BACKGROUND: 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. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: 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.

Congenital Metabolic Diseases Unit Hospital Clínico Universitario de Santiago de Compostela IDIS CIBER Compostela Spain

Department of Experimental and Clinical Biomedical Sciences University of Florence Firence Italy

Department of Neurology Neurometabolism Unit and CIBERER Hospital Sant Joan de Deu Barcelona Spain

Division of Inherited Metabolic Diseases Department of Pediatrics University Hospital Padova Padova Italy

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

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

Division of Metabolism Bambino Gesù Children's Research Hospital Rome Italy

Institute of Inherited Metabolic Disorders Charles University 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Laboratory of Clinical Biochemistry and Metabolism Center for Pediatrics and Adolescent Medicine University Hospital Freiburg Freiburg Germany

Metabolic and Newborn Screening Clinical Unit Department of Neurosciences A Meyer Children's University Hospital Florence Italy

Metabolic Unit Centro Hospitalar do Porto Porto Portugal

Newborn Screening Metabolism and Genetics Unit National Institute of Health Porto Portugal

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

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

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

University Dept of Pediatrics Giannina Gaslini Institute Genoa Italy

Willink Biochemical Genetics Unit Saint Mary's Hospital Central Manchester University Hospitals NHS Foundation Trust Manchester Academic Health Science Centre Manchester M13 9WL UK

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$a Huemer, Martina $u 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.

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$a Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency / $c M. Huemer, D. Diodato, B. Schwahn, M. Schiff, A. Bandeira, JF. Benoist, A. Burlina, R. Cerone, ML. Couce, A. Garcia-Cazorla, G. la Marca, E. Pasquini, L. Vilarinho, JD. Weisfeld-Adams, V. Kožich, H. Blom, MR. Baumgartner, C. Dionisi-Vici,

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$a BACKGROUND: 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. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: 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.

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$a Burlina, Alberto $u Division of Inherited Metabolic Diseases, Department of Pediatrics, University Hospital Padova, Padova, Italy.

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