Advertisement

Folate metabolism and chromosomal stability in the fragile X syndrome

      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Folate metabolism and the effects of folic acid on chromosome stability were studied in four related patients with the fragile X syndrome. In three adults, uptake and subsequent utilization of folate compounds for conversion of deoxyuridylate to thymidylate by marrow cells and stimulated lymphocytes, and the affinity and maximal transport velocity of erythrocyte membrane carriers, were normal. Numbers of sister chromatid exchanges and double-stranded DNA breaks were comparable in cells from patients and control subjects, but both were increased after incubation in folate-deficient media. In vitro expression of the fragile site was strikingly reduced by oral folate therapy. It is concluded that the folate-sensitlve chromosomal defect in this syndrome is limited to a specific site, Xq28, and there is no generalized tendency to frequent DNA breaks or recombination. Although expression was modified by folic acid treatment in the patients, no consistent abnormality of folate metabolism could be identified.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Turner G
        • Opitz JM
        X-linked mental retardation.
        Am J Med Genet. 1980; 7: 407-415
        • Lubs HA
        A marker X chromosome.
        Am J Hum Genet. 1969; 21: 231-244
        • Jacobs PA
        • Glover TW
        • Mayer M
        • et al.
        X-linked mental retardation: a study of 7 families.
        Am J Med Genet. 1980; 7: 471-489
        • Jennings M
        • Hall JG
        • Hoehn H
        Significance of phenotypic and chromosomal abnormalities in X-linked mental retardation (Martin-Bell or Renpenning syndrome).
        Am J Med Genet. 1980; 7: 417-432
        • Fishburn J
        • Turner G
        • Daniel A
        • Brookwell R
        The diagnosis and frequency of X-linked conditions in a cohort of moderately retarded males with affected brothers.
        Am J Med Genet. 1983; 14: 713-724
        • Sutherland GR
        Heritable fragile sites on human chromosomes I. Factors affecting expression in lymphocyte culture.
        Am J Hum Genet. 1979; 31: 125-135
        • Fonatsch C
        A simple method to demonstrate the fragile X chromosome in fibroblasts.
        Hum Genet. 1981; 59: 186
        • Shapiro LR
        • Wilmot PL
        • Brenholz P
        • et al.
        Prenatal diagnosis of fragile X chromosome.
        Lancet. 1982; I: 99-100
        • Glover TW
        FUdR induction of the X chromosome fragile site: evidence for the mechanism of folic acid and thymidine inhibition.
        Am J Hum Genet. 1981; 33: 234-242
        • Luhby AL
        • Cooperman JM
        Foiic acid deficiency in man and its interrelationship with vitamin B12 metabolism.
        Adv Metab Disord. 1964; 1: 263-334
        • Lejeune J
        Le metabolisme des monocarbones et la debilite de l'intelligence.
        in: Actas V Congr Latinoam Genet. 1982: 23-24
        • Lejeune J
        • Legrand N
        • Lafourcade J
        • Rethore M-O
        • Raoul O
        • Maunoury C
        Fragilite du chromosome X et effets de la trimethoprime.
        Ann Genet (Paris). 1982; 25: 149-151
        • Branda RF
        • Moldow CF
        • MacArthur JR
        • Wintrobe MM
        • Anthony BK
        • Jacob HS
        Folate-induced remission in aplastic anemia with familial defect of cellular folate uptake.
        N Engl J Med. 1978; 298: 469-475
        • Branda RF
        • Anthony BK
        • Jacob HS
        The mechanism of 5-methyltetrahydrofolate transport by human erythrocytes.
        J Clin Invest. 1978; 61: 1270-1275
        • Branda RF
        • Nelson NL
        Inhibition of 5-methyltetrahydrofolic acid transport by amphipathic drugs.
        Drug-Nutrient Interactions. 1981; 1: 45-53
        • Lineweaver H
        • Burk D
        The determination of enzyme dissociation constants.
        J Am Chem Soc. 1934; 56: 658-666
        • Perry P
        • Wolff S
        New Giemsa method for differential staining of sister chromatids.
        Nature. 1974; 261: 156-158
        • Woods WE
        Quantitation of the repair of gamma-radiation-induced double-strand DNA breaks in human fibroblasts.
        Biochem Biophys Acta. 1981; 655: 342-348
        • Bradley MO
        • Kohn KN
        X-ray induced DNA double strand break production and repair in mammalian cells as measured by neutral filter elution.
        Nucleic Acids Res. 1979; 7: 793-804
        • Hayman RJ
        • Van Der Weyden MB
        Phytohemagglutinin-stimulated normal human peripheral blood lymphocytes in fo late-depleted medium, an in vitro model for megaloblastic hemopoiesis.
        Blood. 1980; 55: 863-865
        • Heath CW
        Cytogenic observations in vitamin B12 and folate deficiency.
        Blood. 1966; 27: 800-815
        • Menzies RC
        • Crossen PE
        • Fitzgerald PH
        • Gunz FW
        Cytogenetic and cytochemical studies on marrow cells in B12 and folate deficiency.
        Blood. 1966; 28: 581-594
        • Knuutila S
        • Helminen E
        • Vuopio P
        • de la Chapelle A
        Increased sister chromatid exchange in megaloblastic anaemia—studies on bone marrow cells and lymphocytes.
        Hereditas. 1978; 89: 175-181
        • Arthur DC
        • Danzl TJ
        • Branda RF
        Cytogenetic studies of a family with a hereditary defect of cellular folate uptake and high incidence of hematologic disease.
        in: Butterworth CE Hutchinson ML Nutritional factors in the induction and maintenance of malignancy. Academic Press, New York1983: 102-111
        • Wichremasinghe RG
        • Hoffbrand AV
        Reduced rate of DNA replication fork movement in megaloblastic anemia.
        J Clin Invest. 1980; 65: 26-36
        • Chudley AE
        • Knoll J
        • Gerrrad JW
        • Shepel L
        • McGahey E
        • Anderson J
        Fragile (X) X-linked mental retardation 1: relationship between age and intelligence and the frequency of expression of fragile (X) (q28).
        Am J Med Genet. 1983; 14: 699-712
        • Wang JC
        • Erbe RW
        Folate metabolism in cells from fragile X syndrome patients and carriers.
        Am J Med Genet. 1984; 17: 303-310
        • Popovich BW
        • Rosenblatt DS
        • Cooper BA
        • Vekemans M
        Intracellular folate distribution in cultured fibroblasts from patients with the fragile X syndrome.
        Am J Hum Genet. 1983; 35: 869-878
        • Meiss M
        • Peyser DP
        • Miller A
        An enzymatic method for the assay of glutamic and formiminoglutamic acid.
        J Lab Clin Med. 1964; 64: 512-518
        • Howe RB
        • Branda RF
        • Douglas SD
        • Brunning RD
        Hereditary dyserythropoiesis with abnormal membrane folate transport.
        Blood. 1979; 54: 1080-1090
        • McBurney MW
        • Whitmore GF
        Isolation and biochemical characterization of folate deficient mutants of Chinese hamster cells.
        Cell. 1974; 2: 173-182
        • Erbe RW
        Inborn errors of folate metabolism.
        N Engl J Med. 1975; 293: 807-812
        • Laurence KM
        • James N
        • Miller MH
        • Tennant GB
        • Campbell H
        Double-blind randomized controlled trial of folate treatment before conception to prevent recurrence of neural tube defects.
        Br Med J. 1981; 282: 1509-1511
        • Lane GA
        • Nahrwold ML
        • Tait AR
        • Taylor-Busch M
        • Cohen PJ
        Anesthetics as teratogens: nitrous oxide is fetotoxic, xenon is not.
        Science. 1980; 210: 899-901
        • Scott JM
        • Dinn JJ
        • Wilson P
        • Weir DG
        Pathogenesis of subacute combined degeneration: a result of methyl group deficiency.
        Lancet. 1981; II: 334-337
        • Turner AJ
        The relationship between brain folate and monoamine metabolism.
        in: Botez MI Reynolds EH Folic acid in neurology, psychiatry and internal medicine. Raven Press, New York1979: 165-177