title: Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency.
abstract: Over a four-year period, we collected clinical and biochemical data from five Amish children who were homozygous for missense mutations in 5,10-methylenetetrahydrofolate reductase (MTHFR c.1129C>T). The four oldest patients had irreversible brain damage prior to diagnosis. The youngest child, diagnosed and started on betaine therapy as a newborn, is healthy at her present age of three years. We compared biochemical data among four groups: 16 control subjects, eight heterozygous parents, and five affected children (for the latter group, both before and during treatment with betaine anhydrous). Plasma amino acid concentrations were used to estimate changes in cerebral methionine uptake resulting from betaine therapy. In all affected children, treatment with betaine (534+/-222 mg/kg/day) increased plasma S-adenosylmethionine, improved markers of tissue methyltransferase activity, and resulted in a threefold increase of calculated brain methionine uptake. Betaine therapy did not normalize plasma total homocysteine, nor did it correct cerebral 5-methyltetrahydrofolate deficiency. We conclude that when the 5-methyltetrahydrofolate content of brain tissue is low, dietary betaine sufficient to increase brain methionine uptake may compensate for impaired cerebral methionine recycling. To effectively support the metabolic requirements of rapid brain growth, a large dose of betaine should be started early in life.
authors.affiliation: Clinic for Special Children, Strasburg, PA 17579, USA. kstrauss@clinicforspecialchildren.org
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strauss
authors.forename: D Holmes
authors.initials: DH
authors.lastname: Morton
authors.forename: Erik G
authors.initials: EG
authors.lastname: Puffenberger
authors.forename: Christine
authors.initials: C
authors.lastname: Hendrickson
authors.forename: Donna L
authors.initials: DL
authors.lastname: Robinson
authors.forename: Conrad
authors.initials: C
authors.lastname: Wagner
authors.forename: Sally P
authors.initials: SP
authors.lastname: Stabler
authors.forename: Robert H
authors.initials: RH
authors.lastname: Allen
authors.forename: Grazyna
authors.initials: G
authors.lastname: Chwatko
authors.forename: Hieronim
authors.initials: H
authors.lastname: Jakubowski
authors.forename: Mihai D
authors.initials: MD
authors.lastname: Niculescu
authors.forename: S Harvey
authors.initials: SH
authors.lastname: Mudd
mesh_terms: D000293:Adolescent; D000328:Adult; D001622:Betaine / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D001927:Brain Diseases / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000517:prevention & control*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007231:Infant, Newborn; D008715:Methionine / Q000134:cerebrospinal fluid / Q000378:metabolism; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency* / Q000235:genetics; D008780:Methyltransferases / Q000378:metabolism; D020125:Mutation, Missense; D015997:Neonatal Screening; D012436:S-Adenosylmethionine / Q000097:blood / Q000134:cerebrospinal fluid
chemical_list: D001622:Betaine; D012436:S-Adenosylmethionine; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008780:Methyltransferases