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ollaborators: Bloxam S, Brody L, Caspi L, Elsbecker S, Fierro L, Lynn A, Mullins M, Mütze U, Papaleo C, Payan I, Seminara J, Simpson K, Singer R, Wallis K, Alber FD, Babikian T, Bender H, Boys C, Breiger D, Buerger C, Caudle SE, NguyenDriver M, Kerr E, Mamak E, Sanz JH, Tangen R, Wilkening G, Cederbaum S, Feigenbaum A, Kerr DS, LichterKonecki U, Seashore MR, Berry SA, Burrage L, Coughlin C, Diaz GA, Gallagher RC, Gropman A, Harding CO, Lee B, Le Mons C, Lawrence Merritt J 2nd, Nagamani SCS, Schulze A, Stricker T, Tuchman M, Waisbren S, WeisfeldAdams J, Wong D, Yudkoff M, Arnoux J, Bari Cacute I, Bosch AM, Chabrol B, Chakrapani A, CortèsSaladefont E, Couce ML, Eyskens F, de Laet C, de Meirleir L, Freisinger P, Gleich F, Grünewald S, Häberle J, Hwu W, Jalan A, Karall D, Lindner M, Lund AM, Martinelli D, Murphy E, Mühlhausen C, Olivieri G, Ottolenghi C, Rodrigues E, Rubert L, Sarajlija A, Schiff M, Sokal E, SykutCegielska J, Walter JH, Williams M, Zeman J. BACKGROUND: To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS: Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS: Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS: The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS: Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.

Stable isotopes have greatly contributed to our understanding of nitrogen metabolism and the urea cycle. The measurement of urea flux via isotopic methods has traditionally been utilized to determine total body protein synthesis in subjects with an intact urea cycle. However, isotopic studies of nitrogen metabolism are also a useful adjunct to conventional clinical investigations in the diagnosis and management of the inherited hyperammonemias. Such studies offer a safe non-invasive method of measuring the reduction of in vivo hepatic ureagenesis, and thus may provide a more accurate measure of phenotypic severity in affected patients. In addition, isotopic methods are ideally suited to evaluate the efficacy of novel therapies to augment urea production.

Urea cycle disorders (UCD) are inborn errors of metabolism caused by deficiency of enzymes required to transfer nitrogen from ammonia into urea. Current paradigms of treatment focus on dietary manipulations, ammonia scavenger drugs, and orthotopic liver transplantation. In the last years, there has been intense preclinical research aiming at developing more effective treatments for UCD, and as a result, several novel approaches based on new knowledge of the disease pathogenesis, cell and gene therapies are currently under clinical investigation. We provide an overview of the latest advances for the development of novel therapies for UCD.