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Suggested guidelines for the diagnosis and management of urea cycle disorders

Johannes Häberle1*, Nathalie Boddaert2, Alberto Burlina3, Anupam Chakrapani4, Marjorie Dixon5, Martina Huemer6, Daniela Karall7, Diego Martinelli8, Pablo Sanjurjo Crespo9, René Santer10, Aude Servais11, Vassili Valayannopoulos12, Martin Lindner13*, Vicente Rubio14* and Carlo Dionisi-Vici8*

Author Affiliations

1 University Children’s Hospital Zurich and Children’s Research Centre, Zurich, 8032, Switzerland

2 Radiologie Hopital Necker, Service Radiologie Pediatrique, 149 Rue De Sevres, Paris 15, 75015, France

3 Department of Pediatrics, Division of Inborn Metabolic Disease, University Hospital Padua, Via Giustiniani 3, Padova, 35128, Italy

4 Birmingham Children’s Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham, B4 6NH, United Kingdom

5 Dietetic Department, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, WC1N 3JH, United Kingdom

6 Kinderabteilung, LKH Bregenz, Carl-Pedenz-Strasse 2, Bregenz, A-6900, Austria

7 University Children’s Hospital, Medical University Innsbruck, Anichstrasse 35, Innsbruck, 6020, Austria

8 Division of Metabolism, Bambino Gesù Children’s Hospital, IRCCS, Piazza S. Onofrio 4, Rome, I-00165, Italy

9 Division of Pediatric Metabolism, Cruces Children Hospital, Baracaldo, 48903, Spain

10 Universitätsklinikum Hamburg Eppendorf, Klinik für Kinder- und Jugendmedizin, Martinistr. 52, Hamburg, 20246, Germany

11 Service de Néphrologie et maladies métaboliques adulte Hôpital Necker 149, rue de Sèvres, Paris, 75015, France

12 Reference Center for Inherited Metabolic Disorders (MaMEA), Hopital Necker-Enfants Malades, 149 Rue de Sevres, Paris, 75015, France

13 University Children’s Hospital, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany

14 Instituto de Biomedicina de Valencia del Consejo Superior de Investigaciones Científicas (IBV-CSIC) and Centro de Investigación Biomédica en Red para Enfermedades Raras (CIBERER), C/ Jaume Roig 11, Valencia, 46010, Spain

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Orphanet Journal of Rare Diseases 2012, 7:32  doi:10.1186/1750-1172-7-32

Published: 29 May 2012


Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000. Patients present with hyperammonemia either shortly after birth (~50%) or, later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns. To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across seven European countries to gather all the existing evidence, score it according to the SIGN evidence level system and draw a series of statements supported by an associated level of evidence. The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training. Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Also, it identified knowledge voids that must be filled by future research. We believe these guidelines will help to: harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.

Urea cycle disorders; UCD; Hyperammonemia; N-acetylglutamate synthase; Carbamoylphosphate synthetase 1; Ornithine transcarbamylase; Ornithine carbamoyl transferase; Argininosuccinate synthetase; Argininosuccinate lyase; Arginase 1; Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome