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

  • Martina HuemerEmail author
  • Daria Diodato
  • Diego Martinelli
  • Giorgia Olivieri
  • Henk Blom
  • Florian Gleich
  • Stefan Kölker
  • Viktor Kožich
  • Andrew A. Morris
  • Burkhardt Seifert
  • D. Sean Froese
  • Matthias R. Baumgartner
  • Carlo Dionisi-ViciEmail author
  • the EHOD consortium
  • C. Alcalde Martin
  • M. Baethmann
  • D. Ballhausen
  • J. Blasco-Alonso
  • N. Boy
  • M. Bueno
  • R. Burgos Peláez
  • R. Cerone
  • B. Chabrol
  • K. A. Chapman
  • M. L. Couce
  • E. Crushell
  • J. Dalmau Serra
  • L. Diogo
  • C. Ficicioglu
  • M. C. García Jimenez
  • M. T. García Silva
  • A. M. Gaspar
  • M. Gautschi
  • D. González-Lamuño
  • S. Gouveia
  • S. Grünewald
  • C. Hendriksz
  • M. C. H. Janssen
  • P. Jesina
  • J. Koch
  • V. Konstantopoulou
  • C. Lavigne
  • A. M. Lund
  • E. G. Martins
  • S. Meavilla Olivas
  • K. Mention
  • F. Mochel
  • H. Mundy
  • E. Murphy
  • S. Paquay
  • C. Pedrón-Giner
  • M. A. Ruiz Gómez
  • S. Santra
  • M. Schiff
  • I. V. Schwartz
  • S. Scholl-Bürgi
  • A. Servais
  • A. Skouma
  • C. Tran
  • I. Vives Piñera
  • J. Walter
  • J. Weisfeld-Adams
Original Article

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 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.

Notes

Acknowledgements

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.

Supplementary material

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Supplementary Table 1 (DOCX 28.2 kb)
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Supplementary Table 2 (DOCX 29.6 kb)
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Supplementary Table 3 (DOCX 28.9 kb)
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Supplementary Table 4 (DOCX 25.7 kb)
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Supplementary Table 5 (DOCX 19.3 kb)
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Supplementary Table 6 (DOCX 17.2 kb)
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Supplementary Figure 1 (DOCX 246 kb)

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Copyright information

© SSIEM 2018

Authors and Affiliations

  • Martina Huemer
    • 1
    • 2
    • 3
    Email author
  • Daria Diodato
    • 4
  • Diego Martinelli
    • 4
  • Giorgia Olivieri
    • 4
  • Henk Blom
    • 5
  • Florian Gleich
    • 6
  • Stefan Kölker
    • 6
  • Viktor Kožich
    • 7
  • Andrew A. Morris
    • 8
  • Burkhardt Seifert
    • 9
  • D. Sean Froese
    • 1
    • 2
  • Matthias R. Baumgartner
    • 1
    • 2
  • Carlo Dionisi-Vici
    • 4
    Email author
  • the EHOD consortium
  • C. Alcalde Martin
    • 10
  • M. Baethmann
    • 11
  • D. Ballhausen
    • 12
  • J. Blasco-Alonso
    • 13
  • N. Boy
    • 6
  • M. Bueno
    • 14
  • R. Burgos Peláez
    • 15
  • R. Cerone
    • 16
  • B. Chabrol
    • 17
  • K. A. Chapman
    • 18
  • M. L. Couce
    • 19
  • E. Crushell
    • 20
  • J. Dalmau Serra
    • 21
  • L. Diogo
    • 22
  • C. Ficicioglu
    • 23
  • M. C. García Jimenez
    • 24
  • M. T. García Silva
    • 25
  • A. M. Gaspar
    • 26
  • M. Gautschi
    • 27
  • D. González-Lamuño
    • 28
  • S. Gouveia
    • 19
  • S. Grünewald
    • 29
  • C. Hendriksz
    • 30
  • M. C. H. Janssen
    • 31
  • P. Jesina
    • 7
  • J. Koch
    • 32
  • V. Konstantopoulou
    • 33
  • C. Lavigne
    • 34
  • A. M. Lund
    • 35
  • E. G. Martins
    • 36
  • S. Meavilla Olivas
    • 37
  • K. Mention
    • 38
  • F. Mochel
    • 39
  • H. Mundy
    • 40
  • E. Murphy
    • 41
  • S. Paquay
    • 42
  • C. Pedrón-Giner
    • 43
  • M. A. Ruiz Gómez
    • 44
  • S. Santra
    • 45
  • M. Schiff
    • 46
  • I. V. Schwartz
    • 47
  • S. Scholl-Bürgi
    • 48
  • A. Servais
    • 49
  • A. Skouma
    • 50
  • C. Tran
    • 12
  • I. Vives Piñera
    • 51
  • J. Walter
    • 8
    • 52
  • J. Weisfeld-Adams
    • 53
  1. 1.Division of Metabolism and Children’s Research CenterUniversity Children’s HospitalZürichSwitzerland
  2. 2.radiz—Rare Disease Initiative ZürichUniversity ZürichZürichSwitzerland
  3. 3.Department of PediatricsLandeskrankenhaus BregenzBregenzAustria
  4. 4.Division of MetabolismBambino Gesù Children’s HospitalRomeItaly
  5. 5.Department of Internal MedicineVU Medical CenterAmsterdamNetherlands
  6. 6.Division of Child Neurology and Metabolic MedicineCentre for Child and Adolescent MedicineHeidelbergGermany
  7. 7.Department of Pediatrics and Adolescent MedicineCharles University—First Faculty of Medicine and General University HospitalPragueCzech Republic
  8. 8.Willink Metabolic Unit, Genomic MedicineManchester University Hospitals NHS Foundation TrustManchesterUK
  9. 9.Department of Biostatistics at Epidemiology, Biostatistics and Prevention InstituteUniversity ZürichZürichSwitzerland
  10. 10.Hospital Universitario Río HortegaValladolidSpain
  11. 11.Klinikum Dritter Orden München-NymphenburgMunichGermany
  12. 12.Center for Molecular DiseasesUniversity Hospital LausanneLausanneSwitzerland
  13. 13.Sección de Gastroenterología y Nutrición PediátricaHospital Regional de MálagaMálagaSpain
  14. 14.Hospital Universitario Virgen del RocíoSevillaSpain
  15. 15.Nutritional Support UnitUniversity Hospital Vall d’HebronBarcelonaSpain
  16. 16.University Department of PediatricsGiannina Gaslini InstituteGenoaItaly
  17. 17.Centre de Référence des Maladies Héréditaires du MétabolismeCHU La Timone EnfantsMarseilleFrance
  18. 18.Children’s National Rare Disease InstituteWashingtonUSA
  19. 19.Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Service of Neonatology, Department of PediatricsHospital Clínico Universitario de Santiago, CIBERER, Health Research Institute of Santiago de Compostela (IDIS)Santiago de CompostelaSpain
  20. 20.National Centre for Inherited Metabolic DisordersTemple Street Children’s University HospitalDublinIreland
  21. 21.Unidad de Nutrición y MetabolopatíasHospital Universitario La FeValenciaSpain
  22. 22.Centro Hospitalar e Universitário de Coimbra, MetaERNCoimbraPortugal
  23. 23.Division of Human Genetics, The Children’s Hospital of PhiladelphiaPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  24. 24.Hospital Infantil Miguel ServetZaragozaSpain
  25. 25.Universitary Hospital 12 OctubreMadridSpain
  26. 26.Centro Academico de Medicina de LisboaLisbonPortugal
  27. 27.Interdisciplinary Metabolic Team, Paediatric Endocrinology, Diabetology and MetabolismUniversity Children’s Hospital and University Institute of Clinical ChemistryBerneSwitzerland
  28. 28.Department of PediatricsUniversity Hospital Marqués de Valdecilla, Universidad de CantabriaSantanderSpain
  29. 29.Institute for Child HealthGreat Ormond Street Hospital, University College LondonLondonUK
  30. 30.Salford Royal NHS Foundation TrustSalfordUK
  31. 31.Department of Internal MedicineRadboud University Medical CenterNijmegenThe Netherlands
  32. 32.Department of PediatricsSalzburger Landeskliniken and Paracelsus Medical UniversitySalzburgAustria
  33. 33.Department of Pediatrics and Adolescent MedicineMedical University ViennaViennaAustria
  34. 34.Médecine Interne et Maladies VasculairesCentre Hospitalier Universitaire AngersAngersFrance
  35. 35.Centre Inherited Metabolic Diseases, Departments of Clinical Genetics and PaediatricsCopenhagen University Hospital, RigshospitaletCopenhagenDenmark
  36. 36.Reference Center for Inherited Metabolic DiseasesCentro Hospitalar do PortoPortoPortugal
  37. 37.Division of Gastroenterology, Hepatology and NutritionSant Joan de Déu HospitalBarcelonaSpain
  38. 38.Hôpital Jeanne de FlandreLilleFrance
  39. 39.Reference Center for Adult Neurometabolic DiseasesUniversity Pierre and Marie Curie, La Pitié-Salpêtrière University HospitalParisFrance
  40. 40.Evelina London Children’s HospitalLondonUK
  41. 41.Charles Dent Metabolic UnitNational Hospital for Neurology and NeurosurgeryLondonUK
  42. 42.Université Catholique de Louvain, Cliniques Universitaires Saint-LucBrusselsBelgium
  43. 43.Division of Gastroenterology and NutritionUniversity Children’s Hospital Niño JesúsMadridSpain
  44. 44.Metabolic Neuropediatric UnitUniversity Hospital Son EspasesPalma de MallorcaSpain
  45. 45.Birmingham Women’s and Children’s NHS Foundation TrustBirminghamUK
  46. 46.Reference Center for Inherited Metabolic Diseases, AP-HP, Robert Debré HospitalUniversity Paris Diderot-Sorbonne Paris Cité and INSERM U1141ParisFrance
  47. 47.Hospital de Clínicas de Porto Alegre and Department of GeneticsUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  48. 48.Clinic for Pediatrics I, Inherited Metabolic DisordersInnsbruckAustria
  49. 49.Nephrology Department, Reference Center of Inherited Metabolic Diseases, Necker hospital, AP-HPUniversity Paris DescartesParisFrance
  50. 50.Agia Sofia Children’s Hospital 1st Department of PediatricsUniversity of Athens Thivon & LevadiasAthensGreece
  51. 51.Hospital Universitario Virgen de la ArrixacaEl PalmarSpain
  52. 52.Bradford Royal InfirmaryBradfordUK
  53. 53.Inherited Metabolic Diseases Clinic, Section of Clinical Genetics and MetabolismUniversity of Colorado DenverAuroraUSA

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