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Journal of Inherited Metabolic Disease

, Volume 38, Issue 5, pp 863–872 | Cite as

Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment

  • P. Burda
  • A. Kuster
  • O. Hjalmarson
  • T. Suormala
  • C. Bürer
  • S. Lutz
  • G. Roussey
  • L. Christa
  • J. Asin-Cayuela
  • G. Kollberg
  • B. A. Andersson
  • D. Watkins
  • D. S. Rosenblatt
  • B. Fowler
  • E. HolmeEmail author
  • D. S. Froese
  • M. R. BaumgartnerEmail author
Original Article

Abstract

In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590–2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [14C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.

Keywords

Hemolytic Uremic Syndrome Folinic Acid Cobalamin Hyperhomocysteinemia Megaloblastic Anaemia 
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

This work was supported by the Swiss National Science Foundation [grant number 31003A_138521 to M.R.B. and B.F.] and the Rare Disease Initiative Zurich (radiz), a clinical research priority program for rare diseases of the University of Zurich, Switzerland.

Compliance with Ethics Guidelines

Conflict of interest

None.

Human and animal rights and informed consent

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

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Copyright information

© SSIEM 2015

Authors and Affiliations

  • P. Burda
    • 1
  • A. Kuster
    • 2
  • O. Hjalmarson
    • 3
  • T. Suormala
    • 1
  • C. Bürer
    • 1
  • S. Lutz
    • 1
  • G. Roussey
    • 2
  • L. Christa
    • 4
  • J. Asin-Cayuela
    • 5
  • G. Kollberg
    • 5
  • B. A. Andersson
    • 6
  • D. Watkins
    • 7
  • D. S. Rosenblatt
    • 7
  • B. Fowler
    • 1
  • E. Holme
    • 5
    Email author
  • D. S. Froese
    • 1
    • 8
  • M. R. Baumgartner
    • 1
    • 8
    • 9
    Email author
  1. 1.Division of Metabolism and Children’s Research CenterUniversity Children’s HospitalZurichSwitzerland
  2. 2.Department of Pediatric NephrologyUniversity Hospital of NantesNantesFrance
  3. 3.Department of PediatricsUniversity of GothenburgGothenburgSweden
  4. 4.Metabolic Biochemistry Department, Necker Hospital, AP-HPUniversity Paris DescartesParisFrance
  5. 5.Department of Clinical ChemistrySahlgrenska University HospitalGothenburgSweden
  6. 6.Department of Clinical Immunology and Transfusion MedicineSahlgrenska University HospitalGothenburgSweden
  7. 7.Department of Human GeneticsMcGill UniversityMontrealCanada
  8. 8.Radiz – Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare DiseasesUniversity of ZurichZurichSwitzerland
  9. 9.Zurich Center for Integrative Human PhysiologyUniversity of ZurichZurichSwitzerland

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