{ "abstract": "This guideline summarizes diagnostic and therapeutic approaches based on a systematic literature review and evidence evaluation using the GRADE methodology. Given the limited high-quality data, expert consensus was additionally obtained through a modified Delphi process. Remethylation disorders are rare inherited conditions that disrupt the methionine-homocysteine cycle and consecutively impair essential methylation dependent metabolic pathways. Remethylation disorders are caused by defects in the cobalamin or folate metabolism. The disorders typically result in elevated homocysteine and often low methionine; combined cobalamin-related defects also affect mitochondrial methylmalonic acid clearance. The cblC-MMACHC defect is the most common cobalamin-related remethylation disorder. Early-onset patients usually present with severe neurological and eye symptoms. Late-onset cases show variable symptoms (e.g., psychiatric, renal, thromboembolic events). Plasma total homocysteine, methionine, methylmalonic acid, serum vitamin B12 (and folates) should be assessed in suspected cases. Early detection through newborn screening is associated with improved clinical outcomes. Betaine as first-line therapy for methylenetetrahydrofolate reductase deficiency and parenteral hydroxocobalamin for cobalamin-related defects have reduced mortality and morbidity. Total homocysteine, methionine (and methylmalonic acid) should be kept as close to normal values as achievable. Emerging evidence suggests that early use of high-dose hydroxocobalamin (> 0.35 mg/kg/day) may improve neurocognitive impairment and may ameliorate eye disease in severe cobalamin-related defects. A major limitation in current practice is the lack of availability of high concentration hydroxocobalamin formulations for parenteral administration.", "abstract_shown": true, "affiliations": [ "Division of Metabolic Diseases and Hepatology Bambino Gesù Children's Hospital IRCCS Rome Italy", "Metabolic and Syndromic Diseases Unit, Regional Coordinating Centre for Rare Diseases. Azienda Ospedaliera Friuli Centrale ASUFC Udine Italy", "Department of Human and Medical Genetics Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University Vilnius Lithuania", "Associazione Italiana Acidemia Metilmalonica con Omocistinuria; cblC APS Rome Italy", "Neonatology, Clinical University Hospital of Santiago de Compostela, CIBERER, Health Research Institute of Santiago de Compostela (IDIS), RICORS, MetabERN: European Reference Network for Rare Hereditary Metabolic Disorders Santiago de Compostela Spain", "Centro de Referência de Doenças Hereditárias do Metabolismo do Centro Hospitalar Universitário de Coimbra, CR‐DHM (CHUC), Praceta Professor Mota Pinto Coimbra Portugal", "Department of Paediatrics Hôpital d'Enfants Brabois, CHU Nancy Vandoeuvre les Nancy France", "INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE) Nancy France", "Reference Center for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy Nancy France", "Division of Metabolism and Children's Research Center University Children's Hospital Zurich, University of Zurich Zurich Switzerland", "Psychology Unit, Bambino Gesù Children's Hospital IRCCS Rome Italy", "Department of Hepato‐Gastroenterology Reference Center of Inborn Errors of Metabolism, University Regional Hospital of Nancy Nancy France", "CIBSS‐Centre for Integrative Biological Signalling Studies, University of Freiburg Freiburg Germany", "Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg Freiburg Germany", "Division of Pediatric Neurology and Metabolic Medicine, Department of Pediatrics Medical Faculty of Heidelberg, Heidelberg University Heidelberg Germany", "Department of Pediatrics and Inherited Metabolic Disorders Charles University‐First Faculty of Medicine and General University Hospital in Prague Prague Czech Republic", "Department of Experimental and Clinical Biomedical Sciences University of Florence Florence Italy", "Newborn Screening, Clinical Chemistry and Clinical Pharmacy, Meyer Children's Hospital IRCCS Florence Italy", "Metabolic Medicine Branch, National Human Genome Research Institute, National Institutes of Health Bethesda Maryland USA", "APHP, Department of Genetics Hôpital Pitié la Salpétrière University Hospital, DMU BioGeM Paris France", "Sorbonne Université, Institut du Cerveau ‐ Paris Brain Institute ‐ ICM, Inserm, CNRS Paris France", "Ophthalmology Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS Rome Italy", "Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular‐SO UAM‐CSIC, Universidad Autónoma de Madrid Madrid Spain", "Instituto de Investigación Sanitaria IdiPAZ Madrid Spain", "U746 ‐ CIBER de Enfermedades Raras (CIBERER) Madrid Spain", "Paediatrics Department Reference Center for Inborn Errors of Metabolism, Necker University, AP‐HP, Université Paris Cité, Institut Imagine, Filière G2m Paris France", "Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester and Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester Manchester UK", "Genetics Department Federal University of Rio Grande do Sul (UFRGS), Medical Genetics Service‐Clinic Hospital of Porto Alegre Porto Alegre Brazil", "Adult Inherited Metabolic Disorders Department Salford Care Organization, Northern Care Alliance NHS Foundation Trust Salford UK", "Department of Inborn Errors of Metabolism and Pediatrics Institute of Mother and Child Warsaw Poland", "European Reference Network for Hereditary Metabolic Disorders Oslo Norway", "Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital Oslo Norway", "Centre for Inherited Metabolic Diseases, Karolinska University Hospital Stockholm Sweden", "Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden", "Competence Area Healthcare and Nursing, Vorarlberg University of Applied Sciences Dornbirn Austria", "Department of Paediatrics LKH Bregenz Bregenz Austria" ], "article_type": null, "arxiv": null, "author_total": 27, "authors": [ { "affs": [ 0 ], "name": "Giorgia Olivieri" }, { "affs": [ 1 ], "name": "Andrea Bordugo", "orcid": "0000-0003-1927-8187" }, { "affs": [ 2 ], "name": "Birutė Burnytė", "orcid": "0000-0002-5845-1045" }, { "affs": [ 3 ], "name": "Alessandro Costetti" }, { "affs": [ 4 ], "name": "María-Luz Couce", "orcid": "0000-0003-4861-9905" }, { "affs": [ 5 ], "name": "Luisa Diogo" }, { "affs": [ 6, 7, 8 ], "name": "François Feillet", "orcid": "0000-0002-8717-469X" }, { "affs": [ 9 ], "name": "D. Sean Froese", "orcid": "0000-0003-1557-3517" }, { "affs": [ 10 ], "name": "Benedetta Greco", "orcid": "0000-0002-8598-2618" }, { "affs": [ 11, 7, 8 ], "name": "Jean‐Louis Guéant", "orcid": "0000-0002-5067-042X" }, { "affs": [ 12, 13 ], "name": "Luciana Hannibal", "orcid": "0000-0002-0911-5758" }, { "affs": [ 14 ], "name": "Friederike Hörster", "orcid": "0000-0002-3859-4161" }, { "affs": [ 15 ], "name": "Viktor Kožich", "orcid": "0000-0001-5820-5277" }, { "affs": [ 16, 17 ], "name": "Giancarlo la Marca", "orcid": "0000-0003-3319-7260" }, { "affs": [ 18 ], "name": "Irini Manoli", "orcid": "0000-0003-1543-2941" }, { "affs": [ 19, 20 ], "name": "Fanny Mochel", "orcid": "0000-0003-3970-3486" }, { "affs": [ 21 ], "name": "Lorenzo Orazi" }, { "affs": [ 22, 23, 24 ], "name": "Belén Pérez", "orcid": "0000-0002-3190-1958" }, { "affs": [ 25 ], "name": "Manuel Schiff", "orcid": "0000-0001-8272-232X" }, { "affs": [ 26 ], "name": "Bernd Schwahn", "orcid": "0000-0003-0961-2508" }, { "affs": [ 27 ], "name": "Ida Schwartz", "orcid": "0000-0002-7933-6687" }, { "affs": [ 28 ], "name": "Karolina M. Stępień", "orcid": "0000-0003-0148-6332" }, { "affs": [ 29 ], "name": "Jolanta Sykut‐Cegielska", "orcid": "0000-0003-0762-3721" }, { "affs": [ 30, 31 ], "name": "Trine Tangeraas", "orcid": "0000-0003-3137-2117" }, { "affs": [ 32, 33 ], "name": "Rolf H Zetterström", "orcid": "0000-0002-3016-0019" }, { "affs": [ 0 ], "name": "Carlo Dionisi‐Vici", "orcid": "0000-0002-0007-3379" }, { "affs": [ 34, 35, 9 ], "name": "Martina Huemer", "orcid": "0000-0002-0590-678X" } ], "bibtex": "https://research.draconitic.com/paper/aqzw0ax1ffvx0.bib", "cited_by": 9, "doi": "10.1002/jimd.70177", "fulltext_url": null, "id": "aqzw0ax1ffvx0", "issns": [ "0141-8955", "1573-2665" ], "landing_url": "https://doi.org/10.1002/jimd.70177", "language": "en", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1308|Metabolism and Genetic Disorders" ] ], "openalex": "W7163429690", "pdf_url": "https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/jimd.70177", "pmcid": null, "pmid": "42231716", "published": "2026-06-03", "publisher": "Springer Science+Business Media", "ris": "https://research.draconitic.com/paper/aqzw0ax1ffvx0.ris", "sources": [ { "first_seen": "2026-10-30T13:26:48Z", "native_id": "W7163429690", "source": "openalex", "url": "https://doi.org/10.1002/jimd.70177" } ], "subjects": [ { "field": "medicine", "origin": "openalex:1308|Metabolism and Genetic Disorders", "subfield": "general" } ], "title": "First Revision of the Guidelines for the Diagnosis and Management of Remethylation Disorders", "title_text": "First Revision of the Guidelines for the Diagnosis and Management of Remethylation Disorders", "type": "peer-reviewed", "updated_at": "2026-11-09T13:21:07Z", "url": "https://research.draconitic.com/paper/aqzw0ax1ffvx0", "venue": "Journal of Inherited Metabolic Disease", "versions": [] }