First Revision of the Guidelines for the Diagnosis and Management of Remethylation Disorders

@article{olivieri2026first,
  title = {{First Revision of the Guidelines for the Diagnosis and Management of Remethylation Disorders}},
  author = {Giorgia Olivieri and Andrea Bordugo and Birutė Burnytė and Alessandro Costetti and María-Luz Couce and Luisa Diogo and François Feillet and D. Sean Froese and Benedetta Greco and Jean‐Louis Guéant and Luciana Hannibal and Friederike Hörster and Viktor Kožich and Giancarlo la Marca and Irini Manoli and Fanny Mochel and Lorenzo Orazi and Belén Pérez and Manuel Schiff and Bernd Schwahn and Ida Schwartz and Karolina M. Stępień and Jolanta Sykut‐Cegielska and Trine Tangeraas and Rolf H Zetterström and Carlo Dionisi‐Vici and Martina Huemer},
  journal = {Journal of Inherited Metabolic Disease},
  year = {2026},
  month = jun,
  doi = {10.1002/jimd.70177},
  url = {https://doi.org/10.1002/jimd.70177},
  note = {CC BY},
}

TY  - JOUR
TI  - First Revision of the Guidelines for the Diagnosis and Management of Remethylation Disorders
AU  - Giorgia Olivieri
AU  - Andrea Bordugo
AU  - Birutė Burnytė
AU  - Alessandro Costetti
AU  - María-Luz Couce
AU  - Luisa Diogo
AU  - François Feillet
AU  - D. Sean Froese
AU  - Benedetta Greco
AU  - Jean‐Louis Guéant
AU  - Luciana Hannibal
AU  - Friederike Hörster
AU  - Viktor Kožich
AU  - Giancarlo la Marca
AU  - Irini Manoli
AU  - Fanny Mochel
AU  - Lorenzo Orazi
AU  - Belén Pérez
AU  - Manuel Schiff
AU  - Bernd Schwahn
AU  - Ida Schwartz
AU  - Karolina M. Stępień
AU  - Jolanta Sykut‐Cegielska
AU  - Trine Tangeraas
AU  - Rolf H Zetterström
AU  - Carlo Dionisi‐Vici
AU  - Martina Huemer
PY  - 2026
DA  - 2026/06/03
JO  - Journal of Inherited Metabolic Disease
DO  - 10.1002/jimd.70177
UR  - https://doi.org/10.1002/jimd.70177
AB  - 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.
SN  - 0141-8955
SN  - 1573-2665
ER  -