3 months. To our knowledge this is the oldest age of onset yet described in a manifesting carrier. She is the fifth patient with heterozygous ornithine transcarbamylase deficiency reported to have had a severe reaction to sodium valproate. Hyperammonaemic encephalopathy should be considered in patients of any age who experience fluctuating confusion.
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ranking = 1.0625178775183
keywords = ornithine transcarbamylase deficiency, transcarbamylase deficiency, ornithine transcarbamylase, transcarbamylase, ornithine, deficiency
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5/31. ornithine transcarbamylase deficiency and pancreatitis.

    We describe a male patient with a Y202H ornithine transcarbamylase deficiency gene mutation who had pancreatitis while taking a low-protein diet, citrulline, and sodium phenylbutyrate.
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ranking = 0.44752689196771
keywords = ornithine transcarbamylase deficiency, transcarbamylase deficiency, ornithine transcarbamylase, transcarbamylase, ornithine, deficiency
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6/31. Successful living-donor liver transplantation from an asymptomatic carrier mother in ornithine transcarbamylase deficiency.

    A liver transplantation from an asymptomatic mother, who was a carrier of ornithine transcarbamylase deficiency, to her daughter, who had severe manifestation, was successfully performed. One-year monitoring of plasma amino acid and urinary orotate/orotidine levels revealed no abnormality in the urea cycle in either subject.
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ranking = 1
keywords = ornithine transcarbamylase deficiency, transcarbamylase deficiency, ornithine transcarbamylase, transcarbamylase, ornithine, deficiency
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7/31. An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency.

    ornithine transcarbamylase deficiency (OTCD) is the most common inherited urea cycle disorder, and is transmitted as an X-linked trait. female OTCD heterozygotes exhibit wide clinical severities, ranging from being apparently asymptomatic to having the profound neurologic impairment observed in affected males. However, clinical and laboratory diagnosis of partial OTCD during asymptomatic periods is difficult, and correlation of phenotypic severity with either dna mutation and/or in vitro enzyme activity is imprecise. Provocative testing, including protein load and allopurinol challenge used in the diagnosis of OTCD females, is not without risk and subject to both false positives and negatives. Although definitive when successful, dna-based diagnosis is unable to detect mutations in all cases. We have previously used the ratio of isotopic enrichments of [(15)N]urea/[(15)N]glutamine ((15)N-U/G) derived from physiologic measurements of ureagenesis by stable isotope infusion as a sensitive index of in vivo urea cycle activity. We have now applied this method in combination with traditional biochemical testing to aid in the diagnosis of a symptomatic OTCD female in whom mutation in the ornithine transcarbamylase (OTC) gene was not found. The (15)N-U/G ratio in this patient showed that she had severe reduction of in vivo urea cycle activity on par with affected male subjects. This was correlated with partially deficient OTC activity in her liver, degree of orotic aciduria, and history of suspected recurrent hyperammonemic episodes before age 3. The measurement of in vivo urea cycle activity in combination with traditional biochemical indices optimizes a diagnostic approach to the at-risk partial OTCD patient, especially in those in whom molecular testing is unproductive. Together they contribute to the risk versus benefit considerations regarding the pursuit of medical therapy versus surgical, ie, orthotopic liver transplantation (OLT) therapy. The decision to resort to OLT in females with partial OTC activity is controversial, requiring consideration of phenotypic severity, failure of medical therapy, access to tertiary care centers experienced in the management of acute hyperammonemia, and social factors. In this patient, the use of in vivo and in vitro measures of urea cycle activity in conjunction with a consideration of her clinical history and medical-social situation led to a decision for OLT.
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ranking = 0.92439960051019
keywords = ornithine transcarbamylase deficiency, transcarbamylase deficiency, ornithine transcarbamylase, transcarbamylase, ornithine, deficiency
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8/31. flumazenil responsive ornithine transcarbamylase deficiency encephalopathy: clinical and radiographic features.

    A 22-year-old woman with a negative urine drug screen and somnolence rapidly reversed by intravenous flumazenil was found to have elevated ammonia levels and punctate calcifications of the subcortical frontal white matter. Abnormally high levels of orotic acid were found in serum and urine, confirming the diagnosis of ornithine transcarbamylase deficiency. Although computed tomography findings are non-specific, young patients with unexplained hyperammonemic states of somnolence reversed by flumazenil should be screened for this X-linked recessive metabolic disorder.
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ranking = 1
keywords = ornithine transcarbamylase deficiency, transcarbamylase deficiency, ornithine transcarbamylase, transcarbamylase, ornithine, deficiency
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9/31. An autopsy case of ornithine transcarbamylase deficiency.

    We present an autopsy case of ornithine transcarbamylase (OTC) deficiency with grumose degeneration in the dentate nucleus of the cerebellum. The patient had intractable neonatal convulsions and hyperammonemia from the 3rd day after birth. diagnosis of OTC deficiency was made based on null activity of the enzyme and four-base deletions in exon 9 of the OTC gene. death was due to sepsis as well as disseminated intravascular coagulation at 1 year and 2 months of age. Neuropathology showed multiple cystic changes and ulegyria in the bilateral frontal and parietal lobes. Multiple cysts were associated with the region, which was infiltrated with macrophages surrounded by astroglia showing palisading pattern. Ferrugination was marked in the thalamus and severe neuronal loss with astrogliotic change in the CA1-2 area of the hippocampus. Grumose degeneration was noted in the dentate nucleus of the cerebellum. This is the first report of grumose degeneration in OTC deficiency.
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ranking = 0.86254719320736
keywords = ornithine transcarbamylase deficiency, transcarbamylase deficiency, ornithine transcarbamylase, transcarbamylase, ornithine, deficiency
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10/31. ornithine transcarbamylase deficiency: a novel splice site mutation in a family with meiotic recombination and a new useful SNP for diagnosis.

    ornithine transcarbamylase (OTC, EC 2.1.3.3) deficiency (OTCD; OMIM #311250) is known to be genetically very heterogeneous, with many cases occurring de novo, due to an exceptional instability of the OTC gene. We report a new G > T substitution in the first nucleotide of intron 2 and we describe also a novel SNP (IVS8 35 nt: G > T) with very convenient frequencies (62%/38%) for its use as an extra tool for OTCD diagnosis in cases of suspected deletions.
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ranking = 0.26164057765737
keywords = transcarbamylase deficiency, transcarbamylase, deficiency
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