title: Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency.
abstract: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions.
  
  
  
  To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management.
  
  
  
  Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach.
  
  
  
  We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early.
authors.affiliation: Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zurich, Switzerland.|radiz - Rare Disease Initiative Zürich, Clinical Research Priority Program, University of Zürich, Zurich, Switzerland.|Department of Paediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria.
authors.forename: Martina
authors.identifier: 0000-0002-8285-9657
authors.initials: M
authors.lastname: Huemer
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Research Hospital, Rome, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Diodato
authors.affiliation: Willink Biochemical Genetics Unit, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schwahn
authors.affiliation: Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, APHP, Paris, France.|Inserm U1141, Robert Debré Hospital, Paris, France.|Université Paris-Diderot, Sorbonne Paris Cité, site Robert Debré, Paris, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
authors.affiliation: Metabolic Unit, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Anabela
authors.initials: A
authors.lastname: Bandeira
authors.affiliation: Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, APHP, Paris, France.|Inserm U1141, Robert Debré Hospital, Paris, France.|Biochimie, faculté de pharmacie, Université Paris Sud, Paris, France.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Benoist
authors.affiliation: Division of Inherited Metabolic Diseases, Department of Pediatrics, University Hospital Padova, Padova, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Burlina
authors.affiliation: University Dept of Pediatrics, Giannina Gaslini Institute, Genoa, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cerone
authors.affiliation: Congenital Metabolic Diseases Unit, Hospital Clínico Universitario de Santiago de Compostela, IDIS, CIBER, Compostela, Spain.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Couce
authors.affiliation: Department of Neurology, Neurometabolism Unit, and CIBERER (ISCIII), Hospital Sant Joan de Deu, Barcelona, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Garcia-Cazorla
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Firence, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: la Marca
authors.affiliation: Metabolic and Newborn Screening Clinical Unit, Department of Neurosciences, A. Meyer Children's University Hospital, Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pasquini
authors.affiliation: Newborn Screening, Metabolism & Genetics Unit, National Institute of Health, Porto, Portugal.
authors.forename: Laura
authors.initials: L
authors.lastname: Vilarinho
authors.affiliation: Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.|Inherited Metabolic Diseases Clinic, Childrens Hospital Colorado, Aurora, CO, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Weisfeld-Adams
authors.affiliation: Institute of Inherited Metabolic Disorders, Charles University-First Faculty of Medicine and General University Hospital, Prague, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Kožich
authors.affiliation: Laboratory of Clinical Biochemistry and Metabolism, Center for Pediatrics and Adolescent Medicine University Hospital, Freiburg, Freiburg, Germany.
authors.forename: Henk
authors.initials: H
authors.lastname: Blom
authors.affiliation: Division of Metabolism and Children's Research Center, University Childrens' Hospital Zürich, Zurich, Switzerland. matthias.baumgartner@kispi.uzh.ch.|radiz - Rare Disease Initiative Zürich, Clinical Research Priority Program, University of Zürich, Zurich, Switzerland. matthias.baumgartner@kispi.uzh.ch.
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
authors.affiliation: Division of Metabolism, Bambino Gesù Children's Research Hospital, Rome, Italy. carlo.dionisivici@opbg.net.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
mesh_terms: D000818:Animals; D006710:Homocysteine / Q000235:genetics; D006801:Humans; D008715:Methionine / Q000235:genetics; D008745:Methylation / Q000187:drug effects*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency*; D050721:Proto-Oncogene Proteins c-cbl / Q000172:deficiency*; D014805:Vitamin B 12 / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D006710:Homocysteine; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D050721:Proto-Oncogene Proteins c-cbl; D014805:Vitamin B 12