Impact of age at onset and newborn screening on outcome in organic acidurias
- 1.2k Downloads
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.
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).
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.
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.
Amino acid mixture(s)
European registry and network for intoxication type metabolic diseases
Early onset (i.e. onset of first symptoms during the newborn period)
Glutaric aciduria type 1
High-risk family screening
Late onset (i.e. onset of first symptoms after the newborn period)
Methylmalonic aciduria (isolated forms)
Cobalamin-responsive methylmalonic aciduria
Cobalamin-nonresponsive methylmalonic aciduria
World Health Organisation
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.
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.
Compliance with ethical standards
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
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.
This article does not contain animal subjects.
- FAO (2001) Human energy requirements: Report of a Joint FAO/WHO/UNU Expert Consultation. FAO Report Series, No. 1. FAO, RomeGoogle Scholar
- Heinze G, Ploner M, Dunkler D, Southworth H (2013) Logistf: Firth’s bias reduced logistic regression. R package version 1.21. http://CRAN.R-project.org/package=logistf
- Hothorn T, Hornik K, Strobl C, Zeileis A (2015) Party: a laboratory for recursive partitioning. R package version 1.0-23. http://CRAN.R-project.org/package=party
- Smucker MD, Allan J, Carterette B (2007) A comparison of statistical significance tests for information retrieval evaluation. CIKM’07 Proceedings of the sixteenth ACM conference on information and knowledge management. 623–632Google Scholar
- World Health Organization, Food and Agriculture Organization of the United Nations, United Nations University (2007) Protein and amino acid requirements in human nutrition. Report of a joint WHO/FAO/UNU expert consultation. WHO Technical Report Series, No. 935, WHO PressGoogle Scholar