title: Mefolinate (5-methyltetrahydrofolate), but not folic acid, decreases mortality in an animal model of severe methylenetetrahydrofolate reductase deficiency.
abstract: 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.
authors.affiliation: Departments of Human Genetics, Pediatrics and Biology, McGill University-Montreal Children's Hospital Research Institute, Montreal, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.forename: N
authors.initials: N
authors.lastname: Karp
authors.forename: Q
authors.initials: Q
authors.lastname: Wu
authors.forename: X-L
authors.initials: XL
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Melnyk
authors.forename: S J
authors.initials: SJ
authors.lastname: James
authors.forename: R
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use*; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D015996:Survival Rate; D013763:Tetrahydrofolates / Q000627:therapeutic use*
chemical_list: D013763:Tetrahydrofolates; D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C005984:5-methyltetrahydrofolate