Journal of Inherited Metabolic Disease

, Volume 31, Issue 3, pp 403–411 | Cite as

Mefolinate (5-methyltetrahydrofolate), but not folic acid, decreases mortality in an animal model of severe methylenetetrahydrofolate reductase deficiency

  • D. Li
  • N. Karp
  • Q. Wu
  • X-L. Wang
  • S. Melnyk
  • S. J. James
  • R. Rozen
Original Article

Summary

Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) results in homocystinuria, with a variety of neurological and vascular complications, and sometimes death in the first year of life. MTHFR (EC 1.5.1.20) catalyses the synthesis of 5-methyltetrahydrofolate (5-methylTHF) which is required for homocysteine remethylation to methionine. Mthfr−/− mice are a good animal model of severe MTHFR deficiency in humans. They have marked hyperhomocysteinaemia and a high rate of mortality in the neonatal period. We attempted to rescue Mthfr−/− mice from postnatal death by treating their Mthfr+/− mothers with mefolinate (a synthetic form of 5-methylTHF, dissolved in their drinking water) or with a folic acid-enriched diet throughout pregnancy and lactation. We monitored pups’ vitality and body weights until 3 weeks of age. The majority of Mthfr−/− pups from the control groups died during the first week of life. Body weights of −/− pups from control groups were significantly less than those of their Mthfr+/− and Mthfr+/+ littermates. Mefolinate treatment significantly improved survival rates (64% survival) in the −/− pups and improved morphology of the cerebellum. Folic acid supplementation did not affect the survival rate or body weights of the −/− pups. Our study suggests that MTHFR is important for postnatal growth and vitality, and that 5-methylTHF deficiency contributes to the high postnatal mortality. Mefolinate may be a good candidate drug for treatment of severe MTHFR deficiency.

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Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • D. Li
    • 1
  • N. Karp
    • 1
  • Q. Wu
    • 1
  • X-L. Wang
    • 1
  • S. Melnyk
    • 2
  • S. J. James
    • 2
  • R. Rozen
    • 1
    • 3
  1. 1.Departments of Human Genetics, Pediatrics and BiologyMcGill University-Montreal Children’s Hospital Research InstituteMontrealCanada
  2. 2.Department of PediatricsUniversity of Arkansas for Medical Sciences, Arkansas Children’s Hospital Research InstituteLittle RockUSA
  3. 3.Montreal Children’s Hospital Research InstituteMontrealCanada

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