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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 McCandless
  • Jennifer Seminara
  • Marshall Summar
  • Georg F. Hoffmann
  • Stefan Kölker
  • Peter Burgard
  • Additional individual contributors of the UCDC and the E-IMD consortium
Original Article
  • 254 Downloads

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 utilising differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.

Abbreviations

ARG1-D

Arginase 1 deficiency

ASx

Asymptomatic

asfOTC-D

Asymptomatic female with ornithine transcarbamylase deficiency

ASL-D

Argininosuccinate lyase deficiency

ASS-D

Argininosuccinate synthetase deficiency

CITR-D

Citrin deficiency

CPS1-D

Carbamyl phosphate synthetase 1 deficiency

E-IMD

European registry and network for Intoxication type Metabolic Diseases

EU

Europe(an)

EO

Early onset

FH

Family history-triggered investigation

fOTC-D

Female with ornithine transcarbamylase deficiency

HHH syndr.

Hyperornithinemia–hyperammonemia–homocitrullinuria syndrome

IQR

Interquartile range

LO

Late onset

LTx

Liver transplantation

mOTC-D

Male with ornithine transcarbamylase deficiency

NA

North America(n)

NAGS-D

N-acetylglutamate synthase deficiency

NBS

Newborn screening

PT

Prenatal testing

SQRT

Square root

SX

Selective metabolic investigation after onset of symptoms

UCDC

Urea Cycle Disorders Consortium

UCD(s)

Urea cycle disorder(s)

Notes

Acknowledgements

The UCDC longitudinal study has received funding from the National Institute for Child Health and Human Development (NICHD U54 HD061221), the O’Malley Family Foundation, the Kettering Fund, the Dietmar Hopp Foundation and the Rothenberg Family Foundation.

The E-IMD patient registry has received funding from the European Union (E-IMD; EAHC no. 2010 12 01; coordinator: Stefan Kölker), in the framework of the Health Programme. After the end of the EU funding period, the E-IMD patient registry has been sustained by funding from the Kindness for Kids Foundation (Munich, Germany), the Kettering Foundation (Dayton, Ohio, USA), and the Dietmar Hopp Foundation (St. Leon-Rot, Germany). M. Baumgartner and J. Häberle (Zurich, Switzerland) are supported by radiz – Rare Disease Initiative Zurich, a clinical research priority programme of the University of Zurich. C. Dionisi-Vici (Rome, Italy) is supported by the association “La vita è un dono”.

All Urea Cycle Disorders Consortium (UCDC) sites contributed to the longitudinal study dataset. Principal investigators have been listed in the individual contributors section. Study coordinators include: Sondra Bloxam, Linnea Brody, Liora Caspi, Sara Elsbecker, Luca Fierro, Audrey Lynn, Mary Mullins, Ulrike Mütze, Cassandra Papaleo, Irma Payan, Jennifer Seminara, Kara Simpson, Rebecca Singer and Kimberly Wallis. Study neuropsychologists include: Fabienne Dietrich Alber, Talin Babikian, Heidi Bender, Christopher Boys, David Breiger, Corinna Buerger, Susan E. Caudle, Mina Nguyen-Driver, Elizabeth Kerr, Eva Mamak, Jacqueline H. Sanz, Rachel Tangen and Greta Wilkening. We would also like to acknowledge the contributions of former longitudinal study PIs: Stephen Cederbaum, Annette Feigenbaum, Douglas S. Kerr, Uta Lichter-Konecki and Margretta R. Seashore.

Additional individual contributors (to be listed in the PubMed, in alphabetical order)

From the UCDC

Susan A. Berry

University of Minnesota, Minneapolis, Minnesota, USA

Lindsay Burrage

Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, USA

Curtis Coughlin

Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, Colorado, USA

George A. Diaz

Icahn School of Medicine at Mount Sinai, New York, New York, USA

Renata C. Gallagher

University of California San Francisco, San Francisco, California, USA

Andrea Gropman

Children’s National Health System and The George Washington School of Medicine, Washington, District of Columbia, USA

Cary O. Harding

Oregon Health and Science University, Portland, Oregon, USA

Brendan Lee

Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, USA

Cynthia Le Mons

National Urea Cycle Disorders Foundation, Pasadena, California, USA

J. Lawrence Merritt II

University of Washington and Seattle Children’s Hospital, Seattle, Washington, USA

Sandesh C. S. Nagamani

Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, USA

Andreas Schulze

The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada

Tamar Stricker

University Children’s Hospital Zurich, Zurich, Switzerland

Mendel Tuchman

Children’s National Health System and The George Washington School of Medicine, Washington, District of Columbia, USA

Susan Waisbren

Harvard Medical School and Boston Children’s Hospital, Boston, Massachusetts, USA

James Weisfeld-Adams

Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, Colorado, USA

Derek Wong

David Geffen School of Medicine at UCLA, Los Angeles, California, USA

Marc Yudkoff

University of Pennsylvania School of Medicine and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

From the E-IMD

Jean-Baptiste Arnoux

Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Service de Maladies Métaboliques, Paris, France

Ivo Barić

University Hospital Center Zagreb and University of Zagreb, School of Medicine, Zagreb, Croatia

Annet M. Bosch

Academisch Medisch Centrum, Department of Pediatrics, Amsterdam, The Netherlands

Brigitte Chabrol

Centre de Référence des Maladies Héréditaires du Métabolisme, Service de Neurologie, Hôpital d’Enfants, CHU Timone, Marseille, France

Anupam Chakrapani

Metabolic Unit Great Ormond Street Hospital and Institute for Child Health, University College London, London, United Kingdom

Elisenda Cortès-Saladefont

Hospital San Joan de Deu, Servicio de Neurologia and CIBERER, ISCIII, Barcelona, Spain

Maria L. Couce

Hospital Clinico Universitario de Santiago de Compostela, Metabolic Unit, Department of Pediatrics, Santiago de Compostela, Spain

Francois Eyskens

Universitair Ziekenhuis Antwerpen, Antwerpen, Belgium

Corine de Laet

Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium

Linda de Meirleir

University Hospital Vrije Universiteit Brussel, Bruxelles, Belgium

Peter Freisinger

Klinik für Kinder- und Jugendmedizin, Klinikum am Steinenberg, Reutlingen, Germany

Florian Gleich

Centre for Pediatric and Adolescent Medicine, Division of Neuropediatrics and Inherited Metabolic Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany

Stephanie Grünewald

Metabolic Unit Great Ormond Street Hospital and Institute for Child Health, University College London, London, United Kingdom

Johannes Häberle

University Children’s Hospital Zurich, Division of Metabolism and Children’s Research Centre, Steinwiesstraße 75, CH-8032 Zurich, Switzerland

Wuh-Liang Hwu

Department of Medical Genetics, National Taiwan University, Hospital, Taipei City, Taiwan

Anil Jalan

N.I.R.M.A.N., Om Rachna Society, Vashi, Navi Mumbai, Mumbai, India

Daniela Karall

Medical University of Innsbruck, Clinic for Pediatrics I, Inherited Metabolic Disorders, Innsbruck, Austria

Martin Lindner

University Children’s Hospital Frankfurt, Frankfurt, Germany

Allan M. Lund

Centre for Inherited Metabolic Diseases, Departments of Pediatrics and Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Diego Martinelli

Ospedale Pediatrico Bambino Gésu, U.O.C. Patologia Metabolica, Rome, Italy

Elaine Murphy

National Hospital for Neurology and Neurosurgery, Charles Dent Metabolic Unit, London, United Kingdom

Chris Mühlhausen

University Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Giorgia Olivieri

Ospedale Pediatrico Bambino Gésu, U.O.C. Patologia Metabolica, Rome, Italy

Chris Ottolenghi

Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Service de Maladies Métaboliques, Paris, France

Esmeralda Rodrigues

Unidade de Doenças Metabólicas, Serviço de Pediatria, Hospital de S. João, EPE, Porto, Portugal

Laura Rubert

Azienda Ospedaliera di Padova, U.O.C. Malattie Metaboliche Ereditarie, Padova, Italy

Adrijan Sarajlija

Belgrade University, School of Medicine, Belgrade, Republic of Serbia

Manuel Schiff

Hôpital Robert Debré, APHP and Université Paris-Diderot, Reference Centre for Inborn Errors of Metabolism, Paris, France

Etienne Sokal

Cliniques Universitaires St Luc, Université Catholique de Louvain, Service Gastroentérologie and Hépatologie Pédiatrique, Bruxelles, Belgium

Jolanta Sykut-Cegielska

Institute of Mother and Child, Screening Department, Warsaw, Poland

John H. Walter

Manchester Academic Health Science Centre, University of Manchester, Willink Biochemical Genetics Unit, Genetic Medicine, Manchester, United Kingdom

Monique Williams

Erasmus MC-Sophia Kinderziekenhuis, Erasmus Universiteit Rotterdam, Rotterdam, The Netherlands

Jiri Zeman

Department of Paediatrics, First Faculty of Medicine and General Faculty Hospital, Prague, Czech Republic

Compliance with ethical standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human studies (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2013. Informed consent was obtained from all patients or their legal guardians prior to study inclusion in countries where this was needed by law.

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.

Animal rights

This article does not contain animal subjects.

Supplementary material

10545_2018_222_MOESM1_ESM.docx (34 kb)
ESM 1 (DOCX 34 kb)
10545_2018_222_MOESM2_ESM.pdf (511 kb)
ESM 2 Supplementary Fig. 1. Age at diagnosis on a logarithmic scale for early and late onset as well as asymptomatic individuals across the seven UCD diagnoses (for detailed numeric information, see Table 3). Supplementary Fig. 2. Age at first symptoms on a logarithmic scale for early and late onset individuals across the seven UCD diagnoses (for detailed numeric information, see Table 3). (PDF 511 kb)

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Copyright information

© SSIEM 2018

Authors and Affiliations

  • Roland Posset
    • 1
  • Sven F. Garbade
    • 1
  • Nikolas Boy
    • 1
  • Alberto B. Burlina
    • 2
  • Carlo Dionisi-Vici
    • 3
  • Dries Dobbelaere
    • 4
  • Angeles Garcia-Cazorla
    • 5
  • Pascale de Lonlay
    • 6
  • Elisa Leão Teles
    • 7
  • Roshni Vara
    • 8
  • Nicholas Ah Mew
    • 9
  • Mark L. Batshaw
    • 9
  • Matthias R. Baumgartner
    • 10
  • Shawn McCandless
    • 11
  • Jennifer Seminara
    • 9
  • Marshall Summar
    • 12
  • Georg F. Hoffmann
    • 1
  • Stefan Kölker
    • 1
  • Peter Burgard
    • 1
  • Additional individual contributors of the UCDC and the E-IMD consortium
  1. 1.Centre for Pediatric and Adolescent Medicine, Division of Neuropediatrics and Inherited Metabolic DiseasesUniversity Hospital HeidelbergHeidelbergGermany
  2. 2.Azienda Ospedaliera di PadovaU.O.C. Malattie Metaboliche EreditariePadovaItaly
  3. 3.Ospedale Pediatrico Bambino GésuU.O.C. Patologia MetabolicaRomeItaly
  4. 4.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 MedicineUniversity Lille 2LilleFrance
  5. 5.Hospital San Joan de Deu, Institut Pediàtric de Recerca, Servicio de Neurologia and CIBERER, ISCIIIBarcelonaSpain
  6. 6.Service de Maladies MétaboliquesHôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de ParisParisFrance
  7. 7.Unidade de Doenças Metabólicas, Serviço de PediatriaHospital de S. João, EPEPortoPortugal
  8. 8.Evelina Children’s HospitalSt Thomas’ HospitalLondonUK
  9. 9.Children’s National Health System and The George Washington School of MedicineWashingtonUSA
  10. 10.University Children’s Hospital ZurichZurichSwitzerland
  11. 11.Case Western Reserve University and University Hospitals Case Medical CenterClevelandUSA
  12. 12.Rare Disease InstituteChildren’s National Health SystemWashingtonUSA

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