Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders

Roland Posset; Sven F Garbade; Florian Gleich; Svenja Scharre; Jürgen G Okun; Andrea L Gropman; Sandesh C S Nagamani; Ann-Catrin Druck; Friederike Epp; Georg F Hoffmann; Stefan Kölker; Matthias Zielonka; Urea Cycle Disorders Consortium (UCDC); European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group

doi:10.1016/j.gim.2023.101039

Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders

Genet Med. 2024 Apr;26(4):101039. doi: 10.1016/j.gim.2023.101039. Epub 2023 Dec 3.

Authors

Collaborators

Nicholas Ah Mew⁶, Jennifer Seminara⁷, Lindsay C Burrage⁸, Gerard T Berry⁹, Margo Breilyn¹⁰, Andreas Schulze¹¹, Cary O Harding¹², Susan A Berry¹³, Derek Wong¹⁴, Shawn E McCandless¹⁵, Matthias R Baumgartner¹⁶, Laura Konczal¹⁷, Can Ficicioglu¹⁸, George A Diaz¹⁹, Curtis R Coughlin 2nd²⁰, Gregory M Enns²¹, Renata C Gallagher²², Christina Lam²³, Tamar Stricker¹⁶, Greta Wilkening²⁴, Carlo Dionisi-Vici²⁵, Dries Dobbelaere²⁶, Javier Blasco-Alonso²⁷, Alberto B Burlina²⁸, Peter Freisinger²⁹, Peter M van Hasselt³⁰, Anastasia Skouma³¹, Allan M Lund³², Roshni Vara³³, Adrijan Sarajlija³⁴, Andrew A Morris³⁵, Anupam Chakrapani³⁶, Ivo Barić³⁷, Persephone Augoustides-Savvopoulou³⁸, Yin-Hsiu Chien³⁹, Elisenda Cortès-Saladelafont⁴⁰, Francois Eyskens⁴¹, Gwendolyn Gramer⁴², Jiri Zeman⁴³, Daniela Karall⁴⁴, Maria L Couce⁴⁵, Chris Mühlhausen⁴⁶, Consuelo Pedrón-Giner⁴⁷, Ute Spiekerkoetter⁴⁸, Jolanta Sykut-Cegielska⁴⁹, Margreet Wagenmakers⁵⁰, Frits A Wijburg⁵¹

Affiliations

¹ Heidelberg University, Medical Faculty Heidelberg, and Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: roland.posset@med.uni-heidelberg.de.
² Heidelberg University, Medical Faculty Heidelberg, and Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany.
³ Children's National Health System and The George Washington School of Medicine, Washington, DC.
⁴ Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.
⁵ Heidelberg University, Medical Faculty Heidelberg, and Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: matthias.zielonka@med.uni-heidelberg.de.
⁶ Children's National Health System, The George Washington School of Medicine, Washington, DC, USA.
⁷ Children's National Health System, Washington, District of Columbia, USA.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
⁹ Harvard Medical School and Boston Children's Hospital, Boston, Massachusetts, USA.
¹⁰ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
¹² Oregon Health and Science University, Portland, Oregon, USA.
¹³ University of Minnesota, Minneapolis, Minnesota, USA.
¹⁴ David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
¹⁵ Children's Hospital Colorado, Aurora, Colorado, USA.
¹⁶ Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Switzerland.
¹⁷ University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
¹⁸ Children's Hospital of Philadelphia, Philadelphia, USA.
¹⁹ Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²⁰ Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Campus, 19Aurora, Colorado, USA.
²¹ Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA.
²² Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
²³ Department of Biochemical Genetics, Seattle Children's Hospital, Washington, USA.
²⁴ Department of Neurology, Children's Hospital of Colorado, Aurora, Colorado, USA.
²⁵ Ospedale Pediatrico Bambino Gesù IRCCS, U.O.C. Malattie Metaboliche, Rome, Italy.
²⁶ Centre de Référence Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte, Jeanne de Flandre Hospital, CHRU Lille, and RADEME EA 7364, Faculty of Medicine, University Lille 2, Lille, France.
²⁷ Hospital Materno-Infantil, AVda Arroyo de los Ángeles s/n; 29011, Málaga, Spain.
²⁸ Division of Inherited Metabolic Diseases Reference Centre Expanded Newborn Screening Department of Woman's and Child's Health University Hospital Padova, Italy.
²⁹ Klinik für Kinder- und Jugendmedizin, Klinikum am Steinenberg, Reutlingen, Germany.
³⁰ Wilhelmina Children's Hospital, Utrecht, The Netherlands.
³¹ Institute of Child Health, Athens, Greece.
³² Centre Inherited Metabolic Diseases, Departments of Paediatrics and Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
³³ Department of Inherited Metabolic Disease, Evelina Children's Hospital, St Thomas' Hospital, London, United Kingdom.
³⁴ Mother and Child Health Care Institute of Serbia, Department of Metabolism and Clinical Genetics and University of Belgrade, School of Medicine, Belgrade, Serbia.
³⁵ The Willink Unit, Genomic Medicine, Manchester University Hospitals NHS Trust, Manchester, United Kingdom.
³⁶ Great Ormond Street Hospital, Institute of Child Health, University College London, London United Kingdom.
³⁷ University Hospital Center Zagreb and University of Zagreb, School of Medicine, Zagreb, Croatia.
³⁸ University 1st Pediatric Department, Metabolic Laboratory, General Hospital of Thessaloniki 'Hippocration', Thessaloniki, Greece.
³⁹ National Taiwan University Hospital, Department of Medical Genetics and Pediatrics, Taipei, Taiwan.
⁴⁰ Department of Paediatrics Universitat Autònoma de Barcelona, Badalona, Spain.
⁴¹ University Hospital of Antwerp UZA, Department of Pediatricy Inherited Metabolic Diseases, Antwerp, Belgium.
⁴² Department for Inborn Metabolic Diseases, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴³ Department of Pediatrics and Inherited Metabolic Disorders, General Faculty Hospital, Prague, Czech Republic.
⁴⁴ Medical University Innsbruck, Clinic for Pediatrics, Innsbruck, Austria.
⁴⁵ Department of Neonatology, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, 15704, Spain.
⁴⁶ Department of Pediatrics and Adolescent Medicine, University Medical Centre Göttingen, Göttingen, Germany.
⁴⁷ Sección de Gastroenterología y Nutrición, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
⁴⁸ Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany.
⁴⁹ Screening Department, Institute of Mother and Child, Warsaw, Poland.
⁵⁰ Porphyria Expertcenter Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁵¹ University Hospital of Amsterdam, Department of Pediatrics, Division of Metabolic Disorders, Amsterdam, The Netherlands.

PMID: 38054409
DOI: 10.1016/j.gim.2023.101039

Abstract

Purpose: Liver transplantation (LTx) is performed in individuals with urea cycle disorders when medical management (MM) insufficiently prevents the occurrence of hyperammonemic events. However, there is a paucity of systematic analyses on the effects of LTx on health-related outcome parameters compared to individuals with comparable severity who are medically managed.

Methods: We investigated the effects of LTx and MM on validated health-related outcome parameters, including the metabolic disease course, linear growth, and neurocognitive outcomes. Individuals were stratified into "severe" and "attenuated" categories based on the genotype-specific and validated in vitro enzyme activity.

Results: LTx enabled metabolic stability by prevention of further hyperammonemic events after transplantation and was associated with a more favorable growth outcome compared with individuals remaining under MM. However, neurocognitive outcome in individuals with LTx did not differ from the medically managed counterparts as reflected by the frequency of motor abnormality and cognitive standard deviation score at last observation.

Conclusion: Whereas LTx enabled metabolic stability without further need of protein restriction or nitrogen-scavenging therapy and was associated with a more favorable growth outcome, LTx-as currently performed-was not associated with improved neurocognitive outcomes compared with long-term MM in the investigated urea cycle disorders.

Keywords: Argininosuccinic aciduria; Citrullinemia type 1; Liver transplantation; Ornithine transcarbamylase deficiency; Urea cycle disorders.

MeSH terms

Humans
Liver Transplantation*
Outcome Assessment, Health Care
Proteins
Urea Cycle Disorders, Inborn* / genetics
Urea Cycle Disorders, Inborn* / surgery

Substances

Proteins

Grants and funding

U54 HD061221/HD/NICHD NIH HHS/United States