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Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders

  • Original Article
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Journal of Inherited Metabolic Disease

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A Correction to this article was published on 12 January 2018

This article has been updated

Abstract

Background

Patients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation.

Aims

Determining the effect of diagnostic and therapeutic interventions on the neurological outcome.

Methods

Evaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry.

Results

About two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 μmol/L) best predicted the neurological outcome.

Conclusions

Promising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment.

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Change history

  • 12 January 2018

    Due to an unfortunate error during the typesetting process, the collaborators were presented incorrectly.

Abbreviations

ARG1:

Arginase 1

ASL:

Argininosuccinate lyase

ASS:

Argininosuccinate synthetase

CPS1:

Carbamylphosphate synthetase 1

E-IMD:

European registry and network for intoxication type metabolic diseases

EO:

Early onset

HHH syndrome:

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

IR:

Interquartile range

LO:

Late onset

NAGS:

N-acetylglutamate synthase

NBS:

Newborn screening

OR(s):

Odds ratio(s)

OTC:

Ornithine transcarbamylase

Q1:

First quartile

Q3:

Third quartile

UCD(s):

Urea cycle disorder(s)

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Acknowledgments

We are indebted to all patients and their families who have been willing to contribute to this study, to share their experience on living with a rare disease, and for their trust. We are grateful for fruitful collaboration with the following clinical partners, patient support groups and industrial partners (in alphabetical order of countries): Lut de Baere, Nathalie Stroobant (Belgische Organisatie voor Kinderen en Volwassenen met een Stofwisselingsziekte VZW [BOKS], Belgium), Nela Carić (Hrvatska udruga za rijetke bolesti, Croatia), Veronika Dvorakova (Charles University and General University of Prague, First Faculty of Medicine, Prague, Czech Republic), Annika and Kennet Rovsing (PND – Protein Nedbrydnings Defekt Foreningen, Denmark), Samantha Parker (Orphan Europe SARL, France), EURORDIS, European Organisation for Rare Disease (France), Markus Ott, Beate Szczerbak (Nutricia Metabolics GmbH, Germany), Hubertus von Voss, Raimund Schmid (Kindernetzwerk e.V., Germany), Mandy Kretschmer (Glutarazidurie e.V., Germany), Reinhild Link (Wiesbaden, representing the SSIEM Dieticians Group), Persephone Augoustides-Savvopoulou (University A’Pediatric Department, Metabolic Laboratory, ‘Hippocration’ General Hospital of Thessaloniki), Zarifis Dimitroulis (KRIKOS ZOIS – Society for patients and friends of patients with inherited metabolic diseases), Evridiki Drogari (University of Athens, Aghia Sophia Children's Hospital, Unit of Metabolic Diseases, Athens), Renza Barbon Galluppi (UNIAMO FIMR, Italy), Susan Udina (COMETA ASMME – Associazione Studio Malattie Metaboliche Ereditarie – ONLUS, Italy), Hanka Meutgeert (Volwassenen en Kinderen met Stoffwisselingsziekten [VKS], Netherlands), Vanessa Ferreira (Associação Portuguesa CDG, Portugal), Miguel Macedo (Apofen, Portugal), Sérgio Braz Antão (Rarrisimas, Portugal), Sergi Faber (Catalana de Trastorns Metabòlics Hereditaris, Spain), Sofia Nordin (Svedish Orphan Biovitrium AB [SOBI], Sweden), Steven Hannigan (CLIMB, Children Living with Inherited Metabolic Diseases, National Information Centre for Metabolic Diseases, and EMDA, the European Metabolic Disorders Alliance), and Robin Lachmann (National Hospital for Neurology and Neurosurgery, Charles Dent Metabolic Unit, London, United Kingdom).

This publication arises from the project “European registry and network for intoxication type metabolic diseases” (E-IMD; EAHC no 2010 12 01) which has received funding from the European Union, in the framework of the Health Programme. After the end of the EU funding period the E-IMD patient registry will be sustained by funding from the Kindness-for-Kids Foundation (Munich, Germany) 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 program of the University of Zurich. C. Dionisi-Vici (Rome, Italy) is supported by the association “La vita è un dono”.

Individual contributors (additional co-authors to be listed in the PubMed, in alphabetical order)

Jean-Baptiste Arnoux, Ivo Barić, Eric Bauchart, Matthias R. Baumgartner, Javier Blasco-Alonso, Maria Teresa Cardoso, Brigitte Chabrol, Maja Djordjevic, Francois Eyskens, Peter Freisinger, Florian Gleich, Wanda Gradowska, Stephanie Grünewald, Gisela Haege, Wuh-Liang Hwu, Hariklea Ioannou, Anil Jalan, Daniela Karall, Corinne de Laet, Martin Lindner, Pascale de Lonlay, Diego Martinelli, Linda de Meirleir, Karine Mention, Chris Mühlhausen, Elaine Murphy, Hélène Ogier de Baulny, Carlos Ortez, Luis Peña-Quintana, Victoria Riches, Esmeralda Rodrigues, Etienne Sokal, Nicholas Thompson, Frits A. Wijburg, Monique Williams, and Matthias Zielonka also contributed to this work.

Affiliations of all authors are listed on the first pages.

Author information

Authors and Affiliations

  1. Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children’s Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany

    Roland Posset, Peter Burgard & Stefan Kölker

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

    Angeles Garcia-Cazorla & Elisenda Cortès-Saladelafont

  3. Assistance Publique-Hôpitaux de Paris, Service de Maladies Metaboliques, Hôpital Necker-Enfants Malades, Paris, France

    Vassili Valayannopoulos & Anaïs Brassier

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

    Elisa Leão Teles

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

    Carlo Dionisi-Vici

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

    Alberto B. Burlina

  7. 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, 59037, France

    Dries Dobbelaere

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

    Maria L. Couce

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

    Jolanta Sykut-Cegielska

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

    Johannes Häberle

  11. Centre for Inherited Metabolic Diseases, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Allan M. Lund

  12. Birmingham Children’s Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham, B4 6NH, UK

    Anupam Chakrapani

  13. Metabolic Unit Great Ormond Street Hospital and Institute for Child Health, University College London, London, UK

    Anupam Chakrapani

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

    Manuel Schiff

  15. Manchester Academic Health Science Centre, Willink Biochemical Genetics Unit, Genetic Medicine, University of Manchester, Manchester, UK

    John H. Walter

  16. First Faculty of Medicine, Charles University and General University of Prague, Prague, Czech Republic

    Jiri Zeman

  17. Evelina Children’s Hospital, St Thomas’ Hospital, London, UK

    Roshni Vara

Authors
  1. Roland Posset
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  2. Angeles Garcia-Cazorla
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  3. Vassili Valayannopoulos
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  4. Elisa Leão Teles
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  5. Carlo Dionisi-Vici
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  6. Anaïs Brassier
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  7. Alberto B. Burlina
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  8. Peter Burgard
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  9. Elisenda Cortès-Saladelafont
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  10. Dries Dobbelaere
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  11. Maria L. Couce
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  12. Jolanta Sykut-Cegielska
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  13. Johannes Häberle
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  14. Allan M. Lund
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  15. Anupam Chakrapani
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  16. Manuel Schiff
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  17. John H. Walter
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  18. Jiri Zeman
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  19. Roshni Vara
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  20. Stefan Kölker
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Consortia

Additional individual contributors of the E-IMD consortium

Corresponding author

Correspondence to Roland Posset.

Ethics declarations

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 2000.

Conflict of Interest

None.

Informed consent

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 2000. Informed consent was obtained from all patients or their legal guardians prior to study inclusion in countries where this was needed by law.

Animal rights

This article does not contain animal subjects.

Additional information

Communicated by: Bridget Wilcken

Additional individual contributors who should be regarded as co-authors are listed on acknowledgements.

A correction to this article is available online at https://doi.org/10.1007/s10545-017-0117-4.

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Posset, R., Garcia-Cazorla, A., Valayannopoulos, V. et al. Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders. J Inherit Metab Dis 39, 661–672 (2016). https://doi.org/10.1007/s10545-016-9938-9

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