title: Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters.
abstract: Objectives Isolated methylmalonic acidurias (MMAurias) are caused by deficiency of methylmalonyl-CoA mutase or by defects in the synthesis of its cofactor 5'-deoxyadenosylcobalamin. The aim of this study was to evaluate which parameters best predicted the long-term outcome. Methods Standardized questionnaires were sent to 20 European metabolic centres asking for age at diagnosis, birth decade, diagnostic work-up, cobalamin responsiveness, enzymatic subgroup (mut(0), mut(-), cblA, cblB) and different aspects of long-term outcome. Results 273 patients were included. Neonatal onset of the disease was associated with increased mortality rate, high frequency of developmental delay, and severe handicap. Cobalamin non-responsive patients with neonatal onset born in the 1970s and 1980s had a particularly poor outcome. A more favourable outcome was found in patients with late onset of symptoms, especially when cobalamin responsive or classified as mut(-). Prevention of neonatal crises in pre-symptomatically diagnosed newborns was identified as a protective factor concerning handicap. Chronic renal failure manifested earlier in mut(0) patients than in other enzymatic subgroups. Conclusion Outcome in MMAurias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset and birth decade. The prognosis is still unfavourable in patients with neonatal metabolic crises and non-responsiveness to cobalamin, in particular mut(0) patients.
authors.affiliation: Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany. friederike.hoerster@med.uni-heidelberg.de.
authors.forename: F
authors.initials: F
authors.lastname: Hörster
authors.affiliation: Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.
authors.forename: S F
authors.initials: SF
authors.lastname: Garbade
authors.affiliation: Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Zwickler
authors.affiliation: Department of Metabolism, Children's Hospital, Hacettepe University Ankara, Ankara, Turkey.
authors.forename: H I
authors.initials: HI
authors.lastname: Aydin
authors.affiliation: Department of Paediatrics, Allgemeines Krankenhaus, Vienna, Austria.
authors.forename: O A
authors.initials: OA
authors.lastname: Bodamer
authors.affiliation: Department of Paediatrics, Division of Metabolic Disorders, University Hospital Padova, Padova, Italy.
authors.forename: A B
authors.initials: AB
authors.lastname: Burlina
authors.affiliation: Department of Paediatrics II, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Das
authors.affiliation: Sophia Children's Hospital, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: J B C
authors.initials: JBC
authors.lastname: De Klerk
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Dionisi-Vici
authors.affiliation: University Children's Hospital I, Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Geb
authors.affiliation: Department of Nutrition and Metabolism, Istanbul University Medical Faculty Children's Hospital, Istanbul, Turkey.
authors.forename: G
authors.initials: G
authors.lastname: Gökcay
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Femme Mère Enfant, Lyon, France.
authors.forename: N
authors.initials: N
authors.lastname: Guffon
authors.affiliation: Dr. von Hauner Children's Hospital, Munich, Germany.
authors.forename: E M
authors.initials: EM
authors.lastname: Maier
authors.affiliation: Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Morava
authors.affiliation: Willink Unit, Royal Manchester Children's Hospital, Manchester, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: Walter
authors.affiliation: Department of General Pediatrics, University Children's Hospital, Düsseldorf, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schwahn
authors.affiliation: Department of Pediatrics, Academic Medical Centre, University Hospital, Amsterdam, The Netherlands.
authors.forename: F A
authors.initials: FA
authors.lastname: Wijburg
authors.affiliation: Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Lindner
authors.affiliation: Metabolic Unit, Great Ormond Street Hospital, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Grünewald
authors.affiliation: Metabolism and Molecular Paediatrics, University Children's Hospital, Zurich, Switzerland.
authors.forename: M R
authors.initials: MR
authors.lastname: Baumgartner
authors.affiliation: Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kölker
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics / Q000401:mortality; D015415:Biomarkers / Q000032:analysis*; D002648:Child; D002675:Child, Preschool; D003038:Cobamides / Q000172:deficiency; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008765:Methylmalonyl-CoA Mutase / Q000172:deficiency* / Q000235:genetics; D017063:Outcome Assessment, Health Care; D011379:Prognosis; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D015415:Biomarkers; D003038:Cobamides; D008765:Methylmalonyl-CoA Mutase; C000913:cobamamide