title: Impact of age at onset and newborn screening on outcome in organic acidurias.
abstract: 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.
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Inherited Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Heringer
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Centre de Référence de Maladies Métaboliques (MaMEA), Hôpital Universitaire Necker-Enfants Malades and Insitut MAGINE, Paris, France.
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.affiliation: Centre for Inherited Metabolic Diseases, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Allan M
authors.initials: AM
authors.lastname: Lund
authors.affiliation: Department of Pediatrics, Academic Medical Center, Amsterdam, Netherlands.
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.affiliation: Klinikum am Steinenberg, Klinik für Kinder- und Jugendmedizin, Reutlingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.affiliation: School of Medicine, University Hospital Center Zagreb and University of Zagreb, Zagreb, Croatia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Barić
authors.affiliation: Division of Metabolism and Children's Research Centre, University Children's Hospital Zurich, Steinwiesstraße 75, CH-8032, Zurich, Switzerland.
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Inherited Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Burgard
authors.affiliation: U.O.C. Malattie Metaboliche Ereditarie, Azienda Ospedaliera di Padova, Padova, Italy.
authors.forename: Alberto B
authors.initials: AB
authors.lastname: Burlina
authors.affiliation: Children's National Medical Center, 111 Michigan Avenue, N.W., Washington, DC, 20010, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Chapman
authors.affiliation: Hospital San Joan de Deu, Servicio de Neurologia and CIBERER, ISCIII, Barcelona, Spain.
authors.forename: Elisenda Cortès
authors.initials: EC
authors.lastname: I Saladelafont
authors.affiliation: Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Karall
authors.affiliation: Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Mühlhausen
authors.affiliation: Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Riches
authors.affiliation: Reference Center for Inborn Errors of Metabolism, APHP, University Paris-Diderot and INSERM U1141, Robert-Debré Hospital, Paris, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
authors.affiliation: Screening Department, Institute of Mother and Child, Warsaw, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Sykut-Cegielska
authors.affiliation: Willink Biochemical Genetics Unit, Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
authors.forename: John H
authors.initials: JH
authors.lastname: Walter
authors.affiliation: First Faculty of Medicine, Charles University and General University of Prague, Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Zeman
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Service de Neurologie, Hôpital d'Enfants, CHU Timone, Marseilles, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Chabrol
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Inherited Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany. Stefan.Koelker@med.uni-heidelberg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism / Q000473:pathology*; D020157:Amino Acid Transport Disorders, Inborn / Q000378:metabolism / Q000473:pathology*; D001928:Brain Diseases, Metabolic / Q000378:metabolism / Q000473:pathology*; D020739:Brain Diseases, Metabolic, Inborn / Q000378:metabolism / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000378:metabolism / Q000473:pathology; D008297:Male; D008659:Metabolic Diseases / Q000378:metabolism / Q000473:pathology*; D008764:Methylmalonic Acid / Q000378:metabolism; D008875:Middle Aged; D015997:Neonatal Screening / Q000379:methods; D014805:Vitamin B 12 / Q000378:metabolism; D055815:Young Adult
chemical_list: D008764:Methylmalonic Acid; D050770:Glutaryl-CoA Dehydrogenase; D014805:Vitamin B 12