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Impact of age at onset and newborn screening on outcome in organic acidurias

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

A Correction to this article was published on 12 December 2017

This article has been updated

Abstract

Background and aim

To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation.

Methods

Datasets of 567 OAD patients from the E-IMD registry were analysed. The sample includes patients with methylmalonic (MMA, n = 164), propionic (PA, n = 144) and isovaleric aciduria (IVA, n = 83), and glutaric aciduria type 1 (GA1, n = 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO).

Results

Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group (363 days, p < 0.001], but not compared to the EO group. Of all OAD patients 71 % remained asymptomatic until day 8. Patients with cobalamin-nonresponsive MMA (MMA-Cbl−) and GA1 identified by NBS were less likely to have movement disorders than those diagnosed by selective screening (MMA-Cbl−: 10 % versus 39 %, p = 0.002; GA1: 26 % versus 73 %, p < 0.001). For other OADs, the clinical benefit of NBS was less clear. Reported age-adjusted intake of natural protein and calories was significantly higher in LO patients than in EO patients reflecting different disease severities. Variable drug combinations, ranging from 12 in MMA-Cbl− to two in isovaleric aciduria, were used for maintenance treatment. The effects of specific metabolic treatment strategies on the health outcomes remain unclear because of the strong influences of age at onset (EO versus LO), diagnostic mode (NBS versus selective screening), and the various treatment combinations used.

Conclusions

NBS is an effective intervention to reduce time until diagnosis especially for LO patients and to prevent irreversible cerebral damage in GA1 and MMA-Cbl−. Huge diversity of therapeutic interventions hampers our understanding of optimal treatment.

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Change history

  • 12 December 2017

    Due to an unfortunate error during the typesetting process, the collaborators were presented incorrectly.

Abbreviations

AAM(s):

Amino acid mixture(s)

E-IMD:

European registry and network for intoxication type metabolic diseases

EO:

Early onset (i.e. onset of first symptoms during the newborn period)

GA1:

Glutaric aciduria type 1

HRF:

High-risk family screening

IVA:

Isovaleric aciduria

IVD:

Isovaleryl-CoA dehydrogenase

LO:

Late onset (i.e. onset of first symptoms after the newborn period)

MMA:

Methylmalonic aciduria (isolated forms)

MMA-Cbl+ :

Cobalamin-responsive methylmalonic aciduria

MMA-Cbl− :

Cobalamin-nonresponsive methylmalonic aciduria

NBS:

Newborn screening

OAD(s):

Organic aciduria(s)

OR:

Odds ratio

PA:

Propionic aciduria

Q1:

First quartile

Q3:

Third quartile

WHO:

World Health Organisation

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Acknowledgments

We are indebted to all patients and their families who have contributed to this study, shared their experience of 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 and Tomas Honzik (Charles University and General University of Prague, First Faculty of Medicine, Prague, Czech Republic), Annika and Kenneth Rovsing (PND – Protein Nedbrydnings Defekt Foreningen, Denmark), Samantha Parker (Lysogene, Paris, 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 1st Pediatric Department, Metabolic Laboratory, ‘Hippocration’ General Hospital of Thessaloniki, Greece), Ioannis Anagnostopoulos (KRIKOS ZOIS – Society for patients and friends of patients with inherited metabolic diseases, Greece), Evridiki Drogari (University of Athens, Aghia Sophia Children’s Hospital, Unit of Metabolic Diseases, Athens, Greece), 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), Lara Abulhoul, Maureen Cleary and Paula Gissen (Metabolic Unit, Great Ormond Street Hospital, 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 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”. R. Lachmann is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.

Individual contributors

Lise Aksglaede, Paula Avram, Elena Balmaseda-Serrano, Eric Bauchart, Javier Blasco-Alonso, Anaïs Brassier, Anupam Chakrapani, Yin-Hsiu Chien, Maria L. Couce, Corinne de Laet, Pascale de Lonlay, Linda de Meirleir, Carlo Dionisi-Vici, Dries Dobbelaere, Angeles Garcia-Cazorla, Florian Gleich, Wanda Gradowska, Stephanie Grünewald, Gisela Haege, Johannes Häberle, Wuh-Liang Hwu, Harikleia Ioannou, Robin Lachmann, Eveline Langereis, Elisa Leão Teles, Eduardo López-Laso, Shirou Matsumoto, Hélène Ogier de Baulny, Carlos Ortez, Luis Peña-Quintana, Angeles Ruiz-Gomez, Adrijan Sarajlija, Marshall L. Summar, Nicholas Thompson, Roshni Vara, Inmaculada Vives Pinera, Monique Williams, and Matthias Zielonka also contributed to this work.

Author information

Authors and Affiliations

  1. Department of General Pediatrics, Division of Neuropediatrics and Inherited Metabolic Diseases, University Children’s Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany

    Jana Heringer, Peter Burgard & Stefan Kölker

  2. Assistance Publique-Hôpitaux de Paris, Centre de Référence de Maladies Métaboliques (MaMEA), Hôpital Universitaire Necker-Enfants Malades and Insitut MAGINE, Paris, France

    Vassili Valayannopoulos

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

    Allan M. Lund

  4. Department of Pediatrics, Academic Medical Center, Amsterdam, Netherlands

    Frits A. Wijburg

  5. Klinikum am Steinenberg, Klinik für Kinder- und Jugendmedizin, Reutlingen, Germany

    Peter Freisinger

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

    Ivo Barić

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

    Matthias R. Baumgartner

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

    Alberto B. Burlina

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

    Kimberly A. Chapman

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

    Elisenda Cortès i Saladelafont

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

    Daniela Karall

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

    Chris Mühlhausen

  13. Reference Center for Inborn Errors of Metabolism, APHP, University Paris-Diderot and INSERM U1141, Robert-Debré Hospital, Paris, France

    Manuel Schiff

  14. Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, UK

    Victoria Riches

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

    Jolanta Sykut-Cegielska

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

    John H. Walter

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

    Jiri Zeman

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

    Brigitte Chabrol

Authors
  1. Jana Heringer
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  2. Vassili Valayannopoulos
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  3. Allan M. Lund
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  4. Frits A. Wijburg
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  5. Peter Freisinger
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  6. Ivo Barić
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  7. Matthias R. Baumgartner
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  8. Peter Burgard
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  9. Alberto B. Burlina
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  10. Kimberly A. Chapman
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  13. Chris Mühlhausen
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  20. Stefan Kölker
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Consortia

additional individual contributors of the E-IMD consortium

  • Lise Aksglaede
  • , Paula Avram
  • , Elena Balmaseda-Serrano
  • , Eric Bauchart
  • , Javier Blasco-Alonso
  • , Anaïs Brassier
  • , Anupam Chakrapani
  • , Yin-Hsiu Chien
  • , Maria L. Couce
  • , Corinne de Laet
  • , Pascale de Lonlay
  • , Linda de Meirleir
  • , Carlo Dionisi-Vici
  • , Dries Dobbelaere
  • , Angeles Garcia-Cazorla
  • , Florian Gleich
  • , Wanda Gradowska
  • , Stephanie Grünewald
  • , Gisela Haege
  • , Johannes Häberle
  • , Wuh-Liang Hwu
  • , Harikleia Ioannou
  • , Robin Lachmann
  • , Eveline Langereis
  • , Elisa Leão Teles
  • , Eduardo López-Laso
  • , Shirou Matsumoto
  • , Hélène Ogier de Baulny
  • , Carlos Ortez
  • , Luis Peña-Quintana
  • , Angeles Ruiz-Gomez
  • , Adrijan Sarajlija
  • , Marshall L. Summar
  • , Nicholas Thompson
  • , Roshni Vara
  • , Inmaculada Vives Pinera
  • , Monique Williams
  •  & Matthias Zielonka

Corresponding author

Correspondence to Stefan Kölker.

Ethics declarations

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

None.

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 inclusion in the study in countries where this was needed by law.

Animal rights

This article does not contain animal subjects.

Additional information

Communicated by: Jerry Vockley

A correction to this article is available online at https://doi.org/10.1007/s10545-017-0116-5.

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Heringer, J., Valayannopoulos, V., Lund, A.M. et al. Impact of age at onset and newborn screening on outcome in organic acidurias. J Inherit Metab Dis 39, 341–353 (2016). https://doi.org/10.1007/s10545-015-9907-8

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