Original Article

Journal of Inherited Metabolic Disease

, Volume 31, Issue 3, pp 403-411

First online:

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

  • D. LiAffiliated withDepartments of Human Genetics, Pediatrics and Biology, McGill University-Montreal Children’s Hospital Research Institute
  • , N. KarpAffiliated withDepartments of Human Genetics, Pediatrics and Biology, McGill University-Montreal Children’s Hospital Research Institute
  • , Q. WuAffiliated withDepartments of Human Genetics, Pediatrics and Biology, McGill University-Montreal Children’s Hospital Research Institute
  • , X-L. WangAffiliated withDepartments of Human Genetics, Pediatrics and Biology, McGill University-Montreal Children’s Hospital Research Institute
  • , S. MelnykAffiliated withDepartment of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital Research Institute
  • , S. J. JamesAffiliated withDepartment of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital Research Institute
  • , R. RozenAffiliated withDepartments of Human Genetics, Pediatrics and Biology, McGill University-Montreal Children’s Hospital Research InstituteMontreal Children’s Hospital Research Institute Email author 

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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.