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Journal of Inherited Metabolic Disease

, Volume 38, Issue 6, pp 1041–1057 | Cite as

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

  • Stefan Kölker
  • Angeles Garcia Cazorla
  • Vassili Valayannopoulos
  • Allan M. Lund
  • Alberto B. Burlina
  • Jolanta Sykut-Cegielska
  • Frits A. Wijburg
  • Elisa Leão Teles
  • Jiri Zeman
  • Carlo Dionisi-Vici
  • Ivo Barić
  • Daniela Karall
  • Persephone Augoustides-Savvopoulou
  • Lise Aksglaede
  • Jean-Baptiste Arnoux
  • Paula Avram
  • Matthias R. Baumgartner
  • Javier Blasco-Alonso
  • Brigitte Chabrol
  • Anupam Chakrapani
  • Kimberly Chapman
  • Elisenda Cortès i Saladelafont
  • Maria L. Couce
  • Linda de Meirleir
  • Dries Dobbelaere
  • Veronika Dvorakova
  • Francesca Furlan
  • Florian Gleich
  • Wanda Gradowska
  • Stephanie Grünewald
  • Anil Jalan
  • Johannes Häberle
  • Gisela Haege
  • Robin Lachmann
  • Alexander Laemmle
  • Eveline Langereis
  • Pascale de Lonlay
  • Diego Martinelli
  • Shirou Matsumoto
  • Chris Mühlhausen
  • Hélène Ogier de Baulny
  • Carlos Ortez
  • Luis Peña-Quintana
  • Danijela Petković Ramadža
  • Esmeralda Rodrigues
  • Sabine Scholl-Bürgi
  • Etienne Sokal
  • Christian Staufner
  • Marshall L. Summar
  • Nicholas Thompson
  • Roshni Vara
  • Inmaculada Vives Pinera
  • John H. Walter
  • Monique Williams
  • Peter Burgard
Original Article

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.

Keywords

Newborn Screening Newborn Period Urea Cycle Disorder Metabolic Crisis Propionic Aciduria 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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

Notes

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

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.

Supplementary material

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Copyright information

© SSIEM 2015

Authors and Affiliations

  • Stefan Kölker
    • 1
  • Angeles Garcia Cazorla
    • 2
  • Vassili Valayannopoulos
    • 3
  • Allan M. Lund
    • 4
  • Alberto B. Burlina
    • 5
  • Jolanta Sykut-Cegielska
    • 6
  • Frits A. Wijburg
    • 7
  • Elisa Leão Teles
    • 8
  • Jiri Zeman
    • 9
  • Carlo Dionisi-Vici
    • 10
  • Ivo Barić
    • 11
  • Daniela Karall
    • 12
  • Persephone Augoustides-Savvopoulou
    • 13
  • Lise Aksglaede
    • 4
  • Jean-Baptiste Arnoux
    • 3
  • Paula Avram
    • 14
  • Matthias R. Baumgartner
    • 15
  • Javier Blasco-Alonso
    • 16
  • Brigitte Chabrol
    • 17
  • Anupam Chakrapani
    • 18
  • Kimberly Chapman
    • 19
  • Elisenda Cortès i Saladelafont
    • 2
  • Maria L. Couce
    • 20
  • Linda de Meirleir
    • 21
  • Dries Dobbelaere
    • 22
  • Veronika Dvorakova
    • 9
  • Francesca Furlan
    • 5
  • Florian Gleich
    • 1
  • Wanda Gradowska
    • 23
  • Stephanie Grünewald
    • 24
  • Anil Jalan
    • 25
  • Johannes Häberle
    • 15
  • Gisela Haege
    • 1
  • Robin Lachmann
    • 26
  • Alexander Laemmle
    • 15
  • Eveline Langereis
    • 7
  • Pascale de Lonlay
    • 3
  • Diego Martinelli
    • 10
  • Shirou Matsumoto
    • 27
  • Chris Mühlhausen
    • 28
  • Hélène Ogier de Baulny
    • 29
  • Carlos Ortez
    • 2
  • Luis Peña-Quintana
    • 31
  • Danijela Petković Ramadža
    • 30
  • Esmeralda Rodrigues
    • 8
  • Sabine Scholl-Bürgi
    • 12
  • Etienne Sokal
    • 32
  • Christian Staufner
    • 1
  • Marshall L. Summar
    • 19
  • Nicholas Thompson
    • 24
  • Roshni Vara
    • 33
  • Inmaculada Vives Pinera
    • 34
  • John H. Walter
    • 35
  • Monique Williams
    • 36
  • Peter Burgard
    • 1
  1. 1.Department of General Pediatrics, Division of Inherited Metabolic DiseasesUniversity Children’s Hospital HeidelbergHeidelbergGermany
  2. 2.Servicio de Neurologia and CIBERER, ISCIIIHospital San Joan de DeuBarcelonaSpain
  3. 3.Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Reference Center for Inherited Metabolic DiseaseNecker-Enfants Malades University Hospital and IMAGINE InstituteParisFrance
  4. 4.Centre for Inherited Metabolic Diseases, Department of Clinical GeneticsCopenhagen University Hospital, RigshospitaletCopenhagenDenmark
  5. 5.U.O.C. Malattie Metaboliche EreditarieAzienda Ospedaliera di PadovaPadovaItaly
  6. 6.Screening DepartmentInstitute of Mother and ChildWarsawPoland
  7. 7.Department of PediatricsAcademisch Medisch CentrumAmsterdamNetherlands
  8. 8.Unidade de Doenças Metabólicas, Serviço de PediatriaHospital de S. João, EPEPortoPortugal
  9. 9.First Faculty of MedicineCharles University and General University of PraguePragueCzech Republic
  10. 10.U.O.C. Patologia MetabolicaOspedale Pediatrico Bambino GésuRomeItaly
  11. 11.School of MedicineUniversity Hospital Center Zagreb and University of ZagrebZagrebCroatia
  12. 12.Clinic for Pediatrics I, Inherited Metabolic DisordersMedical University of InnsbruckInnsbruckAustria
  13. 13.1st Pediatric Department, Metabolic LaboratoryGeneral Hospital of Thessaloniki ‘Hippocration’ThessalonikiGreece
  14. 14.Institute of Mother and Child Care “Alfred Rusescu”BucharestRomania
  15. 15.Division of Metabolism and Children’s Research CentreUniversity Children’s Hospital ZurichZurichSwitzerland
  16. 16.Hospital Materno-Infantil (HRU Carlos Haya)MálagaSpain
  17. 17.Centre de Référence des Maladies Héréditaires du Métabolisme, Service de NeurologieHôpital d’Enfants, CHU TimoneMarseillesFrance
  18. 18.Birmingham Children’s Hospital NHS Foundation TrustBirminghamUK
  19. 19.Children’s National Medical CenterWashingtonUSA
  20. 20.Metabolic Unit, Department of PediatricsHospital Clinico Universitario de Santiago de CompostelaSantiago de CompostelaSpain
  21. 21.University Hospital Vrije Universiteit BrusselBruxellesBelgium
  22. 22.Centre de Référence des Maladies Héréditaires du Métabolisme de l’Enfant et de l’AdulteHôpital Jeanne de FlandreLilleFrance
  23. 23.Department of Laboratory DiagnosticsThe Children’s Memorial Health InstituteWarsawPoland
  24. 24.Metabolic Unit Great Ormond Street Hospital and Institute for Child HealthUniversity College LondonLondonUK
  25. 25.N.I.R.M.A.N., Om Rachna SocietyNavi MumbaiIndia
  26. 26.Charles Dent Metabolic UnitNational Hospital for Neurology and NeurosurgeryLondonUK
  27. 27.Department of PediatricsKumamoto University HospitalKumamoto CityJapan
  28. 28.Klinik für Kinder- und JugendmedizinUniversitätsklinikum Hamburg-EppendorfHamburgGermany
  29. 29.Hôpital Robert DebréUniversité de ParisParisFrance
  30. 30.University Hospital Center ZagrebZagrebCroatia
  31. 31.Hospital Universitario Materno-Infantil de Canarias, Unit of Pediatric Gastroenterology, Hepatology and NutritionUniversity of Las Palmas de Gran CanariaLas Palmas de Gran CanariaSpain
  32. 32.Service Gastroentérologie and Hépatologie PédiatriqueCliniques Universitaires St Luc, Université Catholique de LouvainBruxellesBelgium
  33. 33.Evelina Children’s Hospital, St Thomas’ HospitalLondonUK
  34. 34.Inborn Metabolic Disease UnitHospital Virgen de la Arrixaca de MurciaEl PalmarSpain
  35. 35.Manchester Academic Health Science Centre, Willink Biochemical Genetics Unit, Genetic MedicineUniversity of ManchesterManchesterUK
  36. 36.Erasmus MC-Sophia KinderziekenhuisErasmus Universiteit RotterdamRotterdamNetherlands

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