Häberle
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Stoffwechsel und Molekulare Pädiatrie, Abteilung für » Prof. Dr. Matthias R. Baumgartner » Häberle
Current research project
| Title / Titel | UNDERSTANDING PHENOTYPIC VARIABILITY OF UREA CYCLE DISORDERS | ||||
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| Abstract (PDF, 14 KB) | |||||
| Summary / Zusammenfassung | The urea cycle is responsible for nitrogen detoxification and comprises six enzymes and two transporters. Urea cycle disorders (UCDs), characterized by neonatal or late onset hyperammonemia, occur with an incidence of 1 per 8.000 and always carry a high rate of morbidity and mortality. All UCDs can be diagnosed by genetic means. The Kinderspital is the only institution in Europe offering molecular genetic analysis for all UCDs including prenatal testing. There is a longstanding experience in the genetic analysis of these disorders resulting in a referral status of the Kinderspital. The Metabolic Division at the Kinderspital overviews a large cohort of patients and is interested particularly in variants of the phenotype. Prokaryotic and eukaryotic expression systems are used for the characterization of naturally occurring mutants of UCDs. Research work applying various methods is further carried out for single patients with an unusual presentation. The elucidation of the molecular pathology of classical and variant UCDs will eventually contribute to the development of new therapeutical strategies. Regarding clinical research, the Kinderspital takes part, as one of two European centres, in the NIH sponsored longitudinal study on the natural course and outcome of patients with UCDs. In addition, the Division of Metabolism is in charge of the working group for the development of European Guidelines for the Diagnosis and Treatment of UCDs, a work that has recently been finished. |
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| Publications / Publikationen | Schmidt E, Nuoffer JM, Häberle J, Pauli S, Guffon N, Vianey-Saban C, Wermuth B, Koch HG (2005) Identification of novel mutations of the human N-acetylglutamate synthase gene and their functional investigation by expression studies. Biochim Biophys Acta 1740: 54-9Guffon N, Schiff M, Cheillan D, Wermuth B, Häberle J, Vianey-Saban C (2005) Neonatal hyperammonemia: the N-carbamoyl-L-glutamic acid test. J Pediatr 147: 260-2Kleijer WJ, Garritsen VH, van der Sterre ML, Berning C, Häberle J, Huijmans JG (2006) Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia. Prenat Diagn 26: 242-247Häberle J (2006) Grundsätzliche und praktische Aspekte zur Hyperammonämie im Kindesalter. Kinder- und Jugendmedizin 6: 233-240Roze E, Azuar C, Menuel C, Häberle J, Guillevin R (2007) Usefulness of magnetic resonance spectroscopy in urea cycle disorders. Pediatr Neurol 37: 222-225Engel K, Nuoffer JM, Mühlhausen C, Klaus V, Largiadèr CR, Tsiakas K, Santer R, Wermuth B, Häberle J (2008) Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency. Mol Genet Metab 94: 292-297Berning C, Bieger I, Pauli S, Vermeulen T, Vogl T, Rummel T, Höhne W, Koch HG, Rolinski B, Gempel K, Häberle J (2008) Investigation of citrullinemia type I variants by in vitro expression studies. Hum Mutat 29: 1222-1227Engel K, Höhne W, Häberle J (2009) Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene. Hum Mutat 30: 300-307Klaus V, Vermeulen T, Minassian B, Israelian N, Engel K, Lund AM, Roebrock K, Christensen E, Häberle J (2009) Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression? Clin Genet 75: 263-269Häberle J, Vilaseca MA, Meli C, Rigoldi M, Jara F, Vecchio I, Capra C, Parini R (2010) First manifestation of citrullinemia type I as differential diagnosis to postpartum psychosis in the puerperal period. Eur J Obstet Gynecol Reprod Biol 149: 228-229Mercimek-Mahmutoglu S, Moeslinger D, Häberle J, Engel K, Herle M, Strobl MW, Scheibenreiter S, Muehl A, Stöckler-Ipsiroglu S (2010) Long-term outcome of patients with argininosuccinate lyase deficiency diagnosed by newborn screening in Austria. Mol Genet Metab 100: 24-28Wang J, Shchelochkov OA, Zhan H, Li F, Chen LC, Brundage EK, Pursley AN, Schmitt ES, Häberle J, Wong LJ (2011) Molecular characterization of CPS1 deletions by array CGH, Mol Genet Metab, 102: 103-106Amstutz U, Andrey-Zürcher G, Suciu D, Jaggi R, Häberle J, Largiadèr CR (2011) Sequence Capture and Next-Generation Resequencing of Multiple Tagged Nucleic Acid Samples for Mutation Screening of Urea Cycle Disorders, Clin Chem, 57: 102-111Häberle J (2010) Diagnosis and treatment of urea cycle disorders. J Pediatr Sciences, onlineHäberle J (2011) Clinical Practice: The Management of Hyperammonemia. Eur J Pediatr, 170: 21-34Häberle J, Shchelochkov OA, Wang J, Katsonis P, Hall L, Reiss S, Eeds A, Willis A, Yadav M, Summar S, and the Urea Cycle Disorders Consortium, Lichtarge O, Rubio V, Wong LJ, Summar M (2011) Molecular Defects in Human Carbamoyl Phosphate Synthetase I: Mutational Spectrum, Diagnostic and Protein Structure Considerations, Hum Mutat, 32: 579-589Faghfoury H, Baruteau J, Ogier de Baulny H, Häberle J, Schulze A (2011) Transient fulminant liver failure as an initial presentation in citrullinemia type I, Mol Genet Metab, 102: 413-417Häberle J (2011) Role of carglumic acid in the treatment of acute hyperammonemia due to N-acetylglutamate synthase deficiency. Therapeutics and Clinical Risk Management, 7: 327–332Häberle J (2011) Varianten von Harnstoffzyklusstörungen. Monatsschrift Kinderheilkunde, 159:834–841Engel K, Vuissoz JM, Eggimann S, Groux M, Berning C, Klaus V, Hu L, Moeslinger D, Mercimek-Mahmutoglu S, Stöckler S, Wermuth B, Häberle J, Nuoffer JM (2011) Bacterial expression of mutant argininosuccinate lyase reveals imperfect correlation of in-vitro enzyme activity with clinical phenotype in argininosuccinic aciduria, J Inherit Metab Dis 35: 133-140 | ||||
| Keywords / Suchbegriffe | Urea cycle disorders, inborn errors of metabolism, ornithine transcarbamylase, citrullinemia, hyperammonemia | ||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
SNF (Personen- und Projektförderung) National Institutes of Health |
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| In collaboration with / In Zusammenarbeit mit |
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| Duration of Project / Projektdauer | Sep 2008 to Dec 2012 |