Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders-A successful strategy for clinical research of rare diseases
Roland Posset, Sven F Garbade, Nikolas Boy, Alberto B Burlina, Carlo Dionisi-Vici, Dries Dobbelaere, Angeles Garcia-Cazorla, Pascale de Lonlay, Elisa Leão Teles, Roshni Vara, Nicholas Ah Mew, Mark L Batshaw, Matthias R Baumgartner, Shawn E McCandless, Jennifer Seminara, Marshall Summar, Georg F Hoffmann, Stefan Kölker, Peter Burgard, Additional individual contributors of the UCDC and the E-IMD consortium, Susan A Berry, Lindsay Burrage, Curtis Coughlin, George A Diaz, Renata C Gallagher, Andrea Gropman, Cary O Harding, Brendan Lee, Cynthia Le Mons, J Lawrence Merritt 2nd, Sandesh C S Nagamani, Andreas Schulze, Tamar Stricker, Mendel Tuchman, Susan Waisbren, James WeisfeldAdams, Derek Wong, Marc Yudkoff, JeanBaptiste Arnoux, Ivo Bari Cacute, Annet M Bosch, Brigitte Chabrol, Anupam Chakrapani, Elisenda CortèsSaladefont, Maria L Couce, Francois Eyskens, Corine de Laet, Linda de Meirleir, Peter Freisinger, Florian Gleich, Stephanie Grünewald, Johannes Häberle, WuhLiang Hwu, Anil Jalan, Daniela Karall, Martin Lindner, Allan M Lund, Diego Martinelli, Elaine Murphy, Chris Mühlhausen, Giorgia Olivieri, Chris Ottolenghi, Esmeralda Rodrigues, Laura Rubert, Adrijan Sarajlija, Manuel Schiff, Etienne Sokal, Jolanta SykutCegielska, John H Walter, Monique Williams, Jiri Zeman, Roland Posset, Sven F Garbade, Nikolas Boy, Alberto B Burlina, Carlo Dionisi-Vici, Dries Dobbelaere, Angeles Garcia-Cazorla, Pascale de Lonlay, Elisa Leão Teles, Roshni Vara, Nicholas Ah Mew, Mark L Batshaw, Matthias R Baumgartner, Shawn E McCandless, Jennifer Seminara, Marshall Summar, Georg F Hoffmann, Stefan Kölker, Peter Burgard, Additional individual contributors of the UCDC and the E-IMD consortium, Susan A Berry, Lindsay Burrage, Curtis Coughlin, George A Diaz, Renata C Gallagher, Andrea Gropman, Cary O Harding, Brendan Lee, Cynthia Le Mons, J Lawrence Merritt 2nd, Sandesh C S Nagamani, Andreas Schulze, Tamar Stricker, Mendel Tuchman, Susan Waisbren, James WeisfeldAdams, Derek Wong, Marc Yudkoff, JeanBaptiste Arnoux, Ivo Bari Cacute, Annet M Bosch, Brigitte Chabrol, Anupam Chakrapani, Elisenda CortèsSaladefont, Maria L Couce, Francois Eyskens, Corine de Laet, Linda de Meirleir, Peter Freisinger, Florian Gleich, Stephanie Grünewald, Johannes Häberle, WuhLiang Hwu, Anil Jalan, Daniela Karall, Martin Lindner, Allan M Lund, Diego Martinelli, Elaine Murphy, Chris Mühlhausen, Giorgia Olivieri, Chris Ottolenghi, Esmeralda Rodrigues, Laura Rubert, Adrijan Sarajlija, Manuel Schiff, Etienne Sokal, Jolanta SykutCegielska, John H Walter, Monique Williams, Jiri Zeman
Abstract
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.
Keywords: Urea cycle Disorders; diagnostic methods; international registry and database.
Conflict of interest statement
Conflict of Interest
Stefan Kölker receives funding from Horizon Pharma Ireland Limited for the European Post-Authorization Registry for Ravicti® (glycerol phenylbutyrate) oral liquid in partnership with the E-IMD (RRPE) (EU PAS Register no. EUPAS17267; http://www.encepp.eu/). Georg F. Hoffmann, Peter Burgard and Stefan Kölker receive funding from the Dietmar Hopp Foundation (St. Leon-Rot, Germany) for coordinating the study “Newborn Screening and Metabolic Medicine 2020 (NBS2020)” including individuals with urea cycle disorders. The sponsors have in no way influenced the design, conductance, analysis and report of the present study.All other authors declare that they have no conflict of interest.
© 2018 SSIEM.
Figures
Source: PubMed