DNA sequence; Rett syndrome; Biogenic Monoamines; Biological Markers; Blood-Brain Barrier; Carrier Proteins; Central Nervous System; Child, Preschool; Female; Folic Acid; Humans; Leucovorin; Protein Isoforms; Pterins; Receptors, Cell Surface; Sequence Analysis, DNA; Tetrahydrofolates
Abstract :
[en] Background: Previous CSF studies in Rett syndrome suggest reduced turnover of the biogenic monoamines serotonin and dopamine. Because diminished turnover may result from CNS folate depletion, the authors studied transport of folate across the blood-brain barrier. Methods: In four patients with Rett syndrome, the authors measured CSF values of 5-methyltetrahydrofolate (5MTHF), biogenic monoamine end-metabolites, and pterins together with serum and red blood cell folate. In CSF, the overall folate binding capacity by the two soluble folate-binding proteins FBP1 and FBP2 (sFBP) was measured using a radioligand binding method for H3-labeled folate. A specific immunoreactive test (ELISA) detected sFBP1, which normally contributes to 30 to 35% of the total folate binding capacity. Genetic analysis included DNA sequencing of the MECP2, FBP1, and FBP2 genes. Empirical treatment with oral folinic acid was evaluated. Results: Two patients without and two with mutations of the MECP2 gene had normal values for red blood cell folate, serum folate, homocysteine, and methionine. In CSF, all patients had low values for 5MTHF, neopterin, and the serotonin end-metabolite 5-hydroxyindoleacetic acid (5-HIAA). Genetic analysis of FBP1 and FBP2 genes had normal results. Compared to controls, patients with Rett syndrome had normal immunoreactive sFBP1 in CSF, whereas the total folate binding capacity was disproportionately lowered. Empirical treatment with oral folinic acid normalized 5-MHTF and 5-HIAA levels in CSF, and led to partial clinical improvement. Conclusion: Irrespective of the MECP2 genotype, 5MTHF transfer to the CNS is reduced in Rett syndrome. Folinic acid supplementation restores 5MTHF levels and serotoninergic turnover. The lowered folate binding capacity of FBP is not explained by a defect of the FBP1 or FBP2 gene, but most likely occurs as a secondary phenomenon in Rett syndrome.
Disciplines :
Neurology Pediatrics
Author, co-author :
RAMAEKERS, Vincent ; University Hospital Aachen, Germany > Pediatrics > Pediatric Neurology
Hansen, Sylvain ; Department of Clinical Chemistry, Hillerød Sygehus, Hillerød, Denmark
Holm, J.; Department of Clinical Chemistry, Hillerød Sygehus, Hillerød, Denmark
Opladen, T.; Division of Pediatric Neurology, Department of Pediatrics, University Hospital Aachen, Aachen, Germany
Senderek, J.; Division of Pediatric Neurology, Department of Pediatrics, University Hospital Aachen, Aachen, Germany
Häusler, M.; Division of Pediatric Neurology, Department of Pediatrics, University Hospital Aachen, Aachen, Germany
Heimann, G.; Division of Pediatric Neurology, Department of Pediatrics, University Hospital Aachen, Aachen, Germany
Fowler, B.; Department of Clinical Chemistry, University Children's Hospital, Basel, Switzerland
Maiwald, R.; Inst. of Med. Genet./Molec. Medicine, Cologne, Germany
Blau, N.; Div. of Clin. Chem. and Biochemistry, University Children's Hospital, Zürich, Switzerland
Language :
English
Title :
Reduced folate transport to the CNS in female Rett patients
Publication date :
26 August 2003
Journal title :
Neurology
ISSN :
0028-3878
eISSN :
1526-632X
Publisher :
Lippincott Williams & Wilkins, United States - Maryland
Rett A. Uber ein eigenartiges hirnatrophisches Syndrom bei Hyperammonaemie im Kindesalter. Wien Med Wochenschr 1966;116:723-738.
Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Ann Neurol 1983;14:471-479.
Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein. Nat Genet 1999;23:185-188.
Wan M, Sung Jae Lee S, Zhang X, et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet 1999;65:1520-1529.
Jones PL, Veenstra GJ, Wade PA, et al. Methylated DNA and MECP2 recruit histone deacetylase to repress transcription. Nat Genet 1998;19:187-191.
Nan X, Ng HH, Johnson CA, et al. Transcriptional repression by the Methyl-CpG-binding protein MECP2 involves a histone deacetylase complex. Nature 1998;393:386-389.
Ng HH, Bird A. DNA methylation and chromatin modification. Curr Opin Genet Dev 1999;9:158-163.
Zoghbi HY, Milstien S, Butler IJ, et al. Cerebrospinal fluid biogenic amines and biopterin in Rett syndrome. Ann Neurol 1989;25:56-60.
Blau N. The hyperphenylalaninemias. A differential diagnosis and international database of tetrahydrobiopterin deficiencies. Tectum Verlag Marburg, 1996.
Surtees R, Heales S, Bowron A. Association of cerebrospinal fluid deficiency of 5-methyltetrahydrofolate, but not S-adenosylmethionine, with reduced concentrations of the acid metabolites of 5-hydroxytryptamine and dopamine. Clin Sci (Colch) 1994;86:697-702.
Gospe SM, Gietzen DW, Summers PJ, et al. Behavioral and neurochemical changes in folate-deficient mice. Physiol Behav 1995;58:935-941.
Bottiglieri T, Hyland K, Laundy M, et al. Folate deficiency, biopterin and monoamine metabolism in depression. Psychol Med 1992;22:871-876.
Trevathan E, Moser HW. Diagnostic criteria for Rett syndrome. Ann Neurol 1988;23:425-428.
Blau N, Thöny B, Renneberg A, et al. Variant of dihydropteridine reductase deficiency without hyperphenylalaninemia: effect of oral phenylalanine loading. J Inherit Metab Dis 1999;22:216-220.
Curtius HC, Blau N, Kuster T. Pterins. In: Hommes FC, ed. Techniques in diagnostic human biochemical genetics. New York: Wiley-Liss, 1991; 377-396.
Blau N, Duran M, Blaskovics ME, Gibson KM. Physician's guide to the laboratory diagnosis of metabolic diseases. 2nd ed. Heidelberg: Springer-Verlag, 2002.
Löhrer FM, Angst CP, Brunner FP, et al. Evidence for disturbed S-adenosylmethionine: S-adenosylhomocysteine ratio in patients with end-stage renal failure: a cause for disturbed methylation reactions? Nephrol Dial Transplant 1998;13:656-661.
Surtees R, Hyland K. A method for the measurement of S-adenosylmethionine in small volume samples of cerebrospinal fluid using high pressure liquid chromatography. Anal Biochem 1989;181: 331-335.
Surtees R, Hyland K. Cerebrospinal fluid concentration of S-adenosylmethionine, methionine and 5-methyltetrahydrofolate in a reference population: cerebrospinal fluid S-adenosylmethionine falls with age in humans. Biochem Med Metab Biol 1990;44:192-199.
Holm J, Hansen SI, Hoier-Madsen M, Bostad L. High-affinity folate binding in human choroid plexus. Characterization of radioligand binding, immunoreactivity, molecular heterogeneity and hydrophobic domain of the binding protein. Biochem J 1991;280:267-271.
Weitman SD, Lark RH, Coney LR, et al. Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res 1992;52:3396-3401.
Wu D, Pardridge WM. Blood-brain barrier transport of reduced folic acid. Pharm Res 1999;16:415-419.
Wang Y, Zhao R, Russell RG, Goldman ID. Localization of the murine reduced folate carrier as assessed by immunohistochemical analysis. Biochim Biophys Acta 2001;1513:49-54.
Hansen SI, Holm J, Lyngbye J. A high-affinity folate binding protein in human cerebrospinal fluid. Acta Neurol Scand 1985;71:133-135.
Hansen SI, Holm J, Hoier-Madsen M. Quantitation of the folate binding protein in human cerebrospinal fluid by an enzyme-linked immunosorbent assay (ELISA). Pteridines 1989;1:231-233.
Holm J, Hansen SI, Hoier-Madsen M. Immunological heterogeneity of folate binding protein in human cerebrospinal fluid. Med Sci Res 1998; 26:71-72.
Hansen SI, Holm J. Conversion of an apparent 100 kDa folate binding protein from human milk, choroid plexus and semen to a 25 kDa molecular species by phosphatidylinositol-specific phospholipase C. Biosci Rep 1992;12:87-93.
Holm J, Hansen SI, Hoier-Madsen M, Nichols CW. Characterization of a folate receptor in parotid gland and a folate binding protein in saliva from humans. Epitope relatedness to human milk folate binding protein. APMIS 2000;108:517-524.
Ross JF, Chaudhuri PK, Ratnam M. Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. Cancer 1994;73: 2432-2443.
Høier-Madsen M, Hansen SI, Holm J. Rabbit Antibodies against the low molecular weight folate binding protein from human milk. Use for immunological characterization of human folate binding proteins in an enzyme-linked immunosorbent assay (ELISA). Biosci Rep 1987;7:553-557.
Elwood PC, Nachmanoff K, Saikawa Y, et al. The divergent 5′ termini of the alpha human folate receptor (hFR) mRNAs originate from two tissue-specific promotors and alternative splicing: characterization of the alpha hFR gene structure. Biochemistry 1997;36:1467-1478.
Heil SG, Van der Put NMJ, Trijbels FJM, et al. Molecular genetic analysis of human folate receptors in neural tube defects. Eur J Hum Genet 1999;7:393-396.
Said HM, Nguyen TT, Dyer DL, et al. Intestinal folate transport: identification of a cDNA involved in folate transport and the functional expression and distribution of its mRNA. Biochim Biophys Acta Biomembranes 1996;1281:164-172.
Shen F, Ross JF, Wang X, et al. Identification of a novel folate receptor, a truncated receptor, and receptor type beta in hematopoietic cells - cDNA cloning, expression, immunoreactivity and tissue specificity. Biochemistry 1994;33:1209-1215.
Wang TTY, Chandler CJ, Halsted CH. Intracellular pteroylpolyglutamate hydrolase from human jejunal mucosa: isolation and characterization. J Biol Chem 1986;261:13551-13555.
Kamen BA, Capdevila A. Receptor-mediated folate accumulation is regulated by the cellular folate content. Proc Natl Acad Sci USA 1986;83: 5983-5987.
Kane MA, Elwood PC, Portillo RM, et al. Influence on immunoreactive folate-binding protein of extracellular folate concentration in cultured human cells. J Clin Invest 1988;81:1398-406.
Anderson RG, Kamen BA, Rothberg KG, Lacey SW. Potocytosis: sequestration and transport of small molecules by caveolae. Science 1992; 255:410-411.
Fan J, Vitols KS, Huennekens FM. Multiple folate transport systems in L 1210 cells. Adv Enzyme Regul 1992;32:3-15.
Mineo C, Anderson RGW. Potocytosis. Robert Feulgen Lecture. Histochem Cell Biol 2001;116:109-118.
Rothberg KG, Ying Y, Kolhouse JF, et al. The glycophospholipid-linked folate receptor internalizes folate without entering the clathrin-coated pit endocytotic pathway. J Cell Biol 1990;110:637-649.
Spector R, Lorenzo A. Folate transport in the central nervous system. Am J Physiol 1975;229:777-782.
Spector R. Micronutrient homeostasis in mammalian brain and cerebrospinal fluid. J Neurochem 1989;53:1667-1674.
Weitman SD, Weinberg AG, Coney LR, et al. Cellular localization of the folate receptor: potential role in drug toxicity and folate homeostasis. Cancer Res 1992;52:6708-6711.
Verma RS, Anthony AC. Immunoreactive folate-binding proteins from human saliva. Isolation and comparison of two distinct species. Biochem J 1992;286:707-715.
Holm J, Hansen SI, Høier-Madsen M, et al. High-affinity folate receptor in human ovary, serous ovarian carcinoma, and ascites: radioligand binding mechanism, molecular size, ionic properties, hydrophobic domain, and immunoreactivity. Arch Biochem Biophys 1999;366:183-191.
Ramaekers VT, Häusler M, Opladen T, Heimann G, Blau N. Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics 2002;33:301-308.
Clayton PT, Smith I, Harding B, Hyland K, Leonard JV, Leeming RJ. Subacute combined degeneration of the cord, dementia and parkinsonism due to an inborn error of folate metabolism. J Neurol Neurosurg Psychiatry 1986;49:920-927.
Smith I, Howells DW, Hyland K. Pteridines and mono-amines: relevance to neurological damage. Postgrad Med J 1986;62:113-123.
Botez MI, Young SN, Bachevalier J, Gauthier S. Effect of folic acid and vitamin B12 deficiencies on 5-hydroxyindoleacetic acid in human cerebrospinal fluid. Ann Neurol 1982;12:479-484.
Kaufman S. Some metabolic relationships between biopterin and folate: implications for the "Methyl Trap Hypothesis." Neurochem Res 1991; 16:1031-1036.
Matthews RG, Kaufman S. Characterization of the dihydropterin reductase activity of pig liver methylenetetrahydrofolate reductase. J Biol Chem 1980;255:6014-6017.
Wijngaarden JB, Kelley WN. Gout and hyperuricemia. New York: Grune and Stratton, 1976;1-512.
Blau N, Thöny B, Cotton RGH, Hyland K. Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B, eds. The metabolic and molecular bases on inherited disease. 8th ed. New York: McGraw-Hill, 2000;1275-1776.
Blom HJ, Wevers RA, Verrips A, et al. Cerebrospinal fluid homocysteine and the cobalamin status of the brain. J Inherit Metab Dis 1993; 16:517-519.
Surtees R. Biochemical pathogenesis of subacute combined degeneration of the spinal cord and brain. J Inherit Metab Dis 1993;16:762-770.
Oldfors A, Hagberg B, Nordgren H, Sourander P, Witt-Engerstrom I. Rett syndrome: spinal cord neuropathology. Pediatr Neurol 1988;4:172-174.
