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Journal of Inherited Metabolic Disease

, Volume 38, Issue 6, pp 1059–1074 | Cite as

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype

  • Stefan Kölker
  • Vassili Valayannopoulos
  • Alberto B. Burlina
  • Jolanta Sykut-Cegielska
  • Frits A. Wijburg
  • Elisa Leão Teles
  • Jiri Zeman
  • Carlo Dionisi-Vici
  • Ivo Barić
  • Daniela Karall
  • Jean-Baptiste Arnoux
  • Paula Avram
  • Matthias R. Baumgartner
  • Javier Blasco-Alonso
  • S. P. Nikolas Boy
  • Marlene Bøgehus Rasmussen
  • Peter Burgard
  • Brigitte Chabrol
  • Anupam Chakrapani
  • Kimberly Chapman
  • Elisenda Cortès i Saladelafont
  • Maria L. Couce
  • Linda de Meirleir
  • Dries Dobbelaere
  • Francesca Furlan
  • Florian Gleich
  • Maria Julieta González
  • Wanda Gradowska
  • Stephanie Grünewald
  • Tomas Honzik
  • Friederike Hörster
  • Hariklea Ioannou
  • Anil Jalan
  • Johannes Häberle
  • Gisela Haege
  • Eveline Langereis
  • Pascale de Lonlay
  • Diego Martinelli
  • Shirou Matsumoto
  • Chris Mühlhausen
  • Elaine Murphy
  • Hélène Ogier de Baulny
  • Carlos Ortez
  • Consuelo C. Pedrón
  • Guillem Pintos-Morell
  • Luis Pena-Quintana
  • Danijela Petković Ramadža
  • Esmeralda Rodrigues
  • Sabine Scholl-Bürgi
  • Etienne Sokal
  • Marshall L. Summar
  • Nicholas Thompson
  • Roshni Vara
  • Inmaculada Vives Pinera
  • John H. Walter
  • Monique Williams
  • Allan M. Lund
  • Angeles Garcia Cazorla
Original Article

Abstract

Background

The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood.

Aims

To evaluate the complex clinical phenotype of OAD and UCD patients at different ages.

Results

Acquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut0 patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population.

Conclusions

Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.

Keywords

Chronic Renal Failure Movement Disorder Standard Deviation Score Urea Cycle Disorder Optic Nerve Atrophy 
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-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 (isolated forms)

NAGS

N-acetylglutamate synthase

OAD

Organic aciduria

OTC

Ornithine transcarbamylase

PA

Propionic acidurias

SDS

Standard deviation score

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), 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), Erich 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), 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 has been 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.

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

10545_2015_9840_MOESM1_ESM.docx (40 kb)
Supplementary Table 1 Growth: the impact of age at disease onset (DOCX 39 kb)
10545_2015_9840_MOESM2_ESM.docx (38 kb)
Supplementary Table 2 Growth: the impact of movement disorders (DOCX 37 kb)
10545_2015_9840_MOESM3_ESM.docx (36 kb)
Supplementary Table 3 Movement disorder (DOCX 35 kb)
10545_2015_9840_MOESM4_ESM.docx (38 kb)
Supplementary Table 4 Laboratory tests evaluating the liver (DOCX 38 kb)
10545_2015_9840_MOESM5_ESM.docx (37 kb)
Supplementary Table 5 Whole blood cell count (DOCX 37 kb)
10545_2015_9840_MOESM6_ESM.docx (30 kb)
Supplementary Table 6 Synopsis of organ-specific manifestations in OAD and UCD patients (DOCX 30 kb)
10545_2015_9840_MOESM7_ESM.docx (33 kb)
ESM 1 (DOCX 32 kb)

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Copyright information

© SSIEM 2015

Authors and Affiliations

  • Stefan Kölker
    • 1
  • Vassili Valayannopoulos
    • 2
  • Alberto B. Burlina
    • 3
  • Jolanta Sykut-Cegielska
    • 4
  • Frits A. Wijburg
    • 5
  • Elisa Leão Teles
    • 6
  • Jiri Zeman
    • 7
  • Carlo Dionisi-Vici
    • 8
  • Ivo Barić
    • 9
  • Daniela Karall
    • 10
  • Jean-Baptiste Arnoux
    • 2
  • Paula Avram
    • 12
  • Matthias R. Baumgartner
    • 13
  • Javier Blasco-Alonso
    • 14
  • S. P. Nikolas Boy
    • 1
  • Marlene Bøgehus Rasmussen
    • 11
  • Peter Burgard
    • 1
  • Brigitte Chabrol
    • 15
  • Anupam Chakrapani
    • 16
  • Kimberly Chapman
    • 17
  • Elisenda Cortès i Saladelafont
    • 18
  • Maria L. Couce
    • 19
  • Linda de Meirleir
    • 20
  • Dries Dobbelaere
    • 21
  • Francesca Furlan
    • 3
  • Florian Gleich
    • 1
  • Maria Julieta González
    • 18
  • Wanda Gradowska
    • 22
  • Stephanie Grünewald
    • 23
  • Tomas Honzik
    • 7
  • Friederike Hörster
    • 1
  • Hariklea Ioannou
    • 24
  • Anil Jalan
    • 25
  • Johannes Häberle
    • 13
  • Gisela Haege
    • 1
  • Eveline Langereis
    • 5
  • Pascale de Lonlay
    • 2
  • Diego Martinelli
    • 8
  • Shirou Matsumoto
    • 26
  • Chris Mühlhausen
    • 27
  • Elaine Murphy
    • 28
  • Hélène Ogier de Baulny
    • 29
  • Carlos Ortez
    • 18
  • Consuelo C. Pedrón
    • 30
  • Guillem Pintos-Morell
    • 31
  • Luis Pena-Quintana
    • 32
  • Danijela Petković Ramadža
    • 32
  • Esmeralda Rodrigues
    • 6
  • Sabine Scholl-Bürgi
    • 10
  • Etienne Sokal
    • 33
  • Marshall L. Summar
    • 17
  • Nicholas Thompson
    • 23
  • Roshni Vara
    • 34
  • Inmaculada Vives Pinera
    • 35
  • John H. Walter
    • 36
  • Monique Williams
    • 37
  • Allan M. Lund
    • 11
  • Angeles Garcia Cazorla
    • 18
  1. 1.Department of General Pediatrics, Division of Inherited Metabolic DiseasesUniversity Children’s Hospital HeidelbergHeidelbergGermany
  2. 2.Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Reference Center for Inherited Metabolic DiseaseNecker-Enfants Malades University Hospital and IMAGINE InstituteParisFrance
  3. 3.Azienda Ospedaliera di PadovaU.O.C. Malattie Metaboliche EreditariePadovaItaly
  4. 4.Screening DepartmentInstitute of Mother and ChildWarsawPoland
  5. 5.Department of PediatricsAcademisch Medisch CentrumAmsterdamNetherlands
  6. 6.Unidade de Doenças Metabólicas, Serviço de PediatriaHospital de S. João, EPEPortoPortugal
  7. 7.First Faculty of Medicine Charles University and General University of PraguePragueCzech Republic
  8. 8.Ospedale Pediatrico Bambino Gésu, U.O.C. Patologia MetabolicaRomeItaly
  9. 9.School of Medicine University Hospital Center Zagreb and University of ZagrebZagrebCroatia
  10. 10.Medical University of Innsbruck, Clinic for Pediatrics I, Inherited Metabolic DisordersInnsbruckAustria
  11. 11.Centre for Inherited Metabolic Diseases, Department of Clinical GeneticsCopenhagen University Hospital, RigshospitaletCopenhagenDenmark
  12. 12.Institute of Mother and Child Care “Alfred Rusescu”BucharestRomania
  13. 13.Division of Metabolism and Children’s Research CentreUniversity Children’s Hospital ZurichZurichSwitzerland
  14. 14.Hospital Materno-Infantil (HRU Carlos Haya)MálagaSpain
  15. 15.Centre de Référence des Maladies Héréditaires du Métabolisme, Service de Neurologie, Hôpital d’Enfants, CHU TimoneMarseillesFrance
  16. 16.Birmingham Children’s Hospital NHS Foundation TrustBirminghamUK
  17. 17.Children’s National Medical CenterWashingtonUSA
  18. 18.Hospital San Joan de Deu, Servicio de Neurologia and CIBERER, ISCIIIBarcelonaSpain
  19. 19.Metabolic Unit, Department of PediatricsHospital Clinico Universitario de Santiago de CompostelaSantiago de CompostelaSpain
  20. 20.University Hospital Vrije Universiteit BrusselBruxellesBelgium
  21. 21.Centre de Référence des Maladies Héréditaires du Métabolisme de l’Enfant et de l’Adulte, Hôpital Jeanne de FlandreLilleFrance
  22. 22.Department of Laboratory DiagnosticsThe Children’s Memorial Health InstituteWarsawPoland
  23. 23.Metabolic Unit Great Ormond Street Hospital and Institute for Child HealthUniversity College LondonLondonUK
  24. 24.1st Pediatric Department, Metabolic LaboratoryGeneral Hospital of Thessaloniki ‘Hippocration’ThessalonikiGreece
  25. 25.N.I.R.M.A.N., Om Rachna SocietyVashi, Navi MumbaiIndia
  26. 26.Department of PediatricsKumamoto University HospitalKumamoto CityJapan
  27. 27.Universitätsklinikum Hamburg-Eppendorf, Klinik für Kinder- und JugendmedizinHamburgGermany
  28. 28.National Hospital for Neurology and Neurosurgery, Charles Dent Metabolic UnitLondonUK
  29. 29.Hôpital Robert Debré, Université de ParisParisFrance
  30. 30.Department of Pediatrics, Metabolic Diseases UnitHospital Infantil Universitario Niño JesúsMadridSpain
  31. 31.Department of PediatricsHospital Universitari Germans Trias I PujolBadalonaSpain
  32. 32.University Hospital Center ZagrebZagrebCroatia
  33. 33.Cliniques Universitaires St Luc, Université Catholique de Louvain, Service Gastroentérologie and Hépatologie PédiatriqueBruxellesBelgium
  34. 34.Evelina Children’s Hospital, St Thomas’ HospitalLondonUnited Kingdom
  35. 35.Hospital Virgen de la Arrixaca de Murcia, Inborn Metabolic Disease UnitEl PalmarSpain
  36. 36.Manchester Academic Health Science Centre, University of Manchester, Willink Biochemical Genetics Unit, Genetic MedicineManchesterUK
  37. 37.Erasmus MC-Sophia KinderziekenhuisErasmus Universiteit RotterdamRotterdamNetherlands

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