Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency q Kevin A. Strauss a, * , D. Holmes Morton a , Erik G. Puffenberger a , Christine Hendrickson a , Donna L. Robinson a , Conrad Wagner b , Sally P. Stabler c , Robert H. Allen c , Grazyna Chwatko d , Hieronim Jakubowski d,e , Mihai D. Niculescu f , S. Harvey Mudd g a Clinic for Special Children, Strasburg, PA 17579, USA b Department of Biochemistry, Vanderbilt University and Department of Veteran’s Affairs Medical Center, Nashville, TN, USA c Division of Hematology, University of Colorado Health Sciences Center, Denver, CO, USA d Department of Microbiology and Molecular Genetics, UMDNJ, New Jersey Medical School, International Center for Public Health, Newark, NJ, USA e Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61074 Poznan, Poland f Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA g Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD, USA Received 12 January 2007; received in revised form 16 February 2007; accepted 16 February 2007 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-meth- yltetrahydrofolate deficiency. We conclude that when the 5-methyltetrahydrofolate content of brain tissue is low, dietary betaine suffi- cient 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. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Amish; Betaine; Blood–brain barrier; Homocysteine; Methionine; 5,10-Methylenetetrahydrofolate reductase; Newborn screening; S-Adenosylmethionine Introduction 5-Methyltetrahydrofolate (5MTHF) is used to recycle homocysteine back to methionine in human tissues [1]. Methionine recycling by the brain is absolutely dependent on 5MTHF [2], whereas liver and kidney can recycle homocysteine to methionine by an alternate route, using betaine as the methyl donor for betaine-homocysteine-S- methyltransferase (BHMT) [3]. The transmethylation cycle produces S-adenosylmethionine, the methyl donor for a large group of methyltransferase enzymes. Collectively, methyltransferases catalyze an array of reactions necessary for brain development, including DNA modification, phospholipid synthesis, polyamine formation, and myelin assembly [4]. Homozygous loss-of-function mutations in 5,10-methylenetetrahydrofolate reductase (MTHFR) result 1096-7192/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2007.02.012 q There are no conflicts of interest to declare. * Corresponding author. Fax: +1 717 687 9237. E-mail address: kstrauss@clinicforspecialchildren.org (K.A. Strauss). www.elsevier.com/locate/ymgme Molecular Genetics and Metabolism xxx (2007) xxx–xxx ARTICLE IN PRESS Please cite this article in press as: K.A. Strauss et al., Prevention of brain disease from severe ..., Mol. Genet. Metab. (2007), doi:10.1016/j.ymgme.2007.02.012