Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: data from the E-HOD registry
To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry.
This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities.
Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.
This publication arises from the project E-HOD that has received funding from the European Union in the framework of the Health Programme. VK and PJ were supported by Institutional Research Programme RVO/VFN64165.
Compliance with ethical standards
The authors of this manuscript declare no competing interests but disclose the following: MR Baumgartner has received financial support for attending E-HOD steering committee meetings from Orphan Europe. MR Baumgartner and M Huemer have received support from Nutricia Metabolics for travel grants to develop patient education materials and a quality of life assessment tool for patients with intoxication type metabolic diseases. M Huemer has received consultancy honoraria from SOBI and Orphan Europe. Charles University—First Faculty of Medicine received support from the Recordati Rare Diseases Foundation for organising an educational course on homocystinurias and methylation defects. M Huemer, MR Baumgartner, C Dionisi-Vici, H Blom and AA Morris received speakers’ honoraria for their contribution to this educational course. AA Morris has received honoraria for speaking about homocystinuria from Recordati/Orphan Europe at other meetings and from Nutricia, has attended Advisory Board meetings for Nutricia and has received support from Vitaflo to attend SSIEM meetings. H Blom received a research grant on myopia and homocystinuria from Orphan Europe. J Weisfeld-Adams has attended Advisory Board meetings for Recordati Rare Diseases Foundation. C Dionisi-Vici has received research grants, speaker and consultancy honoraria from Nutricia, Medifood, SOBI and Dr. Schär Medical Nutrition. C Pedrón-Giner has received support from Vitaflo to attend SSIEM meetings. E Murphy has received unrestricted educational grant funding from Nutricia and clinical trial funding from Vitaflo UK. C Hendriksz is the owner of FYMCA Medical Ltd. and consults for companies, regulators and patient organisations.
This work was part of the European Network and Registry for Homocystinurias and Methylation Defects (EHOD) project (no. 2012_12_02), which has received funding from the European Union in the framework of the Health Programme. This article does not contain any studies with human or animal subjects performed by any of the authors.
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