Journal of Inherited Metabolic Disease

, Volume 39, Issue 5, pp 661–672 | Cite as

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

  • Roland PossetEmail author
  • 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
  • Additional individual contributors of the E-IMD consortium
Original Article



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


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


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.


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.


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.



Arginase 1


Argininosuccinate lyase


Argininosuccinate synthetase


Carbamylphosphate synthetase 1


European registry and network for intoxication type metabolic diseases


Early onset

HHH syndrome

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome


Interquartile range


Late onset


N-acetylglutamate synthase


Newborn screening


Odds ratio(s)


Ornithine transcarbamylase


First quartile


Third quartile


Urea cycle disorder(s)



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.

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 2000.

Conflict of Interest


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.

Supplementary material

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Table S8 (DOCX 47 kb)


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Copyright information

© SSIEM 2016

Authors and Affiliations

  • Roland Posset
    • 1
    Email author
  • Angeles Garcia-Cazorla
    • 2
  • Vassili Valayannopoulos
    • 3
  • Elisa Leão Teles
    • 4
  • Carlo Dionisi-Vici
    • 5
  • Anaïs Brassier
    • 3
  • Alberto B. Burlina
    • 6
  • Peter Burgard
    • 1
  • Elisenda Cortès-Saladelafont
    • 2
  • Dries Dobbelaere
    • 7
  • Maria L. Couce
    • 8
  • Jolanta Sykut-Cegielska
    • 9
  • Johannes Häberle
    • 10
  • Allan M. Lund
    • 11
  • Anupam Chakrapani
    • 12
    • 13
  • Manuel Schiff
    • 14
  • John H. Walter
    • 15
  • Jiri Zeman
    • 16
  • Roshni Vara
    • 17
  • Stefan Kölker
    • 1
  • Additional individual contributors of the E-IMD consortium
    • 18
    • 19
    • 20
    • 21
    • 22
    • 23
    • 24
    • 25
    • 26
    • 27
    • 28
    • 29
    • 30
    • 31
    • 32
    • 33
    • 34
    • 35
    • 36
    • 37
    • 38
  1. 1.Department of General Pediatrics, Division of Inherited Metabolic DiseasesUniversity Children’s Hospital HeidelbergHeidelbergGermany
  2. 2.Hospital San Joan de Deu, Servicio de Neurologia and CIBERER, ISCIIIBarcelonaSpain
  3. 3.Assistance Publique-Hôpitaux de Paris, Service de Maladies MetaboliquesHôpital Necker-Enfants MaladesParisFrance
  4. 4.Hospital de S. João, EPEUnidade de Doenças Metabólicas, Serviço de PediatriaPortoPortugal
  5. 5.Ospedale Pediatrico Bambino Gésu, U.O.C. Patologia MetabolicaRomeItaly
  6. 6.Azienda Ospedaliera di Padova, U.O.C. Malattie Metaboliche EreditariePadovaItaly
  7. 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 MedicineUniversity Lille 2LilleFrance
  8. 8.Metabolic Unit, Department of PediatricsHospital Clinico Universitario de Santiago de CompostelaSantiago de CompostelaSpain
  9. 9.Screening DepartmentInstitute of Mother and ChildWarsawPoland
  10. 10.Division of Metabolism and Children’s Research CentreUniversity Children’s Hospital ZurichZurichSwitzerland
  11. 11.Centre for Inherited Metabolic Diseases, Department of Clinical GeneticsCopenhagen University Hospital, RigshospitaletCopenhagenDenmark
  12. 12.Birmingham Children’s Hospital NHS Foundation TrustBirminghamUK
  13. 13.Metabolic Unit Great Ormond Street Hospital and Institute for Child HealthUniversity College LondonLondonUK
  14. 14.Hôpital Robert Debré, Reference Centre for Inborn Errors of MetabolismAPHP and Université Paris-DiderotParisFrance
  15. 15.Manchester Academic Health Science Centre, Willink Biochemical Genetics Unit, Genetic MedicineUniversity of ManchesterManchesterUK
  16. 16.First Faculty of MedicineCharles University and General University of PraguePragueCzech Republic
  17. 17.Evelina Children’s Hospital, St Thomas’ HospitalLondonUK
  18. 18.University Hospital Center Zagreb and University of Zagreb, School of MedicineZagrebCroatia
  19. 19.Hospital Materno-Infantil (HRU Carlos Haya)MálagaSpain
  20. 20.Centre de Référence des Maladies Héréditaires du Métabolisme, Service de Neurologie, Hôpital d’Enfants, CHU TimoneMarseillesFrance
  21. 21.Institut za zdravstvenu zaštitu majke i deteta SrbijeBelgradeRepublic of Serbia
  22. 22.Belgrade University, School of MedicineBelgradeRepublic of Serbia
  23. 23.Universitair Ziekenhuis AntwerpenAntwerpenBelgium
  24. 24.Klinik für Kinder- und Jugendmedizin, Klinikum am SteinenbergReutlingenGermany
  25. 25.Department of Laboratory DiagnosticsThe Children’s Memorial Health InstituteWarsawPoland
  26. 26.Department of Medical GeneticsNational Taiwan University HospitalTaipei CityTaiwan
  27. 27.1st Pediatric Department, Metabolic LaboratoryGeneral Hospital of Thessaloniki ‘Hippocration’ThessalonikiGreece
  28. 28.N.I.R.M.A.N., Om Rachna SocietyMumbaiIndia
  29. 29.Medical University of Innsbruck, Clinic for Pediatrics I, Inherited Metabolic DisordersInnsbruckAustria
  30. 30.Hôpital Universitaire des Enfants Reine FabiolaBrusselsBelgium
  31. 31.University Children’s Hospital FrankfurtFrankfurtGermany
  32. 32.University Hospital Vrije Universiteit BrusselBruxellesBelgium
  33. 33.University Children’s Hospital, University Medical Center Hamburg-EppendorfHamburgGermany
  34. 34.National Hospital for Neurology and Neurosurgery, Charles Dent Metabolic UnitLondonUnited Kingdom
  35. 35.Universidad de Las Palmas de Gran Canaria, CIBER OBN, Hospital Universitario Materno Infantil de Canarias, Unit of Pediatric Gastroenterology, Hepatology and NutritionLas PalmasSpain
  36. 36.Cliniques Universitaires St Luc, Université Catholique de Louvain, Service Gastroentérologie and Hépatologie PédiatriqueBruxellesBelgium
  37. 37.Department of PediatricsAcademisch Medisch CentrumAmsterdamNetherlands
  38. 38.Erasmus MC-Sophia Kinderziekenhuis, Erasmus Universiteit RotterdamRotterdamNetherlands

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