Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry

EHOD consortium

Research output: Contribution to journalArticle

Abstract

AIM: 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.

RESULTS: 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 (MMA) 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.

CONCLUSION: 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.

Original languageEnglish
Pages (from-to)333-352
Number of pages20
JournalJournal of Inherited Metabolic Disease
Volume42
Issue number2
DOIs
Publication statusPublished - Mar 2019

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Vitamin B 12
Registries
Phenotype
Eye Diseases
Therapeutics
Methylmalonic Acid
Homocystinuria
Morbidity
Failure to Thrive
Homocysteine
Rare Diseases
Methylation
Psychiatry
Molecular Biology
Observation
Kidney
Amino Acids
Mortality

Cite this

@article{e57754ea288945dba98c38fe42b03dc7,
title = "Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry",
abstract = "AIM: 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.RESULTS: 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 (MMA) 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.CONCLUSION: 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.",
author = "{EHOD consortium} and Martina Huemer and Daria Diodato and Diego Martinelli and Giorgia Olivieri and Henk Blom and Florian Gleich and Stefan K{\"o}lker and Viktor Kožich and Morris, {Andrew A} and Burkhardt Seifert and Froese, {D Sean} and Baumgartner, {Matthias R} and Carlo Dionisi-Vici and Martin, {Carlos Alcalde} and Martina Baethmann and Diana Ballhausen and Javier Blasco-Alonso and Nikolas Boy and Maria Bueno and {Burgos Pel{\'a}ez}, Rosa and Roberto Cerone and Brigitte Chabrol and Chapman, {Kimberly A} and Couce, {Maria Luz} and Ellen Crushell and {Dalmau Serra}, Jaime and Luisa Diogo and Can Ficicioglu and {Garc{\'i}a Jimenez}, {Maria Concepcion} and {Garc{\'i}a Silva}, {Maria Teresa} and Gaspar, {Ana Maria} and Matthias Gautschi and Domingo Gonz{\'a}lez-Lamu{\~n}o and Sofia Gouveia and Stephanie Gr{\"u}newald and Chris Hendriksz and Janssen, {Mirian C H} and Pavel Jesina and Johannes Koch and Vassiliki Konstantopoulou and Christian Lavigne and Lund, {Allan M} and Martins, {Esmeralda G} and {Meavilla Olivas}, Silvia and Karine Mention and Fanny Mochel and Helen Mundy and Elaine Murphy and Stephanie Paquay and Consuelo Pedr{\'o}n-Giner",
note = "{\circledC} 2018 SSIEM.",
year = "2019",
month = "3",
doi = "10.1002/jimd.12041",
language = "English",
volume = "42",
pages = "333--352",
journal = "Journal of Inherited Metabolic Disease",
issn = "0141-8955",
publisher = "Springer Netherlands",
number = "2",

}

TY - JOUR

T1 - Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency

T2 - Data from the E-HOD registry

AU - EHOD consortium

AU - Huemer, Martina

AU - Diodato, Daria

AU - Martinelli, Diego

AU - Olivieri, Giorgia

AU - Blom, Henk

AU - Gleich, Florian

AU - Kölker, Stefan

AU - Kožich, Viktor

AU - Morris, Andrew A

AU - Seifert, Burkhardt

AU - Froese, D Sean

AU - Baumgartner, Matthias R

AU - Dionisi-Vici, Carlo

AU - Martin, Carlos Alcalde

AU - Baethmann, Martina

AU - Ballhausen, Diana

AU - Blasco-Alonso, Javier

AU - Boy, Nikolas

AU - Bueno, Maria

AU - Burgos Peláez, Rosa

AU - Cerone, Roberto

AU - Chabrol, Brigitte

AU - Chapman, Kimberly A

AU - Couce, Maria Luz

AU - Crushell, Ellen

AU - Dalmau Serra, Jaime

AU - Diogo, Luisa

AU - Ficicioglu, Can

AU - García Jimenez, Maria Concepcion

AU - García Silva, Maria Teresa

AU - Gaspar, Ana Maria

AU - Gautschi, Matthias

AU - González-Lamuño, Domingo

AU - Gouveia, Sofia

AU - Grünewald, Stephanie

AU - Hendriksz, Chris

AU - Janssen, Mirian C H

AU - Jesina, Pavel

AU - Koch, Johannes

AU - Konstantopoulou, Vassiliki

AU - Lavigne, Christian

AU - Lund, Allan M

AU - Martins, Esmeralda G

AU - Meavilla Olivas, Silvia

AU - Mention, Karine

AU - Mochel, Fanny

AU - Mundy, Helen

AU - Murphy, Elaine

AU - Paquay, Stephanie

AU - Pedrón-Giner, Consuelo

N1 - © 2018 SSIEM.

PY - 2019/3

Y1 - 2019/3

N2 - AIM: 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.RESULTS: 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 (MMA) 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.CONCLUSION: 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.

AB - AIM: 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.RESULTS: 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 (MMA) 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.CONCLUSION: 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.

U2 - 10.1002/jimd.12041

DO - 10.1002/jimd.12041

M3 - Article

C2 - 30773687

VL - 42

SP - 333

EP - 352

JO - Journal of Inherited Metabolic Disease

JF - Journal of Inherited Metabolic Disease

SN - 0141-8955

IS - 2

ER -