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Journal of Inherited Metabolic Disease

, Volume 39, Issue 1, pp 115–124 | Cite as

Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency

  • Martina Huemer
  • Regina Mulder-Bleile
  • Patricie Burda
  • D. Sean Froese
  • Terttu Suormala
  • Bruria Ben Zeev
  • Patrick F. Chinnery
  • Carlo Dionisi-Vici
  • Dries Dobbelaere
  • Gülden Gökcay
  • Mübeccel Demirkol
  • Johannes Häberle
  • Alexander Lossos
  • Eugen Mengel
  • Andrew A. Morris
  • Klary E. Niezen-Koning
  • Barbara Plecko
  • Rossella Parini
  • Dariusz Rokicki
  • Manuel Schiff
  • Mareike Schimmel
  • Adrian C. Sewell
  • Wolfgang Sperl
  • Ute Spiekerkoetter
  • Beat Steinmann
  • Grazia Taddeucci
  • Jose M. Trejo-Gabriel-Galán
  • Friedrich Trefz
  • Megumi Tsuji
  • María Antònia Vilaseca
  • Jürgen-Christoph von Kleist-Retzow
  • Valerie Walker
  • Jiri Zeman
  • Matthias R. BaumgartnerEmail author
  • Brian FowlerEmail author
Original Article

Abstract

Background

Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients.

Methods

Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts.

Results

Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5 %) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7–34.8 %) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious.

Discussion

MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.

Keywords

Betaine Folinic Acid Microcephaly Residual Enzyme Activity Muscular Hypotonia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We are indebted to the patients and their families who participated in this study.

Compliance with Ethics Guidelines

Conflict of interest

None.

Human rights and informed concent

All procedures followed were in accordance with the ethical standards of the responsible local committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained by the reporting physicians from their patients for being included in the study.

Supplementary material

10545_2015_9860_MOESM1_ESM.doc (66 kb)
ESM 1 (DOC 65 kb)

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Copyright information

© SSIEM 2015

Authors and Affiliations

  • Martina Huemer
    • 1
    • 2
    • 3
  • Regina Mulder-Bleile
    • 4
  • Patricie Burda
    • 1
  • D. Sean Froese
    • 1
  • Terttu Suormala
    • 1
  • Bruria Ben Zeev
    • 5
  • Patrick F. Chinnery
    • 6
  • Carlo Dionisi-Vici
    • 7
  • Dries Dobbelaere
    • 8
  • Gülden Gökcay
    • 9
  • Mübeccel Demirkol
    • 9
  • Johannes Häberle
    • 1
  • Alexander Lossos
    • 10
  • Eugen Mengel
    • 10
  • Andrew A. Morris
    • 11
  • Klary E. Niezen-Koning
    • 12
  • Barbara Plecko
    • 2
    • 13
  • Rossella Parini
    • 14
  • Dariusz Rokicki
    • 15
  • Manuel Schiff
    • 16
  • Mareike Schimmel
    • 17
  • Adrian C. Sewell
    • 18
    • 19
  • Wolfgang Sperl
    • 20
  • Ute Spiekerkoetter
    • 21
  • Beat Steinmann
    • 1
  • Grazia Taddeucci
    • 22
  • Jose M. Trejo-Gabriel-Galán
    • 23
  • Friedrich Trefz
    • 24
  • Megumi Tsuji
    • 25
  • María Antònia Vilaseca
    • 26
  • Jürgen-Christoph von Kleist-Retzow
    • 27
  • Valerie Walker
    • 28
  • Jiri Zeman
    • 29
  • Matthias R. Baumgartner
    • 1
    • 2
    Email author
  • Brian Fowler
    • 1
    • 4
    Email author
  1. 1.Division of Metabolism and Children’s Research CenterUniversity Childrens’ Hospital ZürichZürichSwitzerland
  2. 2.radiz – Rare Disease Initiative Zürich, Clinical Research Priority ProgramUniversity of ZürichZürichSwitzerland
  3. 3.Department of PaediatricsLandeskrankenhaus BregenzBregenzAustria
  4. 4.University Childrens’ Hospital Basel (UKBB)BaselSwitzerland
  5. 5.Edmond and Lilly Safra Pediatric HospitalSheba Med Center and Sackler School of Medicine Tel AvivTel AvivIsrael
  6. 6.Institute of Genetic MedicineNewcastle UniversityNewcastle upon TyneUK
  7. 7.Division of MetabolismBambino Gesù Children’s Hospital, IRCCSRomeItaly
  8. 8.Centre de Référence Maladies Héréditaires du Métabolisme de l’enfant et de l’adulteHôpital Jeanne de FlandreLilleFrance
  9. 9.Istanbul Medical Faculty, Children’s Hospital, Pediatric Nutrition and MetabolismIstanbul UniversityIstanbulTurkey
  10. 10.Villa metabolica, Center for Pediatric and Adolescent MedicineMC Johannes-Gutenberg-University MainzMainzGermany
  11. 11.Willink Unit, Manchester Centre for Genomic MedicineCentral Manchester University HospitalsManchesterUK
  12. 12.Laboratory Metabolic DiseasesUniversity Medical Center GroningenGroningenThe Netherlands
  13. 13.Division of Child Neurology and Children’s Research CenterUniversity Children’s Hospital ZürichZürichSwitzerland
  14. 14.Unit for rare metabolic diseases, Department of PediatricsFondazione MBBM/San Gerardo HospitalMonzaItaly
  15. 15.Department of Pediatrics, Nutrition and Metabolic DiseasesThe Children’s Memorial Health InstituteWarsawPoland
  16. 16.Reference Center for Inborn Errors of MetabolismHôpital Robert Debré, APHP, INSERM U1141 and Université Paris-Diderot, Sorbonne Paris CitéParisFrance
  17. 17.Children’s Hospital AugsburgAugsburgGermany
  18. 18.Department of PaediatricsUniversity Children’s HospitalFrankfurt am MainGermany
  19. 19.Bioscientia Institute for Laboratory DiagnosticsIngelheimGermany
  20. 20.Department of PediatricsParacelsus Medical University (PMU)SalzburgAustria
  21. 21.Department of General Pediatrics and Adolescent MedicineUniversity Children’s HospitalFreiburgGermany
  22. 22.Department of Pediatrics, Section of Paediatric NeurologyUniversity of PisaPisaItaly
  23. 23.Neurology DepartmentHospital Universitario de BurgosBurgosSpain
  24. 24.Department of PediatricsUniversity of HeidelbergHeidelbergGermany
  25. 25.Department of NeuroscienceJikei University School of MedicineTokyoJapan
  26. 26.Laboratori de Malalties Metabòliques HereditàriasHospital Sant Joan de DéuBarcelonaSpain
  27. 27.Department of PaediatricsUniversity of CologneCologneGermany
  28. 28.University Hospital Southampton NHS Foundation TrustSouthamptonUK
  29. 29.Department of Paediatrics, First Faculty of MedicineCharles University in PraguePragueCzech Republic

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