Roland Posset1, Stefan Kölker1, Florian Gleich1, Jürgen G Okun1, Andrea L Gropman2, Sandesh C S Nagamani3, Svenja Scharre1, Joris Probst1, Magdalena E Walter1, Georg F Hoffmann1, Sven F Garbade1, Matthias Zielonka4. 1. Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany. 2. Children's National Health System and The George Washington School of Medicine, Washington, DC, USA. 3. Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA. 4. Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany; Heidelberg Research Center for Molecular Medicine (HRCMM), Heidelberg, Germany. Electronic address: Matthias.Zielonka@med.uni-heidelberg.de.
Abstract
OBJECTIVE: The implementation of newborn screening (NBS) programs for citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) is subject to controversial debate. The aim of this study was to assess the impact of NBS on the metabolic disease course and clinical outcome of affected individuals. METHODS: In 115 individuals with CTLN1 and ASA, we compared the severity of the initial hyperammonemic episode (HAE) and the frequency of (subsequent) HAEs with the mode of diagnosis. Based on a recently established functional disease prediction model, individuals were stratified according to their predicted severe or attenuated phenotype. RESULTS: Individuals with predicted attenuated forms of CTLN1 and ASA were overrepresented in the NBS group, while those with a predicted severe phenotype were underrepresented compared to individuals identified after the manifestation of symptoms (SX). Identification by NBS was associated with reduced severity of the initial HAE both in individuals with predicted severe and attenuated phenotypes, while it was not associated with lower frequency of (subsequent) HAEs. Similar results were obtained when including some patients diagnosed presymptomatically (i.e. prenatal testing, and high-risk family screening) in this analysis. CONCLUSION: Since one of the major challenges of NBS outcome studies is the potential overrepresentation of individuals with predicted attenuated phenotypes in NBS cohorts, severity-adjusted evaluation of screened and unscreened individuals is important to avoid overestimation of the NBS effect. NBS enables the attenuation of the initial HAE but does not affect the frequency of subsequent metabolic decompensations in individuals with CTLN1 and ASA. Future long-term studies will need to evaluate the clinical impact of this finding, especially with regard to mortality, as well as cognitive outcome and quality of life of survivors.
OBJECTIVE: The implementation of newborn screening (NBS) programs for citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) is subject to controversial debate. The aim of this study was to assess the impact of NBS on the metabolic disease course and clinical outcome of affected individuals. METHODS: In 115 individuals with CTLN1 and ASA, we compared the severity of the initial hyperammonemic episode (HAE) and the frequency of (subsequent) HAEs with the mode of diagnosis. Based on a recently established functional disease prediction model, individuals were stratified according to their predicted severe or attenuated phenotype. RESULTS: Individuals with predicted attenuated forms of CTLN1 and ASA were overrepresented in the NBS group, while those with a predicted severe phenotype were underrepresented compared to individuals identified after the manifestation of symptoms (SX). Identification by NBS was associated with reduced severity of the initial HAE both in individuals with predicted severe and attenuated phenotypes, while it was not associated with lower frequency of (subsequent) HAEs. Similar results were obtained when including some patients diagnosed presymptomatically (i.e. prenatal testing, and high-risk family screening) in this analysis. CONCLUSION: Since one of the major challenges of NBS outcome studies is the potential overrepresentation of individuals with predicted attenuated phenotypes in NBS cohorts, severity-adjusted evaluation of screened and unscreened individuals is important to avoid overestimation of the NBS effect. NBS enables the attenuation of the initial HAE but does not affect the frequency of subsequent metabolic decompensations in individuals with CTLN1 and ASA. Future long-term studies will need to evaluate the clinical impact of this finding, especially with regard to mortality, as well as cognitive outcome and quality of life of survivors.
Authors: Roland Posset; Angeles Garcia-Cazorla; Vassili Valayannopoulos; Elisa Leão Teles; Carlo Dionisi-Vici; Anaïs Brassier; Alberto B Burlina; Peter Burgard; Elisenda Cortès-Saladelafont; Dries Dobbelaere; Maria L Couce; Jolanta Sykut-Cegielska; Johannes Häberle; Allan M Lund; Anupam Chakrapani; Manuel Schiff; John H Walter; Jiri Zeman; Roshni Vara; Stefan Kölker Journal: J Inherit Metab Dis Date: 2016-04-22 Impact factor: 4.982
Authors: S C Grünert; S Müllerleile; L de Silva; M Barth; M Walter; K Walter; T Meissner; M Lindner; R Ensenauer; R Santer; O A Bodamer; M R Baumgartner; M Brunner-Krainz; D Karall; C Haase; I Knerr; T Marquardt; J B Hennermann; R Steinfeld; S Beblo; H G Koch; V Konstantopoulou; S Scholl-Bürgi; A van Teeffelen-Heithoff; T Suormala; W Sperl; J P Kraus; A Superti-Furga; K O Schwab; J O Sass Journal: J Inherit Metab Dis Date: 2011-12-02 Impact factor: 4.982
Authors: S Mercimek-Mahmutoglu; D Moeslinger; J Häberle; K Engel; M Herle; M W Strobl; S Scheibenreiter; A Muehl; S Stöckler-Ipsiroglu Journal: Mol Genet Metab Date: 2010-02-04 Impact factor: 4.797
Authors: Roland Posset; Andrea L Gropman; Sandesh C S Nagamani; Lindsay C Burrage; Jirair K Bedoyan; Derek Wong; Gerard T Berry; Matthias R Baumgartner; Marc Yudkoff; Matthias Zielonka; Georg F Hoffmann; Peter Burgard; Andreas Schulze; Shawn E McCandless; Angeles Garcia-Cazorla; Jennifer Seminara; Sven F Garbade; Stefan Kölker Journal: Ann Neurol Date: 2019-05-13 Impact factor: 10.422
Authors: Martin Lindner; Gwendolyn Gramer; Gisela Haege; Junmin Fang-Hoffmann; Karl O Schwab; Uta Tacke; Friedrich K Trefz; Eugen Mengel; Udo Wendel; Michael Leichsenring; Peter Burgard; Georg F Hoffmann Journal: Orphanet J Rare Dis Date: 2011-06-20 Impact factor: 4.123
Authors: Julien Baruteau; Elisabeth Jameson; Andrew A Morris; Anupam Chakrapani; Saikat Santra; Suresh Vijay; Huriye Kocadag; Clare E Beesley; Stephanie Grunewald; Elaine Murphy; Maureen Cleary; Helen Mundy; Lara Abulhoul; Alexander Broomfield; Robin Lachmann; Yusof Rahman; Peter H Robinson; Lesley MacPherson; Katharine Foster; W Kling Chong; Deborah A Ridout; Kirsten McKay Bounford; Simon N Waddington; Philippa B Mills; Paul Gissen; James E Davison Journal: J Inherit Metab Dis Date: 2017-03-01 Impact factor: 4.982
Authors: Mara Scharping; Heiko Brennenstuhl; Sven F Garbade; Beate Wild; Roland Posset; Matthias Zielonka; Stefan Kölker; Markus W Haun; Thomas Opladen Journal: Children (Basel) Date: 2022-05-12