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The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

An Erratum to this article was published on 16 June 2015

Abstract

Background

The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific.

Aims/methods

To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry.

Results

We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OTC) deficiency (n = 196), glutaric aciduria type 1 (GA1; n = 150) and methylmalonic aciduria (MMA; n = 149) being the most frequent diseases. Overall, 548 patients (69 %) were symptomatic. The majority of them (n = 463) presented with acute metabolic crisis during (n = 220) or after the newborn period (n = 243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (n = 94) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only).

Conclusions

The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.

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Abbreviations

ARG1:

Arginase 1

ASL:

Argininosuccinate lyase

ASS:

Argininosuccinate synthetase

CPS1:

Carbamylphosphate synthetase 1

E-HOD:

European network and registry for homocystinurias and methylation defects

E-IMD:

European registry and network for intoxication type metabolic diseases

GA1:

Glutaric aciduria type 1

HHH:

Hyperornithinemia-hyperammonemia-homocitrullinuria

IVA:

Isovaleric aciduria

MMA:

Methylmalonic aciduria

NAGS:

N-acetylglutamate synthase

OAD:

Organic aciduria

OTC:

Ornithine transcarbamylase

PA:

Propionic aciduria

Q:

Quartile

QoL:

Quality of life

UCD:

Urea cycle disorder

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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, and we thank all colleagues very much for their contribution to the project. 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), Tomas Honzik (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), Eric Bauchart (Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Reference Center for Inherited Metabolic Disease, Necker-Enfants Malades University Hospital and IMAGINE Institute, Paris, 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), Harikleia Ioannou (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), and Steven Hannigan (CLIMB, Children Living with Inherited Metabolic Diseases, National Information Centre for Metabolic Diseases, and EMDA, the European Metabolic Disorders Alliance).

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).

M. Baumgartner, J. Häberle and A. Laemmle (Zurich, Switzerland) are supported by radiz – Rare Disease Initiative Zurich, a clinical research priority programme of the University of Zurich.

Drs Murphy and Lachmann were supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.

Compliance with ethics guidelines

ᅟ

Conflict of interest

none.

Human and animal rights and 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 being included in the study in countries where this was needed by law.

This article does not contain animal subjects.

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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

    Stefan Kölker, Florian Gleich, Gisela Haege, Christian Staufner & Peter Burgard

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

    Angeles Garcia Cazorla, Elisenda Cortès i Saladelafont & Carlos Ortez

  3. Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Reference Center for Inherited Metabolic Disease, Necker-Enfants Malades University Hospital and IMAGINE Institute, Paris, France

    Vassili Valayannopoulos, Jean-Baptiste Arnoux & Pascale de Lonlay

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

    Allan M. Lund & Lise Aksglaede

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

    Alberto B. Burlina & Francesca Furlan

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

    Jolanta Sykut-Cegielska

  7. Department of Pediatrics, Academisch Medisch Centrum, Amsterdam, Netherlands

    Frits A. Wijburg & Eveline Langereis

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

    Elisa Leão Teles & Esmeralda Rodrigues

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

    Jiri Zeman & Veronika Dvorakova

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

    Carlo Dionisi-Vici & Diego Martinelli

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

    Ivo Barić

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

    Daniela Karall & Sabine Scholl-Bürgi

  13. 1st Pediatric Department, Metabolic Laboratory, General Hospital of Thessaloniki ‘Hippocration’, Thessaloniki, Greece

    Persephone Augoustides-Savvopoulou

  14. Institute of Mother and Child Care “Alfred Rusescu”, Bucharest, Romania

    Paula Avram

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

    Matthias R. Baumgartner, Johannes Häberle & Alexander Laemmle

  16. Hospital Materno-Infantil (HRU Carlos Haya), Málaga, Spain

    Javier Blasco-Alonso

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

    Brigitte Chabrol

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

    Anupam Chakrapani

  19. Children’s National Medical Center, 111 Michigan Avenue, N.W., Washington, DC, 20010, USA

    Kimberly Chapman & Marshall L. Summar

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

    Maria L. Couce

  21. University Hospital Vrije Universiteit Brussel, Bruxelles, Belgium

    Linda de Meirleir

  22. Centre de Référence des Maladies Héréditaires du Métabolisme de l’Enfant et de l’Adulte, Hôpital Jeanne de Flandre, Lille, France

    Dries Dobbelaere

  23. Department of Laboratory Diagnostics, The Children’s Memorial Health Institute, Warsaw, Poland

    Wanda Gradowska

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

    Stephanie Grünewald & Nicholas Thompson

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

    Anil Jalan

  26. Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK

    Robin Lachmann

  27. Department of Pediatrics, Kumamoto University Hospital, Kumamoto City, Japan

    Shirou Matsumoto

  28. Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

    Chris Mühlhausen

  29. Hôpital Robert Debré, Université de Paris, Paris, France

    Hélène Ogier de Baulny

  30. University Hospital Center Zagreb, Zagreb, Croatia

    Danijela Petković Ramadža

  31. Hospital Universitario Materno-Infantil de Canarias, Unit of Pediatric Gastroenterology, Hepatology and Nutrition, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

    Luis Peña-Quintana

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

    Etienne Sokal

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

    Roshni Vara

  34. Inborn Metabolic Disease Unit, Hospital Virgen de la Arrixaca de Murcia, El Palmar, Spain

    Inmaculada Vives Pinera

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

    John H. Walter

  36. Erasmus MC-Sophia Kinderziekenhuis, Erasmus Universiteit Rotterdam, Rotterdam, Netherlands

    Monique Williams

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  1. Stefan Kölker
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  2. Angeles Garcia Cazorla
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  3. Vassili Valayannopoulos
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  4. Allan M. Lund
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  5. Alberto B. Burlina
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  6. Jolanta Sykut-Cegielska
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  7. Frits A. Wijburg
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  8. Elisa Leão Teles
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  9. Jiri Zeman
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  10. Carlo Dionisi-Vici
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  11. Ivo Barić
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  12. Daniela Karall
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  13. Persephone Augoustides-Savvopoulou
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  14. Lise Aksglaede
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  15. Jean-Baptiste Arnoux
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  16. Paula Avram
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  17. Matthias R. Baumgartner
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  18. Javier Blasco-Alonso
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  19. Brigitte Chabrol
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Corresponding author

Correspondence to Stefan Kölker.

Additional information

Communicated by: K. Michael Gibson

For a complete list of affiliations of all authors see end of this article.

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Kölker, S., Cazorla, A.G., Valayannopoulos, V. et al. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis 38, 1041–1057 (2015). https://doi.org/10.1007/s10545-015-9839-3

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  • DOI: https://doi.org/10.1007/s10545-015-9839-3

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