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Chiara F, Allegra S, Mula J, Puccinelli MP, Abbadessa G, Mengozzi G, De Francia S. The Strange Case of Orotic Acid: The Different Expression of Pyrimidines Biosynthesis in Healthy Males and Females. J Pers Med 2023; 13:1443. [PMID: 37888054 PMCID: PMC10608620 DOI: 10.3390/jpm13101443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/25/2023] [Accepted: 09/26/2023] [Indexed: 10/28/2023] Open
Abstract
Orotic acid (OA) is an intermediate metabolite of pyrimidine nucleotide biosynthesis and represents a minor diet constituent. The measurement of urinary orotic acid is useful in confirming the diagnosis of hereditary metabolic diseases. Moreover, it could be of interest to know how the physiological concentration of this metabolite changes in relation to different conditions of clinical normality. The purpose of this study was to determine the orotic acid concentration in the urine of healthy patients, to observe normal oroticuria and to evaluate if the expression of pyrimidine intermediate biosynthesis differs between healthy males and females. The orotic acid concentration in urine was performed via the ICH M10-validated analytical method. Unexpectedly, females showed a greater oroticuria than males in pediatric age (0-10); conversely, we did not find significant differences until 70 years of age. The LC-MS/MS method was suitable for use in the differential diagnosis of hereditary metabolic disease and metabolic monitoring of anticancer drug-induced toxicity. The analytical protocol was found to be rapid and ideal, and was used in the routine analysis of a clinical chemistry laboratory. The biochemical aspects related to the expression of pyrimidine biosynthesis should be further investigated in light of the obtained results.
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Affiliation(s)
- Francesco Chiara
- Laboratory of Clinical Pharmacology “Franco Ghezzo”, Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, 10043 Turin, Italy; (F.C.); (G.A.); (S.D.F.)
| | - Sarah Allegra
- Laboratory of Clinical Pharmacology “Franco Ghezzo”, Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, 10043 Turin, Italy; (F.C.); (G.A.); (S.D.F.)
| | - Jacopo Mula
- Department of Medical Sciences, University of Turin, Amedeo di Savoia Hospital, 10149 Turin, Italy;
| | - Maria Paola Puccinelli
- Laboratory of Clinical Biochemistry “Baldi e Riberi”, Metabolic Diseases Unit, AOU Città della Salute e della Scienza di Torino (TO), 10126 Turin, Italy; (M.P.P.); (G.M.)
| | - Giuliana Abbadessa
- Laboratory of Clinical Pharmacology “Franco Ghezzo”, Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, 10043 Turin, Italy; (F.C.); (G.A.); (S.D.F.)
| | - Giulio Mengozzi
- Laboratory of Clinical Biochemistry “Baldi e Riberi”, Metabolic Diseases Unit, AOU Città della Salute e della Scienza di Torino (TO), 10126 Turin, Italy; (M.P.P.); (G.M.)
| | - Silvia De Francia
- Laboratory of Clinical Pharmacology “Franco Ghezzo”, Department of Clinical and Biological Sciences, University of Turin, S. Luigi Gonzaga Hospital, 10043 Turin, Italy; (F.C.); (G.A.); (S.D.F.)
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Han ST, Anderson KJ, Bjornsson HT, Longo N, Valle D. A promoter variant in the OTC gene associated with late and variable age of onset hyperammonemia. J Inherit Metab Dis 2022; 45:710-718. [PMID: 35605046 DOI: 10.1002/jimd.12524] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 05/12/2022] [Accepted: 05/20/2022] [Indexed: 11/11/2022]
Abstract
Ornithine transcarbamylase deficiency (OTCD) is an X-linked inborn error caused by loss of function variants in the OTC gene typically associated with severe neonatal hyperammonemia. Rare examples of late-onset OTCD have also been described. Here, we describe an OTC promoter variant, c.-106C>A, in a conserved HNF4a binding site, identified in two male siblings in Family 1 whose first and only recognized episodes of severe hyperammonemia occurred at ages 14 and 39 years, respectively. We identified the same OTC variant segregating in a large family with late-onset OTCD with variable expressivity (Family 2). We show that this OTC promoter variant reduces expression >5-fold in a dual-luciferase assay that tests promoter function. Addition of an upstream OTC enhancer increases expression of both the wild type and the c.-106C>A variant promoter constructs >5-fold with the mutant promoter still about fourfold lower than the wild type. Thus, in both contexts, the promoter variant results in substantially lower OTC expression. Under normal demand on urea cycle function, OTC expression in hemizygous males, although reduced, is sufficient to meet the demand for waste nitrogen excretion. However, in response to severe metabolic stress with attendant increased requirements on urea cycle function, the impaired promoter function results in inadequate OTC expression with resultant hyperammonemia. In the absence of precipitating events, hemizygotes with this allele are asymptomatic, explaining the late age of onset of hyperammonemia in affected individuals and the incomplete penetrance observed in some individuals in Family 2.
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Affiliation(s)
- Sangwoo T Han
- Predoctoral Training Program in Human Genetics, McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Katherine J Anderson
- Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
| | - Hans T Bjornsson
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
- Landspitali University Hospital, Reykjavik, Iceland
| | - Nicola Longo
- Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA
| | - David Valle
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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3
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Sun M, Hines N, Scerbo D, Buchanan J, Wu C, Ten Eyck P, Zepeda-Orozco D, Taylor EB, Jalal DI. Allopurinol Lowers Serum Urate but Does Not Reduce Oxidative Stress in CKD. Antioxidants (Basel) 2022; 11:1297. [PMID: 35883787 PMCID: PMC9312025 DOI: 10.3390/antiox11071297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/16/2022] [Accepted: 06/25/2022] [Indexed: 12/31/2022] Open
Abstract
Xanthine oxidase (XO) contributes to oxidative stress and vascular disease. Hyperuricemia and gout are common in patients with chronic kidney disease (CKD), a population at increased risk of vascular disease. We evaluated effects of allopurinol on serum XO activity and metabolome of CKD patients who had participated in a randomized double-blind clinical trial of allopurinol vs. placebo. XO activity was measured in participants' serum. XO expression in venous endothelial cells was evaluated via immunofluorescence. Gas chromatography mass spectrometry (GC/MS) was utilized for metabolomics analysis. We found that in patients with stage 3 CKD and hyperuricemia, allopurinol lowered serum urate while increasing serum xanthine levels. Allopurinol, however, did not significantly suppress measured serum XO activity. Of note, baseline serum XO activity was low. Additionally, neither baseline serum XO activity nor XO protein expression were associated with measures of vascular dysfunction or with systemic or endothelial biomarkers of oxidative stress. Allopurinol affected several pathways, including pentose phosphate, pyrimidine, and tyrosine metabolism. Our findings suggest that circulating XO does not contribute to vascular disease in CKD patients. In addition to inhibition of XO activity, allopurinol was observed to impact other pathways; the implications of which require further study.
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Affiliation(s)
- Mingyao Sun
- Department of Internal Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (M.S.); (N.H.)
| | - Nicole Hines
- Department of Internal Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (M.S.); (N.H.)
| | - Diego Scerbo
- Department of Molecular Physiology, University of Iowa, Iowa City, IA 52242, USA; (D.S.); (J.B.); (E.B.T.)
| | - Jane Buchanan
- Department of Molecular Physiology, University of Iowa, Iowa City, IA 52242, USA; (D.S.); (J.B.); (E.B.T.)
| | - Chaorong Wu
- Institute for Clinical and Translational Science, University of Iowa, Iowa City, IA 52242, USA; (C.W.); (P.T.E.)
| | - Patrick Ten Eyck
- Institute for Clinical and Translational Science, University of Iowa, Iowa City, IA 52242, USA; (C.W.); (P.T.E.)
| | - Diana Zepeda-Orozco
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Pediatrics, Division of Nephrology and Hypertension, The Ohio State University College of Medicine, Columbus, OH 43210, USA
| | - Eric B. Taylor
- Department of Molecular Physiology, University of Iowa, Iowa City, IA 52242, USA; (D.S.); (J.B.); (E.B.T.)
| | - Diana I. Jalal
- Department of Internal Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (M.S.); (N.H.)
- Iowa City VA Medical Center, Iowa City, IA 52242, USA
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4
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Ravindranath A, Sarma MS. Mitochondrial hepatopathy: Anticipated difficulties in management of fatty acid oxidation defects and urea cycle defects. World J Hepatol 2022; 14:180-194. [PMID: 35126847 PMCID: PMC8790400 DOI: 10.4254/wjh.v14.i1.180] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/19/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Fatty acid oxidation defects (FAOD) and urea cycle defects (UCD) are among the most common metabolic liver diseases. Management of these disorders is dotted with challenges as the strategies differ based on the type and severity of the defect. In those with FAOD the cornerstone of management is avoiding hypoglycemia which in turn prevents the triggering of fatty acid oxidation. In this review, we discuss the role of carnitine supplementation, dietary interventions, newer therapies like triheptanoin, long-term treatment and approach to positive newborn screening. In UCD the general goal is to avoid excessive protein intake and indigenous protein breakdown. However, one size does not fit all and striking the right balance between avoiding hyperammonemia and preventing deficiencies of essential nutrients is a formidable task. Practical issues during the acute presentation including differential diagnosis of hyperammonemia, dietary dilemmas, the role of liver transplantation, management of the asymptomatic individual and monitoring are described in detail. A multi-disciplinary team consisting of hepatologists, metabolic specialists and dieticians is required for optimum management and improvement in quality of life for these patients.
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Affiliation(s)
- Aathira Ravindranath
- Division of Pediatric Gastroenterology, Institute of Gastrointestinal Sciences, Apollo BGS Hospitals, Mysore 570023, Karnataka, India
| | - Moinak Sen Sarma
- Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Sugahara G, Yamasaki C, Yanagi A, Furukawa S, Ogawa Y, Fukuda A, Enosawa S, Umezawa A, Ishida Y, Tateno C. Humanized liver mouse model with transplanted human hepatocytes from patients with ornithine transcarbamylase deficiency. J Inherit Metab Dis 2021; 44:618-628. [PMID: 33336822 PMCID: PMC8247293 DOI: 10.1002/jimd.12347] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 12/10/2020] [Accepted: 12/16/2020] [Indexed: 12/20/2022]
Abstract
Ornithine transcarbamylase deficiency (OTCD) is a metabolic and genetic disease caused by dysfunction of the hepatocytic urea cycle. To develop new drugs or therapies for OTCD, it is ideal to use models that are more closely related to human metabolism and pathology. Primary human hepatocytes (HHs) isolated from two patients (a 6-month-old boy and a 5-year-old girl) and a healthy donor were transplanted into host mice (hemi-, hetero-OTCD mice, and control mice, respectively). HHs were isolated from these mice and used for serial transplantation into the next host mouse or for in vitro experiments. Histological, biochemical, and enzyme activity analyses were performed. Cultured HHs were treated with ammonium chloride or therapeutic drugs. Replacement rates exceeded 80% after serial transplantation in both OTCD mice. These highly humanized OTCD mice showed characteristics similar to OTCD patients that included increased blood ammonia levels and urine orotic acid levels enhanced by allopurinol. Hemi-OTCD mice showed defects in OTC expression and significantly low enzymatic activities, while hetero-OTCD mice showed residual OTC expression and activities. A reduction in ammonium metabolism was observed in cultured HHs from OTCD mice, and treatment with the therapeutic drug reduced the ammonia levels in the culture medium. In conclusion, we established in vivo OTC mouse models with hemi- and hetero-patient HHs. HHs isolated from the mice were useful as an in vitro model of OTCD. These OTC models could be a source of valuable patient-derived hepatocytes that would enable large scale and reproducible experiments using the same donor.
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Affiliation(s)
- Go Sugahara
- Research and Development DepartmentPhoenixBio Co., LtdHigashi‐HiroshimaJapan
| | - Chihiro Yamasaki
- Research and Development DepartmentPhoenixBio Co., LtdHigashi‐HiroshimaJapan
| | - Ami Yanagi
- Research and Development DepartmentPhoenixBio Co., LtdHigashi‐HiroshimaJapan
| | - Suzue Furukawa
- Research and Development DepartmentPhoenixBio Co., LtdHigashi‐HiroshimaJapan
| | - Yuko Ogawa
- Research and Development DepartmentPhoenixBio Co., LtdHigashi‐HiroshimaJapan
| | - Akinari Fukuda
- National Center for Child Health and DevelopmentTokyoJapan
| | - Shin Enosawa
- Division for Advanced Medical SciencesNational Center for Child Health and DevelopmentTokyoJapan
| | - Akihiro Umezawa
- Regenerative MedicineNational Center for Child Health and DevelopmentTokyoJapan
| | - Yuji Ishida
- Research and Development DepartmentPhoenixBio Co., LtdHigashi‐HiroshimaJapan
- Research Center for Hepatology and GastroenterologyHiroshima UniversityHiroshimaJapan
| | - Chise Tateno
- Research and Development DepartmentPhoenixBio Co., LtdHigashi‐HiroshimaJapan
- Research Center for Hepatology and GastroenterologyHiroshima UniversityHiroshimaJapan
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6
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Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis 2019; 42:1192-1230. [PMID: 30982989 DOI: 10.1002/jimd.12100] [Citation(s) in RCA: 292] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 04/04/2019] [Accepted: 04/08/2019] [Indexed: 02/06/2023]
Abstract
In 2012, we published guidelines summarizing and evaluating late 2011 evidence for diagnosis and therapy of urea cycle disorders (UCDs). With 1:35 000 estimated incidence, UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death, even while effective therapies do exist. In the 7 years that have elapsed since the first guideline was published, abundant novel information has accumulated, experience on newborn screening for some UCDs has widened, a novel hyperammonemia-causing genetic disorder has been reported, glycerol phenylbutyrate has been introduced as a treatment, and novel promising therapeutic avenues (including gene therapy) have been opened. Several factors including the impact of the first edition of these guidelines (frequently read and quoted) may have increased awareness among health professionals and patient families. However, under-recognition and delayed diagnosis of UCDs still appear widespread. It was therefore necessary to revise the original guidelines to ensure an up-to-date frame of reference for professionals and patients as well as for awareness campaigns. This was accomplished by keeping the original spirit of providing a trans-European consensus based on robust evidence (scored with GRADE methodology), involving professionals on UCDs from nine countries in preparing this consensus. We believe this revised guideline, which has been reviewed by several societies that are involved in the management of UCDs, will have a positive impact on the outcomes of patients by establishing common standards, and spreading and harmonizing good practices. It may also promote the identification of knowledge voids to be filled by future research.
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Affiliation(s)
- Johannes Häberle
- University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland
| | - Alberto Burlina
- Division of Inborn Metabolic Disease, Department of Pediatrics, University Hospital Padua, Padova, Italy
| | - Anupam Chakrapani
- Department of Metabolic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Marjorie Dixon
- Dietetics, Great Ormond Street Hospital for Children, NHS Trust, London, UK
| | - Daniela Karall
- Clinic for Pediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria
| | - Martin Lindner
- University Children's Hospital, Frankfurt am Main, Germany
| | - Hanna Mandel
- Institute of Human Genetics and metabolic disorders, Western Galilee Medical Center, Nahariya, Israel
| | - Diego Martinelli
- Division of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy
| | - Guillem Pintos-Morell
- Centre for Rare Diseases, University Hospital Vall d'Hebron, Barcelona, Spain
- CIBERER_GCV08, Research Institute IGTP, Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | - René Santer
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anastasia Skouma
- Institute of Child Health, Agia Sofia Children's Hospital, Athens, Greece
| | - Aude Servais
- Service de Néphrologie et maladies métaboliques adulte Hôpital Necker 149, Paris, France
| | - Galit Tal
- The Ruth Rappaport Children's Hospital, Rambam Medical Center, Haifa, Israel
| | - Vicente Rubio
- Instituto de Biomedicina de Valencia (IBV-CSIC), Centro de Investigación Biomédica en Red para Enfermedades Raras (CIBERER), Valencia, Spain
| | - Martina Huemer
- University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland
- Department of Paediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria
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Hershman M, Carmody R, Udayasankar UK. Case 252: Acute Hyperammonemic Encephalopathy Resulting from Late-Onset Ornithine Transcarbamylase Deficiency. Radiology 2018; 287:353-359. [PMID: 29558304 DOI: 10.1148/radiol.2018161834] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
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.
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Affiliation(s)
- Michelle Hershman
- From the Department of Medical Imaging, University of Arizona College of Medicine, 1501 N Campbell Ave, Tucson, AZ 85724
| | - Raymond Carmody
- From the Department of Medical Imaging, University of Arizona College of Medicine, 1501 N Campbell Ave, Tucson, AZ 85724
| | - Unni K Udayasankar
- From the Department of Medical Imaging, University of Arizona College of Medicine, 1501 N Campbell Ave, Tucson, AZ 85724
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Severe hyperammonemia in late-onset ornithine transcarbamylase deficiency triggered by steroid administration. Case Rep Neurol Med 2015; 2015:453752. [PMID: 25949836 PMCID: PMC4407407 DOI: 10.1155/2015/453752] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 03/29/2015] [Indexed: 12/30/2022] Open
Abstract
Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked disorder of urea synthesis leading to hyperammonemia. Several late-onset cases have been reported. Undiagnosed and untreated patients are at the risk of death or suffering from irreversible sequelae. We describe a 56-year-old patient who presented with acute encephalopathy after steroid treatment. Hyperammonemia due to OTCD was diagnosed and a mutation was found. This allowed us to diagnose two other family members with unexplained encephalopathy who are now asymptomatic on a low-protein diet. OTCD should be considered in any patient with hyperammonemic encephalopathy and immediate treatment should be given to avoid a fatal outcome. We emphasize the need to examine other family members if the diagnosis is confirmed, in order to prevent further life-threatening episodes of encephalopathy or neonatal coma of newborn.
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At the intersection of toxicology, psychiatry, and genetics: a diagnosis of ornithine transcarbamylase deficiency. Am J Emerg Med 2013; 31:1420.e5-6. [DOI: 10.1016/j.ajem.2013.05.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Accepted: 05/07/2013] [Indexed: 11/19/2022] Open
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Simultaneous detection of diagnostic biomarkers of alkaptonuria, ornithine carbamoyltransferase deficiency, and neuroblastoma disease by high-performance liquid chromatography/tandem mass spectrometry. Clin Chim Acta 2012; 420:140-5. [PMID: 23085206 DOI: 10.1016/j.cca.2012.10.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Accepted: 10/10/2012] [Indexed: 11/23/2022]
Abstract
BACKGROUND Urinary homovanillic acid (HVA)/vanillylmandelic acid (VMA), orotic acid (OA), and homogentisic acid (HGA) are diagnostic biomarkers of neuroblastoma, ornithine carbamoyl transferase deficiency (OCTD), and alkaptonuria (AKU), respectively. In this study, a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous quantification of HVA, VMA, OA, and HGA in urine. METHODS After sample preparation, which involved only the dilution procedure, samples were quantified by LC-MS/MS. Full-scan MS/MS mode enabled the urinary markers to be quantified with a high degree of specificity and sensitivity. Rather than using a separate enzymatic method to normalize the concentration of creatinine in urine, we quantified the level of creatinine in urine in one LC-MS run. RESULTS The limits of detection were 10 μg/l for HGA, 25 μg/l for HVA/VMA, and 50 μg/l for OA with a single-to-noise ratio of 3; the limits of quantification were 50 μg/l for HVA and HGA, 100 μg/l for VMA, and 250 μg/l for OA. The linear dynamic range for quantification of the analytes covered 2 to 3 orders of magnitude, depending on the analyte. The relative standard deviation of the developed LC-MS/MS method was less than 4% for the intra-day validation and 10% for the inter-day validation. CONCLUSIONS The results show that our LC-MS/MS technique is a highly sensitive and rapid method for screening for biomarkers that are diagnostic of three metabolic diseases.
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Xiong Y, Guan KL. Mechanistic insights into the regulation of metabolic enzymes by acetylation. ACTA ACUST UNITED AC 2012; 198:155-64. [PMID: 22826120 PMCID: PMC3410420 DOI: 10.1083/jcb.201202056] [Citation(s) in RCA: 184] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The activity of metabolic enzymes is controlled by three principle levels: the amount of enzyme, the catalytic activity, and the accessibility of substrates. Reversible lysine acetylation is emerging as a major regulatory mechanism in metabolism that is involved in all three levels of controlling metabolic enzymes and is altered frequently in human diseases. Acetylation rivals other common posttranslational modifications in cell regulation not only in the number of substrates it modifies, but also the variety of regulatory mechanisms it facilitates.
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Affiliation(s)
- Yue Xiong
- Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Fudan University, Shanghai 20032, China.
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12
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Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 2012; 7:32. [PMID: 22642880 PMCID: PMC3488504 DOI: 10.1186/1750-1172-7-32] [Citation(s) in RCA: 371] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2011] [Accepted: 04/06/2012] [Indexed: 12/11/2022] Open
Abstract
Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000. Patients present with hyperammonemia either shortly after birth (~50%) or, later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns. To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across seven European countries to gather all the existing evidence, score it according to the SIGN evidence level system and draw a series of statements supported by an associated level of evidence. The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training. Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Also, it identified knowledge voids that must be filled by future research. We believe these guidelines will help to: harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.
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Affiliation(s)
- Johannes Häberle
- University Children’s Hospital Zurich and Children’s Research Centre, Zurich, 8032, Switzerland
| | - Nathalie Boddaert
- Radiologie Hopital Necker, Service Radiologie Pediatrique, 149 Rue De Sevres, Paris 15, 75015, France
| | - Alberto Burlina
- Department of Pediatrics, Division of Inborn Metabolic Disease, University Hospital Padua, Via Giustiniani 3, Padova, 35128, Italy
| | - Anupam Chakrapani
- Birmingham Children’s Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham, B4 6NH, United Kingdom
| | - Marjorie Dixon
- Dietetic Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, WC1N 3JH, United Kingdom
| | - Martina Huemer
- Kinderabteilung, LKH Bregenz, Carl-Pedenz-Strasse 2, Bregenz, A-6900, Austria
| | - Daniela Karall
- University Children’s Hospital, Medical University Innsbruck, Anichstrasse 35, Innsbruck, 6020, Austria
| | - Diego Martinelli
- Division of Metabolism, Bambino Gesù Children’s Hospital, IRCCS, Piazza S. Onofrio 4, Rome, I-00165, Italy
| | | | - René Santer
- Universitätsklinikum Hamburg Eppendorf, Klinik für Kinder- und Jugendmedizin, Martinistr. 52, Hamburg, 20246, Germany
| | - Aude Servais
- Service de Néphrologie et maladies métaboliques adulte Hôpital Necker 149, rue de Sèvres, Paris, 75015, France
| | - Vassili Valayannopoulos
- Reference Center for Inherited Metabolic Disorders (MaMEA), Hopital Necker-Enfants Malades, 149 Rue de Sevres, Paris, 75015, France
| | - Martin Lindner
- University Children’s Hospital, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany
| | - Vicente Rubio
- Instituto de Biomedicina de Valencia del Consejo Superior de Investigaciones Científicas (IBV-CSIC) and Centro de Investigación Biomédica en Red para Enfermedades Raras (CIBERER), C/ Jaume Roig 11, Valencia, 46010, Spain
| | - Carlo Dionisi-Vici
- Division of Metabolism, Bambino Gesù Children’s Hospital, IRCCS, Piazza S. Onofrio 4, Rome, I-00165, Italy
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13
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Choi DE, Lee KW, Shin YT, Na KR. Hyperammonemia in a patient with late-onset ornithine carbamoyltransferase deficiency. J Korean Med Sci 2012; 27:556-9. [PMID: 22563224 PMCID: PMC3342550 DOI: 10.3346/jkms.2012.27.5.556] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Accepted: 01/26/2012] [Indexed: 12/31/2022] Open
Abstract
Ornithine carbamoyltransferase (OTC) deficiency is a urea cycle disorder that causes the accumulation of ammonia, which can lead to encephalopathy. Adults presenting with hyperammonemia who are subsequently diagnosed with urea cycle disorders are rare. Herein, we report a case of a late-onset OTC deficient patient who was successfully treated with arginine, benzoate and hemodialysis. A 59-yr-old man was admitted to our hospital with progressive lethargy and confusion. Although hyperammonemia was suspected as the cause of the patient's mental changes, there was no evidence of chronic liver disease. A plasma amino acid and urine organic acid analysis revealed OTC deficiency. Despite the administration of a lactulose enema, the patient's serum ammonia level increased and he remained confused, leading us to initiate acute hemodialysis. After treatment with arginine, sodium benzoate and hemodialysis, the patient's serum ammonia level stabilized and his mental status returned to normal.
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Affiliation(s)
- Dae Eun Choi
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Korea
| | - Kang Wook Lee
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Korea
| | - Young Tai Shin
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Korea
| | - Ki Ryang Na
- Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Korea
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14
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Abstract
Ammonia is produced continuously in the body. It crosses the blood-brain barrier readily and at increased concentration it is toxic to the brain. A highly integrated system protects against this: ammonia produced during metabolism is detoxified temporarily by incorporation into the non-toxic amino acid glutamine. This is transported safely in the circulation to the small intestine, where ammonia is released, carried directly to the liver in the portal blood, converted to non-toxic urea and finally excreted in urine. As a result, plasma concentrations of ammonia in the systemic circulation are normally very low (<40 μmol/L). Hyperammonaemia develops if the urea cycle cannot control the ammonia load. This occurs when the load is excessive, portal blood from the intestines bypasses the liver and/or the urea cycle functions poorly. By far, the commonest cause is liver damage. This review focuses on other causes in adults. Because they are much less common, the diagnosis may be missed or delayed, with disastrous consequences. There is effective treatment for most of them, but it must be instituted promptly to avoid fatality or long-term neurological damage. Of particular concern are unsuspected inherited defects of the urea cycle and fatty acid oxidation presenting with catastrophic illness in previously normal individuals. Early identification of the problem is the challenge.
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Affiliation(s)
- Valerie Walker
- Department of Clinical Biochemistry, University Hospital Southampton NHS Foundation Trust, C Level MP 8, South Block, Southampton Hospital, Tremona Road, Southampton SO16 6YD, UK.
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15
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Balasubramaniam S, Rudduck C, Bennetts B, Peters G, Wilcken B, Ellaway C. Contiguous gene deletion syndrome in a female with ornithine transcarbamylase deficiency. Mol Genet Metab 2010; 99:34-41. [PMID: 19783189 DOI: 10.1016/j.ymgme.2009.08.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Revised: 08/21/2009] [Accepted: 08/21/2009] [Indexed: 10/20/2022]
Abstract
OTC deficiency, a partially dominant X-linked trait, is the most frequent inborn error of the urea cycle. We describe a female patient with a contiguous gene deletion syndrome encompassing the OTC, DMD, RPGR, CYBB and XK genes, amongst others, only manifesting features of OTC deficiency. Molecular characterization was ascertained by MLPA and confirmed by CGH microarray, which revealed an 8.7 Mb deletion of the X-chromosome. Complete de novo deletion of the OTC gene led to a severe clinical phenotype in the proband. The application of high resolution molecular genetic techniques such as MLPA and array CGH, in mutation negative OTC cases allows the identification of chromosomal rearrangements, such as large deletions and provides information for accurate genetic counseling and prenatal diagnosis.
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Affiliation(s)
- S Balasubramaniam
- Genetic Metabolic Disorders Service, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia
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16
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Abstract
The urea cycle is the final pathway for removal of surplus nitrogen from the body, and the major route in humans for detoxification of ammonia. The full complement of enzymes is expressed only in liver. Inherited deficiencies of urea cycle enzymes lead to hyperammonaemia, which causes brain damage. Severe defects present with hyperammonaemic crises in neonates. Equally devastating episodes may occur in previously asymptomatic adults with mild defects, most often X-linked ornithine transcarbamylase (OTC) deficiency. Several mechanisms probably contribute to pathogenesis. Treatment aims to reduce plasma ammonia quickly, reduce production of waste nitrogen, dispose of waste nitrogen using alternative pathways to the urea cycle and replace arginine. These therapies have increased survival and probably improve the neurological outcome. Arginine, sodium benzoate, sodium phenylbutyrate and, less often, sodium phenylacetate are used. Long-term correction is achieved by liver transplantation. Gene therapy for OTC deficiency is effective in animals, and work is ongoing to improve persistence and safety.
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Affiliation(s)
- V Walker
- Department of Clinical Biochemistry, Southampton University Hospitals NHS Trust, Southampton General Hospital, Southampton, UK. valerie.walker @suht.swest.nhs.uk
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17
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Yu W, Lin Y, Yao J, Huang W, Lei Q, Xiong Y, Zhao S, Guan KL. Lysine 88 acetylation negatively regulates ornithine carbamoyltransferase activity in response to nutrient signals. J Biol Chem 2009; 284:13669-13675. [PMID: 19318352 DOI: 10.1074/jbc.m901921200] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Ornithine carbamoyltransferase (OTC) is a key enzyme in the urea cycle to detoxify ammonium produced from amino acid catabolism. OTC deficiency is an X-linked genetic disorder ranging from fatal in newborns to hyperammonemia and anorexia in adults. Through affinity purification of acetylated peptides and mass spectrometry, we identified that OTC is acetylated on lysine residues, including Lys88, which is also mutated in OTC-deficient patients. OTC acetylation was confirmed to occur under physiological conditions. Biochemical characterizations revealed that OTC Lys88 acetylation decreases the affinity for carbamoyl phosphate, one of the two OTC substrates, and the maximum velocity, whereas the K(m) for ornithine, the other OTC substrate, is not affected. Furthermore, Lys88 acetylation is regulated by both extracellular glucose and amino acid availability, indicating that OTC activity may be regulated by cellular metabolic status. Our results provide an example of the novel mechanism of regulating metabolic enzyme activity through protein acetylation.
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Affiliation(s)
- Wei Yu
- School of Life Sciences Fudan University, Shanghai 20032, China; Institute of Biomedical Sciences Fudan University, Shanghai 20032, China
| | - Yan Lin
- Institute of Biomedical Sciences Fudan University, Shanghai 20032, China
| | - Jun Yao
- Institute of Biomedical Sciences Fudan University, Shanghai 20032, China
| | - Wei Huang
- School of Life Sciences Fudan University, Shanghai 20032, China; Institute of Biomedical Sciences Fudan University, Shanghai 20032, China
| | - Qunying Lei
- Institute of Biomedical Sciences Fudan University, Shanghai 20032, China; Department of Biological Chemistry, School of Medicine, Fudan University, Shanghai 20032, China
| | - Yue Xiong
- Institute of Biomedical Sciences Fudan University, Shanghai 20032, China; Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599
| | - Shimin Zhao
- School of Life Sciences Fudan University, Shanghai 20032, China; Institute of Biomedical Sciences Fudan University, Shanghai 20032, China.
| | - Kun-Liang Guan
- Institute of Biomedical Sciences Fudan University, Shanghai 20032, China; Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, California 92093.
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18
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Abstract
INTRODUCTION Urea cycle disorders (UCD) usually present after 24 h to 48 h of life with failure to thrive, lethargy and coma leading to death, but milder forms may occur from infancy to adulthood. STATE OF THE ART Survival of children with UCD has significantly improved and the need for transitional care to adulthood has emerged. Adult onset UCD present with chronic or acute neurological, psychiatric and digestive symptoms associated with protein avoidance. Ornithine transcarbamylase (OTC) deficiency, which is inherited as an X-linked disorder, is the most well-described UCD in adults. Acute decompensations associate the triad of encephalopathy, respiratory alkalosis and hyperammonemia. Acute encephalopathy is characterized by brain edema, which is life-threatening without treatment. Specific urea cycle enzyme deficiency can be suspected in the presence of abnormal plasma amino acids concentrations and urinary excretion of orotic acid. A measurement enzyme activity in appropriate tissue, or DNA analysis if available, is required for diagnosis. Treatment requires restriction of dietary protein intake and the use of alternative pathways of waste nitrogen excretion with sodium benzoate and sodium phenylbutyrate. Patients with acute forms may need hemodialysis or hemodiafiltration. Therapeutic goals for OTC deficiency are to maintain plasma ammonia<80 micromol/L, plasma glutamine<1,000 micromol/L, argininemia 80-150 micromol/L and branched chain amino acids within the normal range, in order to prevent episodes of potentially lethal acute hyperammonemia. CONCLUSION Potentially fatal acute hyperammonemia may occur in male or female patients at any age. Ammonia should be measured promptly in case of acute neurological and psychiatric symptoms or coma.
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Affiliation(s)
- F Maillot
- Service de Médecine Interne et Nutrition, CHRU,Tours, France.
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19
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Ohba Y, Takasu M, Nishii N, Hosoda I, Kitoh K, Matsumoto I, Zhang C, Kitagawa H. Japanese Black Cattle with Orotic Aciduria Detected by Gas-Chromatography/Mass-Spectrometry. J Vet Med Sci 2007; 69:313-6. [PMID: 17409652 DOI: 10.1292/jvms.69.313] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
A 4-months-old calf of Japanese black cattle was diagnosed with orotic aciduria by gas-chromatography/mass-spectrometry (GC/MS). Until now orotic aciduria had not been reported in Japanese black cattle. The animal showed repeated diarrhea. The hematocrit was low, and microcytes and acanthocytes were observed in blood smears. The calf had lower serum total protein concentrations with a higher blood ammonia concentration. Needle-shaped crystals of orotic acid were observed in urinary sediments. Sequence homologous analysis with cattle uridine monophosphate synthase DNA indicated silent mutation in the affected calf.
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Affiliation(s)
- Yasunori Ohba
- Laboratory of Internal Medicine, Division of Veterinary Medicine, Faculty of Applied Sciences, Gifu University, Japan
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20
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Lanpher B, Brunetti-Pierri N, Lee B. Inborn errors of metabolism: the flux from Mendelian to complex diseases. Nat Rev Genet 2006; 7:449-60. [PMID: 16708072 DOI: 10.1038/nrg1880] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Inborn errors of metabolism are characterized by dysregulation of the metabolic networks that underlie development and homeostasis, and constitute an important and expanding group of genetic disorders in humans. Diagnostic methods that are based on molecular genetic tools have a limited ability to correlate phenotypes with subtle changes in metabolic fluxes. We argue that the direct and dynamic measurement of metabolite flux will facilitate the integration of environmental, genetic and biochemical factors with phenotypic information. Ultimately, this integration will lead to new diagnostic and therapeutic approaches that are focused on the manipulation of these pathways.
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Affiliation(s)
- Brendan Lanpher
- Department of Molecular and Human Genetics, Baylor College of Medicine One Baylor Plaza, Houston, Texas 77030, USA
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21
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Oexle K. Useful probability considerations in genetics: the goat problem with tigers and other applications of Bayes' theorem. Eur J Pediatr 2006; 165:299-305. [PMID: 16463135 DOI: 10.1007/s00431-005-0039-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2005] [Revised: 10/25/2005] [Accepted: 10/26/2005] [Indexed: 12/31/2022]
Abstract
Probabilities or risks may change when new information is available. Common sense frequently fails in assessing this change. In such cases, Bayes' theorem may be applied. It is easy to derive and has abundant applications in biology and medicine. Some examples of the application of Bayes' theorem are presented here, such as carrier risk estimation in X-chromosomal disorders, maximal manifestation probability of a dominant trait with unknown penetrance, combination of genetic and non-genetic information, and linkage analysis. The presentation addresses the non-specialist who asks for valid and consistent explanations. The conclusion to be drawn is that Bayes' theorem is an accessible and helpful tool for probability calculations in genetics.
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Affiliation(s)
- Konrad Oexle
- Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
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22
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Oexle K. Biochemical data in ornithine transcarbamylase deficiency (OTCD) carrier risk estimation: logistic discrimination and combination with genetic information. J Hum Genet 2006; 51:204-208. [PMID: 16453063 DOI: 10.1007/s10038-005-0345-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2005] [Accepted: 11/04/2005] [Indexed: 12/31/2022]
Abstract
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.
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Affiliation(s)
- Konrad Oexle
- Institute of Clinical Genetics, Medical Faculty "Carl Gustav Carus", Dresden University of Technology, Fetscherstrasse 74, 01307, Dresden, Germany.
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23
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Morioka D, Kasahara M, Takada Y, Shirouzu Y, Taira K, Sakamoto S, Uryuhara K, Egawa H, Shimada H, Tanaka K. Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University. Liver Transpl 2005; 11:1332-42. [PMID: 16237708 DOI: 10.1002/lt.20587] [Citation(s) in RCA: 103] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
To address the current role of liver transplantation (LT) for urea cycle disorders (UCDs), we reviewed the worldwide English literature on the outcomes of LT for UCD as well as 13 of our own cases of living donor liver transplantation (LDLT) for UCD. The total number of cases was 51, including our 13 cases. The overall cumulative patient survival rate is presumed to be more than 90% at 5 years. Most of the surviving patients under consideration are currently doing well with satisfactory quality of life. One advantage of LDLT over deceased donor liver transplantation (DDLT) is the opportunity to schedule surgery, which beneficially affects neurological consequences. Auxiliary partial orthotopic liver transplantation (APOLT) is no longer considered significant for the establishment of gene therapies or hepatocyte transplantation but plays a significant role in improving living liver donor safety; this is achieved by reducing the extent of the hepatectomy, which avoids right liver donation. Employing heterozygous carriers of the UCDs as donors in LDLT was generally acceptable. However, male hemizygotes with ornithine transcarbamylase deficiency (OTCD) must be excluded from donor candidacy because of the potential risk of sudden-onset fatal hyperammonemia. Given this possibility as well as the necessity of identifying heterozygotes for other disorders, enzymatic and/or genetic assays of the liver tissues in cases of UCDs are essential to elucidate the impact of using heterozygous carrier donors on the risk or safety of LDLT donor-recipient pairs. In conclusion, LT should be considered to be the definitive treatment for UCDs at this stage, although some issues remain unresolved.
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Affiliation(s)
- Daisuke Morioka
- Organ Transplant Unit, Kyoto University Hospital, Kyoto, Japan.
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24
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Morioka D, Kasahara M, Takada Y, Corrales JPG, Yoshizawa A, Sakamoto S, Taira K, Yoshitoshi EY, Egawa H, Shimada H, Tanaka K. Living donor liver transplantation for pediatric patients with inheritable metabolic disorders. Am J Transplant 2005; 5:2754-63. [PMID: 16212637 DOI: 10.1111/j.1600-6143.2005.01084.x] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Forty-six pediatric patients who underwent living donor liver transplantation (LDLT) using parental liver grafts for inheritable metabolic disorders (IMD) were evaluated to determine the outcomes of the surgery, decisive factors for post-transplant patient survival and the impact of using donors who were heterozygous for the particular disorder. Disorders included Wilson disease (WD, n = 21), ornithine transcarbamylase deficiency (OTCD, n = 6), tyrosinemia type I (TTI, n = 6), glycogen storage disease (GSD, n = 4), propionic acidemia (PPA, n = 3), methylmalonic acidemia (MMA, n = 2), Crigler-Najjar syndrome type I (CNSI, n = 2), bile acid synthetic defect (BASD, n = 1) and erythropoietic protoporphyria (EPP, n = 1). The post-transplant cumulative patient survival rates were 86.8 and 81.2% at 1 and 5 years, respectively. Post-transplant patient survival and recovery of the growth retardation were significantly better in the liver-oriented diseases (WD, OTCD, TTI, CNSI and BASD) than in the non-liver-oriented diseases (GSD, PPA, MMA and EPP) and pre-transplant growth retardation disadvantageously affected post-transplant outcomes. Although 40 of 46 donors were considered heterozygous for each disorder, neither mortality nor morbidity related to the heterozygosis has been observed. LDLT using parental donors can be recommended as an effective treatment for pediatric patients with IMD. In the non-liver-oriented diseases, however, satisfactory outcomes were not obtained by hepatic replacement alone.
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Affiliation(s)
- Daisuke Morioka
- Organ Transplant Unit, Kyoto University Hospital, Shogoin-kawara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
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25
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Morioka D, Takada Y, Kasahara M, Ito T, Uryuhara K, Ogawa K, Egawa H, Tanaka K. Living Donor Liver Transplantation for Noncirrhotic Inheritable Metabolic Liver Diseases: Impact of the Use of Heterozygous Donors. Transplantation 2005; 80:623-8. [PMID: 16177636 DOI: 10.1097/01.tp.0000167995.46778.72] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND In living donor liver transplantation (LDLT), the liver donor is almost always a blood relative; therefore, the donor is sometimes a heterozygous carrier of inheritable diseases. The use of such carriers as donors has not been validated. The aim of the present study was to evaluate the outcome of LDLT for noncirrhotic inheritable metabolic liver disease (NCIMLD) to clarify the effects of using a heterozygous carrier as a donor. METHODS Between June 1990 and December 2003, 21 patients with NCIMLD underwent LDLT at our institution. The indications for LDLT included type II citrullinemia (n = 7), ornithine transcarbamylase deficiency (n = 6), propionic acidemia (n = 3), Crigler-Najjar syndrome type I (n = 2), methylmalonic acidemia (n = 2), and familial amyloid polyneuropathy (n = 1). Of these 21 recipients, six underwent auxiliary partial orthotopic liver transplantation. RESULTS The cumulative survival rate of the recipients was 85.7% at both 1 and 5 years after operation. All surviving recipients are currently doing well without sequelae of the original diseases, including neurological impairments or physical growth retardation. Twelve of the 21 donors were considered to be heterozygous carriers based on the modes of inheritance of the recipients' diseases and preoperative donor medical examinations. All donors were uneventfully discharged from the hospital and have been doing well since discharge. No mortality or morbidity related to the use of heterozygous donors was observed in donors or recipients. CONCLUSIONS Our results suggest that the use of heterozygous donors in LDLT for NCIMLD has no negative impact on either donors or recipients, although some issues remain unsolved and should be evaluated in further studies.
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26
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Scaglia F, Brunetti-Pierri N, Kleppe S, Marini J, Carter S, Garlick P, Jahoor F, O'Brien W, Lee B. Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr 2004; 134:2775S-2782S; discussion 2796S-2797S. [PMID: 15465784 DOI: 10.1093/jn/134.10.2775s] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Urea cycle disorders (UCD) are human conditions caused by the dysregulation of nitrogen transfer from ammonia nitrogen into urea. The biochemistry and the genetics of these disorders were well elucidated. Earlier diagnosis and improved treatments led to an emerging, longer-lived cohort of patients. The natural history of some of these disorders began to point to pathophysiological processes that may be unrelated to the primary cause of acute morbidity and mortality, i.e., hyperammonemia. Carbamyl phosphate synthetase I single nucleotide polymorphisms may be associated with altered vascular resistance that becomes clinically relevant when specific environmental stressors are present. Patients with argininosuccinic aciduria due to a deficiency of argininosuccinic acid lyase are uniquely prone to chronic hepatitis, potentially leading to cirrhosis. Moreover, our recent observations suggest that there may be an increased prevalence of essential hypertension. In contrast, hyperargininemia found in patients with arginase 1 deficiency is associated with pyramidal tract findings and spasticity, without significant hyperammonemia. An intriguing potential pathophysiological link is the dysregulation of intracellular arginine availability and its potential effect on nitric oxide (NO) metabolism. By combining detailed natural history studies with the development of tissue-specific null mouse models for urea cycle enzymes and measurement of nitrogen flux through the cycle to urea and NO in UCD patients, we may begin to dissect the contribution of different sources of arginine to NO production and the consequences on both rare genetic and common multifactorial diseases.
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Affiliation(s)
- Fernando Scaglia
- Department of Molecular and Human Genetics, Children's Nutritional Research Center, Baylor College of Medicine, Houston, TX 77030, USA
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27
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Wilcken B. Problems in the management of urea cycle disorders. Mol Genet Metab 2004; 81 Suppl 1:S86-91. [PMID: 15050980 DOI: 10.1016/j.ymgme.2003.10.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2003] [Revised: 10/17/2003] [Accepted: 10/25/2003] [Indexed: 12/11/2022]
Abstract
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."
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Affiliation(s)
- Bridget Wilcken
- The Children's Hospital at Westmead and the Discipline of Paediatrics, University of Sydney, Sydney, Australia.
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28
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Gyato K, Wray J, Huang ZJ, Yudkoff M, Batshaw ML. Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency. Ann Neurol 2004; 55:80-6. [PMID: 14705115 DOI: 10.1002/ana.10794] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
We compared neurocognitive indices with clinical status, mutation analysis, and urea synthetic capacity in 19 women heterozygous for ornithine transcarbamylase deficiency. Although as a group, these women had average IQ scores, they displayed a specific neuropsychological phenotype with significant strengths in verbal intelligence, verbal learning, verbal memory, and reading, and significant weaknesses in fine motor dexterity/speed and nonsignificant weaknesses in nonverbal intelligence, visual memory, attention/executive skills, and math. This suggests selective vulnerability of white matter and better preservation of gray matter. When the group was divided into symptomatic and asymptomatic subgroups, based on either clinical history or residual urea synthetic capacity, the asymptomatic subgroup outperformed the symptomatic subgroup on all tested domains of neuropsychological functioning. Furthermore, the amount of residual urea synthetic capacity was predictive of several end point cognitive measures. There was no correlation between neonatal versus late-onset mutation or between normal or abnormal allopurinol challenge and neuropsychological outcome. In sum, we identified a specific metabolic and neurocognitive phenotype in women heterozygous for ornithine transcarbamylase deficiency. The findings support the importance of maintaining meticulous metabolic control in children with urea cycle disorders, because even mildly symptomatic subjects demonstrate cognitive deficits.
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Affiliation(s)
- Kunsang Gyato
- North Shore-Long Island Jewish Health System, Schneider Children's Hospital, Division of Child and Adolescent Psychiatry, New Hyde Park, NY, USA
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Abstract
Plasma ammonia measurement is a simple yet important screening in the ED for patients with unexplained stupor or delirium. Acute hyperammonemia is a medical emergency for which immediate steps must be taken to minimize permanent brain damage. Although the most common causes of hyperammonemia are severe abnormal liver function, the absence of liver disease in some cases has been observed. This brief report describes four hyperammonemia cases with normal liver function in the ED. On careful history and speculated examinations, ornithine carbamoyltransferase (OTC) deficiency, hematologic malignancy, and the side effects of valproic acid and 5-fluorouracil (5-FU) were considered. Therapy was first aimed at correcting the hyperammonemia. Once a specific diagnosis was reached, protein restriction, essential amino acid supplementation, efficient chemotherapy, and valproic acid and 5-FU level discontinuance were instituted. In this report, the clinical presentation, pathogenesis, and diagnostic workup for various hyperammonemia causes are discussed. Every EP should understand that the clinical symptoms for hyperammonemia and prognosis are related to early diagnosis.
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Affiliation(s)
- Te-I Weng
- Department of Emergency Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
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30
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Grünewald S, Fairbanks L, Genet S, Cranston T, Hüsing J, Leonard JV, Champion MP. How reliable is the allopurinol load in detecting carriers for ornithine transcarbamylase deficiency? J Inherit Metab Dis 2004; 27:179-86. [PMID: 15159648 DOI: 10.1023/b:boli.0000028727.77454.bd] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
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.
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31
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Ito T, Sumi S, Kidouchi K, Ban K, Ueta A, Hashimoto T, Togari H, Wada Y. Allopurinol challenge tests performed before and after living-related donor liver transplantation in citrullinaemia. J Inherit Metab Dis 2003; 26:87-8. [PMID: 12872848 DOI: 10.1023/a:1024096001455] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
We performed allopurinol challenge tests to evaluate the metabolic state of a citrullinaemic patient who received a living-relative donor liver transplant. Before transplantation, large amounts of orotic acid and orotidine were excreted during the challenge test. Following transplantation, excretion of these compounds in response to allopurinol was normalised. The challenge test was a safe and useful method to evaluate the metabolic state of the patient.
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Affiliation(s)
- T Ito
- Department of Pediatrics, Nagoya City University Medical School, Nagoya, Japan
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32
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Gaspari R, Arcangeli A, Mensi S, Wismayer DS, Tartaglione T, Antuzzi D, Conti G, Proietti R. Late-onset presentation of ornithine transcarbamylase deficiency in a young woman with hyperammonemic coma. Ann Emerg Med 2003; 41:104-9. [PMID: 12514690 DOI: 10.1067/mem.2003.6] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Ornithine transcarbamylase deficiency (OTCD) is an X-linked inherited disease and the most common inborn error in urea synthesis in human patients. In adult heterozygous patients, OTCD can be responsible for life-threatening hyperammonemic coma. We report the case of a 32-year-old woman admitted to our hospital with seizures after a recent high protein load. Her parents related a history of recurrent episodes of vomiting, meat refusal, lethargy, and convulsions since childhood, and measurement of plasma ammonemia levels was the key to early diagnosis of OTCD. We report the pathophysiologic characteristics, clinical features, clinical course, and differential diagnosis of OTCD and discuss the therapeutic options, including continuous venovenous hemodiafiltration and pharmacologic therapy for reduction of plasma ammonemia levels. A diagnosis of OTCD should be considered in adult nonhepatic patients with hyperammonemic coma, particularly if they have a history of protein avoidance and neurologic symptoms. Early recognition and appropriate treatment are critical to avoid severe brain damage and death.
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Affiliation(s)
- Rita Gaspari
- Department of Anaesthesiology and Intensive Care, Catholic University of Rome, Rome, Italy.
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33
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Salerno C, Crifò C. Diagnostic value of urinary orotic acid levels: applicable separation methods. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 781:57-71. [PMID: 12450653 DOI: 10.1016/s1570-0232(02)00533-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Urinary orotic acid determination is a useful tool for screening hereditary orotic aciduria and for differentiating the hyperammonemia disorders which cannot be readily diagnosed by amino acid chromatography, thus reducing the need for enzyme determination in tissue biopsies. This review provides an overview of metabolic aberrations that may be related to increased orotic acid levels in urine, and summarises published methods for separation, identification and quantitative determination of orotic acid in urine samples. Applications of high-performance liquid chromatography, gas chromatography, and capillary electrophoresis to the analysis of urinary specimens are described. The advantages and limitations of these separation and identification methodologies as well as other less frequently employed techniques are assessed and discussed.
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Affiliation(s)
- Costantino Salerno
- Department of Biochemical Sciences and Clinical Biochemistry Laboratory, University of Roma La Sapienza, via dei Sardi 58, 00185 Rome, Italy.
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34
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Oexle K, Bonafé L, Steinmann B. Remark on utility and error rates of the allopurinol test in detecting mild ornithine transcarbamylase deficiency. Mol Genet Metab 2002; 76:71-5. [PMID: 12175784 DOI: 10.1016/s1096-7192(02)00025-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
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.
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Affiliation(s)
- Konrad Oexle
- Division of Metabolism and Molecular Pediatrics, University Children's Hospital, Zurich, Switzerland.
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35
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Friedecký D, Adam T, Barták P. Capillary electrophoresis for detection of inherited disorders of purine and pyrimidine metabolism: a selective approach. Electrophoresis 2002; 23:565-71. [PMID: 11870766 DOI: 10.1002/1522-2683(200202)23:4<565::aid-elps565>3.0.co;2-s] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
We developed a capillary electrophoresis method as a diagnostic tool for purine and pyrimidine metabolic disorders. Optimal conditions allowed the separation of the major diagnostic metabolites in urine samples within an analysis time of 10 min and with a separation efficiency of about 350,000 theoretical plates/m. The diagnostically important metabolites (adenine, adenosine, 2-deoxyadenosine, 2-deoxyguanosine, 2,8-dihydroxyadenine, guanosine, hypoxanthine, orotidine, orotic acid, and creatinine) were detectable at concentrations of 1.0-5.7 micromol/L. The method gives a linear calibration curve for tested purine and pyrimidine derivatives within the range of 5-500 micromol/L (r > 0.996) The coefficients of variation for the within- and between-day imprecisions were less than 3.2 and 5.8%, respectively. Characteristic abnormalities were detected in the electropherograms of urine samples from patients with purine and pyrimidine enzyme deficiencies. We provide electrophoretic and spectral characteristics of intermediates in purine and pyrimidine metabolism and possible artifacts from medication and their UV-absorbing compounds. Our method allows the detection of the majority of inborn errors of purine and pyrimidine metabolism.
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Affiliation(s)
- David Friedecký
- Department of Analytical Chemistry, Palacký University, Olomouc, Czech Republic
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36
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Abstract
Most patients with urea cycle disorders who present as neonates, do so with deteriorating feeding, drowsiness and tachypnoea, following a short initial period when they appear well. The plasma ammonia should be measured at the same time as the septic screen in such patients. Ammonia levels above 200 micromol/l are usually caused by inherited metabolic diseases and it is essential to make a diagnosis for genetic counselling, even if the patients die. The aim of treatment is to lower the ammonia concentrations as fast as possible. Sodium benzoate, sodium phenylbutyrate and arginine can exploit alternative pathways for the elimination of nitrogen but haemodialysis or haemofiltration should be instituted if ammonia concentrations are >500 micromol/l or if they do not fall promptly. Long-term management involves drugs, dietary protein restriction and use of an emergency regimen during illness. Severe hyperammonaemia is usually associated with irreversible neurological damage, particularly if levels have been above 800 micromol/l for >24 hours, and the option of withdrawing treatment should be discussed with the family.
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Affiliation(s)
- J V Leonard
- Biochemistry, Endocrine and Metabolic Unit, Institute of Child Health, London, UK.
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37
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Raper SE, Yudkoff M, Chirmule N, Gao GP, Nunes F, Haskal ZJ, Furth EE, Propert KJ, Robinson MB, Magosin S, Simoes H, Speicher L, Hughes J, Tazelaar J, Wivel NA, Wilson JM, Batshaw ML. A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Hum Gene Ther 2002; 13:163-75. [PMID: 11779420 DOI: 10.1089/10430340152712719] [Citation(s) in RCA: 256] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Ornithine transcarbamylase deficiency (OTCD) is an inborn error of urea synthesis that has been considered as a model for liver-directed gene therapy. Current treatment has failed to avert a high mortality or morbidity from hyperammonemic coma. Restoration of enzyme activity in the liver should suffice to normalize metabolism. An E1- and E4-deleted vector based on adenovirus type 5 and containing human OTC cDNA was infused into the right hepatic artery in adults with partial OTCD. Six cohorts of three or four subjects received 1/2 log-increasing doses of vector from 2 x 10(9) to 6 x 10(11) particles/kg. This paper describes the experience in all but the last subject, who experienced lethal complications. Adverse effects included a flu-like episode and a transient rise in temperature, hepatic transaminases, thrombocytopenia, and hypophosphatemia. Humoral responses to the vector were seen in all research subjects and a proliferative cellular response to the vector developed in apparently naive subjects. In situ hybridization studies showed transgene expression in hepatocytes of 7 of 17 subjects. Three of 11 subjects with symptoms related to OTCD showed modest increases in urea cycle metabolic activity that were not statistically significant. The low levels of gene transfer detected in this trial suggest that at the doses tested, significant metabolic correction did not occur.
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Affiliation(s)
- Steven E Raper
- Institute for Human Gene Therapy and Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA
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38
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Scaglia F, Zheng Q, O'Brien WE, Henry J, Rosenberger J, Reeds P, Lee B. An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency. Pediatrics 2002; 109:150-2. [PMID: 11773558 DOI: 10.1542/peds.109.1.150] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
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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Affiliation(s)
- Fernando Scaglia
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
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39
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Trivedi M, Zafar S, Spalding MJ, Jonnalagadda S. Ornithine transcarbamylase deficiency unmasked because of gastrointestinal bleeding. J Clin Gastroenterol 2001; 32:340-3. [PMID: 11276280 DOI: 10.1097/00004836-200104000-00013] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Ornithine transcarbamylase (OTC) is a mitochondrial-matrix enzyme that catalyzes conversion of ornithine and carbamyl phosphate to citrulline, the second step in the urea cycle. The urea cycle is the most important pathway to detoxification of ammonia in human beings. Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder, inherited as an X-linked disorder that can cause fatal hyperammonemia in male newborns. Women with OTCD have a variable expression of their disease, the variability being determined by lyonization (random inactivation) of the X chromosome. We report a case of a 28-year-old woman who presented with hyperammonemic encephalopathy that was precipitated by a gastrointestinal bleed unmasking OTCD.
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Affiliation(s)
- M Trivedi
- Division of Gastroenterology, University of Missouri-Columbia, Columbia, Missouri, USA.
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40
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Potter M, Hammond JW, Sim KG, Green AK, Wilcken B. Ornithine carbamoyltransferase deficiency: improved sensitivity of testing for protein tolerance in the diagnosis of heterozygotes. J Inherit Metab Dis 2001; 24:5-14. [PMID: 11286382 DOI: 10.1023/a:1005682017337] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The most direct test of functional capacity of the liver in nitrogen disposal is to stress the urea cycle with a high protein load. This has been used in the diagnosis of heterozygosity for ornithine carbamoyltransferase deficiency for many years by measuring the subsequent excretion of orotic acid in urine. Reports have shown some ambiguity in both this and the more recent allopurinol test. We investigated the effects of different foods as the protein load and of different analytical methods. A standardized protocol was developed, giving 35 g protein per m2 surface area as steamed fat-free chicken breast to be eaten within 30 min. Urine was collected at zero time and over 0-2, 2-4 and 4-6 h. Compliance was checked by assessing excretion of amino acids. Diagnostic sensitivity was improved by reference to the change in excretion, i.e. the ratio of excretions 2-4 h/0-2 h. Extension of the test to 6 h gave no diagnostic advantage over a 4 h test. Comparison of the analysis of total orotic acids by the photometric method of Harris and Oberholtzer, the reference method for this study, with that by the method of Goldstein and colleagues showed that the latter gave erratic results with some false positives. However, comparison of the method of Harris and Oberholtzer with specific orotic acid analysis by a modification of the stable-isotope internal standard method of Rimoldi and colleagues yielded the same diagnoses. The improved protein load test gave a clearly positive result in all 16 obligate heterozygotes and 2 possible heterozygotes tested from 14 kindred, and a clearly negative result in all 18 control subjects and all 6 of the possible heterozygotes who were later shown by DNA studies not to carry the family mutation. The test appears at least as sensitive and specific as the allopurinol test, and is more convenient because of the short period of sample collection.
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Affiliation(s)
- M Potter
- New South Wales Biochemical Genetics Service, The Children's Hospital at Westmead, (Sydney), Australia
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41
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Abstract
The urea cycle disorders (UCDs) represent a group of inherited metabolic diseases with hyperammonemia as the primary laboratory abnormality. Affected individuals may become comatose or die if not treated rapidly. Diagnosis of a UCD requires a high index of suspicion and judicious use of the laboratory. It is important to rule out other conditions causing hyperammonemia that may require different treatment. The astute clinician may suspect a specific UCD in the appropriate clinical setting, but only laboratory results can confirm a specific diagnosis. The importance of the laboratory in helping the clinician to differentiate among various causes of hyperammonemia, in confirming a specific UCD, in carrier testing, and in prenatal diagnostic testing is highlighted in this review.
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Affiliation(s)
- R D Steiner
- Metabolic Clinic, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health Sciences University, Portland, Oregon 97201, USA
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42
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Abstract
Deficiency of any of the five enzymes in the urea cycle results in the accumulation of ammonia and leads to encephalopathy. Episodes of encephalopathy and associated symptoms are unpredictable and, if untreated, are lethal or produce devastating neurologic sequelae in long-term survivors. Although these disorders do not produce liver disease, the consequences of hyperammonemia resemble those seen in patients with hepatic failure or in a transient interference with the urea cycle, as seen in some forms of organic acidemias. Therefore, investigation for hyperammonemia in any infant or child with altered mental status (in the absence of obvious causes, such as trauma, infection, or poisoning) is essential for prompt diagnosis of urea cycle disorders and institution of treatment to avoid brain damage and death. This article addresses the function of the urea cycle and the diagnosis and management of urea cycle disorders.
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Affiliation(s)
- B K Burton
- Division of Genetics, Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois, USA
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43
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Riudor E, Arranz JA, Rodés M, Rubio V, Sentís M, Burlina AB. Influence of dose and age on the response of the allopurinol test for ornithine carbamoyltransferase deficiency in control infants. J Inherit Metab Dis 2000; 23:662-8. [PMID: 11117427 DOI: 10.1023/a:1005610325170] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
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.
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Affiliation(s)
- E Riudor
- Laboratori de Metabolopaties, Hospital Materno-Infantil Vall d'Hebron, Universitat Autónoma, Barcelona, Spain.
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44
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Asai M, Sumi S, Kidouchi K, Imaeda H, Togari H, Wada Y. Urinary pyrimidine analysis in healthy newborns, infants, children, adults and patients with congenital metabolic diseases. Pediatr Int 2000; 42:499-503. [PMID: 11059538 DOI: 10.1046/j.1442-200x.2000.01274.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND In previous reports, the reference range for urinary pyrimidine was determined on the basis of a small number of samples, with data for only a few patients being reported. In the present study, we measured urinary pyrimidine compounds in 25 healthy newborns, 33 healthy infants, 130 healthy children and 166 healthy adults. In addition, we also analyzed urinary pyrimidine compounds in various patients with abnormal pyrimidine metabolism, such as congenital pyrimidine metabolism disorders and urea cycle disorders. METHODS We analyzed urines by high-performance liquid chromatography with column switching. Analyses were performed with both a reverse-phase column and an anion-exchange column. The columns were connected by a column switch, with all systems being controlled automatically by a computerized system controller. RESULTS The excretion of pyrimidine compounds in patients with abnormal pyrimidine metabolism (containing heterozygotes) was out of our reference ranges. CONCLUSIONS These results suggest that urinary pyrimidine analysis is a useful index for the diagnosis of pyrimidine metabolism disorders, urea cycle disorders and these heterozygotes. Based on this large-group analysis of healthy individuals, we were able to determine the reference ranges of urinary orotic acid, dihydrouracil and uracil for each age group.
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Affiliation(s)
- M Asai
- Department of Pediatrics Nagoya City University Medical School, Nagoya, Japan
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45
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Lee B, Yu H, Jahoor F, O'Brien W, Beaudet AL, Reeds P. In vivo urea cycle flux distinguishes and correlates with phenotypic severity in disorders of the urea cycle. Proc Natl Acad Sci U S A 2000; 97:8021-6. [PMID: 10869432 PMCID: PMC16663 DOI: 10.1073/pnas.140082197] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Urea cycle disorders are a group of inborn errors of hepatic metabolism that result in often life-threatening hyperammonemia and hyperglutaminemia. Clinical and laboratory diagnosis of partial deficiencies during asymptomatic periods is difficult, and correlation of phenotypic severity with either genotype and/or in vitro enzyme activity is often imprecise. We hypothesized that stable isotopically determined in vivo rates of total body urea synthesis and urea cycle-specific nitrogen flux would correlate with both phenotypic severity and carrier status in patients with a variety of different enzymatic deficiencies of the urea cycle. We studied control subjects, patients, and their relatives with different enzymatic deficiencies affecting the urea cycle while consuming a low protein diet. On a separate occasion the subjects either received a higher protein intake or were treated with an alternative route medication sodium phenylacetate/benzoate (Ucephan), or oral arginine supplementation. Total urea synthesis from all nitrogen sources was determined from [(18)O]urea labeling, and the utilization of peripheral nitrogen was estimated from the relative isotopic enrichments of [(15)N]urea and [(15)N]glutamine during i.v. co-infusions of [5-(amide)(15)N]glutamine and [(18)O]urea. The ratio of the isotopic enrichments of (15)N-urea/(15)N-glutamine distinguished normal control subjects (ratio = 0.42 +/- 0.06) from urea cycle patients with late (0.17 +/- 0.03) and neonatal (0.003 +/- 0.007) presentations irrespective of enzymatic deficiency. This index of urea cycle activity also distinguished asymptomatic heterozygous carriers of argininosuccinate synthetase deficiency (0. 22 +/- 0.03), argininosuccinate lyase deficiency (0.35 +/- 0.11), and partial ornithine transcarbamylase deficiency (0.26 +/- 0.06) from normal controls. Administration of Ucephan lowered, and arginine increased, urea synthesis to the degree predicted from their respective rates of metabolism. The (15)N-urea/(15)N-glutamine ratio is a sensitive index of in vivo urea cycle activity and correlates with clinical severity. Urea synthesis is altered by alternative route medications and arginine supplementation to the degree that is to be expected from theory. This stable isotope protocol provides a sensitive tool for evaluating the efficacy of therapeutic modalities and acts as an aid to the diagnosis and management of urea cycle patients.
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Affiliation(s)
- B Lee
- Departments of Molecular and Human Genetics and Pediatrics and Children's Nutrition Research Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
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46
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Batshaw ML, Wilson JM, Raper S, Yudkoff M, Robinson MB. Recombinant adenovirus gene transfer in adults with partial ornithine transcarbamylase deficiency (OTCD). Hum Gene Ther 1999; 10:2419-37. [PMID: 10515461 DOI: 10.1089/10430349950017068] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- M L Batshaw
- Hospital of the Univ. of Pennsylvania General Clinical Research Center, Philadelphia 19104, USA
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47
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Bowling F, McGown I, McGill J, Cowley D, Tuchman M. Maternal gonadal mosaicism causing ornithine transcarbamylase deficiency. AMERICAN JOURNAL OF MEDICAL GENETICS 1999; 85:452-4. [PMID: 10405441 DOI: 10.1002/(sici)1096-8628(19990827)85:5<452::aid-ajmg4>3.0.co;2-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Ornithine transcarbamylase (OTC) deficiency (McKusick 311250), an X-linked inherited disorder, often presents in males with severe neonatal onset of hyperammonemia. Maternal gonadal mosaicism in OTC deficiency was postulated previously, but no cases have been reported. We report on a family in which two consecutive males were affected with OTC deficiency, which was proven biochemically with characteristic metabolites and absent enzyme activity in liver. OTC genotyping in both brothers showed a new mutation in exon 6 (Met206Arg: ATG-->AGG), which encodes part of the equatorial H6 alpha-helix. Biochemical investigations confirmed normal results in the mother and grandmother and the absence of OTC activity in the affected males. Genotyping of the mother and grandmother was performed on peripheral blood leukocytes and skin fibroblasts and showed no mutation in the somatic cells. The recurrence of OTC deficiency in offsprings of a woman with normal genotype strongly suggests gonadal mosaicism. Gonadal mosaicism needs to be considered when counseling couples in which the mother has had a previously affected child with OTC deficiency but apparently is not a carrier.
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Affiliation(s)
- F Bowling
- School of Biomolecular and Biomedical Science, Griffith University, Nathan, Australia.
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Arranz JA, Riudor E, Rodés M, Roig M, Climent C, Rubio V, Sentís M, Burlina A. Optimization of Allopurinol Challenge: Sample Purification, Protein Intake Control, and the Use of Orotidine Response as a Discriminative Variable Improve Performance of the Test for Diagnosing Ornithine Carbamoyltransferase Deficiency. Clin Chem 1999. [DOI: 10.1093/clinchem/45.7.995] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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 · kg−1 · day−1. Measurements of orotidine provide better clinical sensitivity than measurements of orotate.
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Affiliation(s)
- José A Arranz
- Unitat de Metabolopaties, Hospital Materno-Infantil Vall d’Hebron, 08035 Barcelona, Spain
| | - Encarnació Riudor
- Unitat de Metabolopaties, Hospital Materno-Infantil Vall d’Hebron, 08035 Barcelona, Spain
| | - Margarita Rodés
- Institut de Bioquímica Clínica, C/Mejia Lequerica s/n, Edifici Helios III, Planta Baixa, Corporació Sanitària, 08028 Barcelona, Spain
| | - Manuel Roig
- Unitat de Metabolopaties, Hospital Materno-Infantil Vall d’Hebron, 08035 Barcelona, Spain
| | - Consuelo Climent
- Instituto de Biomedicina de Valencia (CSIC), C/Jaume Roig 11, 46010 Valencia, Spain
| | - Vicente Rubio
- Instituto de Biomedicina de Valencia (CSIC), C/Jaume Roig 11, 46010 Valencia, Spain
| | - Margarita Sentís
- Unitat de Metabolopaties, Hospital Materno-Infantil Vall d’Hebron, 08035 Barcelona, Spain
| | - Alberto Burlina
- Dipartimento di Pediatria, Università di Padova, Via Giustiniani 3, 35128 Padua, Italy
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Bonham JR, Guthrie P, Downing M, Allen JC, Tanner MS, Sharrard M, Rittey C, Land JM, Fensom A, O'Neill D, Duley JA, Fairbanks LD. The allopurinol load test lacks specificity for primary urea cycle defects but may indicate unrecognized mitochondrial disease. J Inherit Metab Dis 1999; 22:174-84. [PMID: 10234613 DOI: 10.1023/a:1005406205548] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Thirty-three children ranging from 2 weeks to 12 years of age were selected for allopurinol loading, 16 on the basis of an increased urinary ourotate excretion detected by routine organic acid analysis (group A), and 17 for clinical reasons suggesting a urea cycle defect (group B). The allopurinol load test proved positive in 13 of 16 patients from group A, mean peak orotate 64.0 mumol/mmol creatinine (upper limit of reference range, 13.2) and 11 of 17 patients from group B, mean peak orotate 41.0 mumol/mmol creatinine (upper limit of reference range, 13.2). Thorough investigation of these patients including urinary and plasma amino acid analysis and, in 17 cases, liver biopsy for histology and measurement of ornithine carbamyltransferase (OCT) and carbamyl-phosphate synthetase (CPS) activity failed to identify any evidence of a urea cycle disorder. However, muscle biopsies performed in 11 patients showed some evidence of mitochondrial disease in four cases, two defined on the basis of reduced respiratory chain enzyme activity and two on the basis of mtDNA abnormalities. These findings indicate that an increased excretion of orotate in sick children may not be uncommon and that a positive allopurinol load test result may not indicate a specific inherited urea cycle defect. In addition, these results raise the interesting possibility that defective ureagenesis may be a feature of mitochondrial disease in some individuals.
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Affiliation(s)
- J R Bonham
- Department of Chemical Pathology and Neonatal Screening, Children's Hospital NHS Trust, Sheffield, UK
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Ausems MGEM, Bakker E, Berger R, Duran M, van Diggelen OP, Keulemans JLM, de Valk HW, Kneppers ALJ, Dorland L, Eskes PF, Beemer FA, Poll-The BT, Smeitink JAM. Asymptomatic and late-onset ornithine transcarbamylase deficiency caused by a A208T mutation: Clinical, biochemical and DNA analyses in a four-generation family. ACTA ACUST UNITED AC 1998. [DOI: 10.1002/(sici)1096-8628(19970120)68:2<236::aid-ajmg23>3.0.co;2-u] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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