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Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis

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Abstract

Some subjects with multiple sclerosis (MS) present with low blood iron parameters. Anecdotal reports and a single patient study suggest that iron supplementation may be beneficial in these subjects. Myelin is regenerated continually, but prerequisites for this process are iron and a functional folate-vitamin B12-methylation pathway. The aim of this study was to determine iron status, folate and homocysteine in MS subjects, and to evaluate the effect on MS symptoms if deficiencies were addressed. Results: In relapsing-remitting MS subjects, serum iron concentration correlated significantly with age at diagnosis (r=0.49; p=0.008). In Caucasian female MS subjects, serum iron and ferritin concentrations were significantly lower than in matched controls. In a 6-month pilot study, 12 subjects taking a regimen of nutritional supplements designed to promote myelin regeneration, improved significantly neurologically as measured by the Kurzke EDSS (Total Score means 3.50 to 2.45, 29.9%; p=0.021). These were significantly improved (p=0.002) compared to 6 control group patients taking multivitamins (Kurzke Score increased by 13.9% from 4.83 to 5.50). Both groups had significantly reduced homocysteine concentrations at 6 months, suggesting that methylation is necessary but not sufficient for myelin regeneration.

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References

  • Badenoch J, Evans JR, Richards WCD (1959) The stomach in hypochromic anaemia. Brit J Haemat 3:175–185

    Google Scholar 

  • Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–68

    Article  PubMed  Google Scholar 

  • Beard JL, Wiesinger JA, Connor JR (2003) Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats. Dev Neurosci 25:308–315

    Article  PubMed  CAS  Google Scholar 

  • Clausen J (1993) Mercury and multiple sclerosis. Acta Neurol Scand 87:461–464

    Article  PubMed  CAS  Google Scholar 

  • Connor JR, Menzies SL (1996) Relationship of iron to oligodendrocytes and myelination. Glia 17:83–93

    Article  PubMed  CAS  Google Scholar 

  • Cox EV, Meynell MJ, Gaddie R, Cooke WT (1959) Inter-relation of vitamin B12 and iron. Lancet: ii 998–1001

    Article  Google Scholar 

  • Davidson WMB, Markson JL (1955) The gastric mucosa in iron-deficiency anemia. Lancet ii 639

    Article  Google Scholar 

  • Dean G, Bhigjee AI, Bill PL, Fritz V, Chikanza IC, Thomas JE, Levy LF, Saffer D (1994) Multiple sclerosis in black South Africans and Zimbabweans. J Neurol Neurosurg Psychiatry 57:1064–1069

    PubMed  CAS  Google Scholar 

  • De Villiers, JNP, Treurnicht FK, Warnich L, Carr J, Kotze MJ (2006) Analysis of viral and genetic factors in South African patients with multiple sclerosis. Metabolic Brain Disease (In press) 21:

    Article  CAS  Google Scholar 

  • Field EJ, Joyce G (1983) Multiple sclerosis: effect of gamma linolenate administration upon membranes and the need for extended clinical trials of unsaturated fatty acids. Eur Neurol 22:78–83

    PubMed  CAS  Google Scholar 

  • Fitzsimons EJ, Brock JH (2001) Editorial: The anaemia of chronic disease. BMJ 322:811–812

    Article  PubMed  CAS  Google Scholar 

  • Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni G, Grimsley G, Keir G, Ohman S, Racke MK, Sharief M, Sindic CJ, Sellebjerg F, Tourtellotte WW (2005) Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol 62:865– 870

    Article  PubMed  Google Scholar 

  • Frequin ST, Wevers RA, Braam M, Barkhof F, Hommes OR (1993) Decreased vitamin B12 and folate levels in cerebrospinal fluid and serum of multiple sclerosis patients after high-dose intravenous methylprednisolone. J Neurol 240:305–308

    Google Scholar 

  • Grant SM, Wiesinger JA, Beard JL, Cantorna MT (2003) Iron-deficient mice fail to develop autoimmune encephalomyelitis. J Nutr 133:2635–2638

    PubMed  CAS  Google Scholar 

  • Helming L, Bose J, Ehrchen J, Schiebe S, Frahm T, Geffers R, Probst-Kepper M, Balling R, Lengeling A (2005) 1α,25-dihydroxyvitamin D3 is a potent suppressor of interferon-γ mediated macrophage activation. Blood. 2005 Aug 23; [Epub ahead of print]

  • Hulet SW, Hess EJ, Debinski W, Arosio P, Bruce K, Powers S, Connor JR (1999) Characterization and distribution of ferritin binding sites in the adult mouse brain. J Neurochem 72:868–874

    Article  PubMed  CAS  Google Scholar 

  • Jensen GE, Clausen J (1984) Glutathione peroxidase and reductase, glucose-6-phosphate dehydrogenase and catalase activities in multiple sclerosis. J Neurol Sci 63:45–53

    Article  PubMed  CAS  Google Scholar 

  • Kolesar T (2000) What is the cause of low concentration of B12 in cerebrovascular fluid in multiple sclerosis? Lakartidningen 97:3644–3645

    PubMed  CAS  Google Scholar 

  • Kotze MJ, de Villiers JN, Rooney RN, Grobbelaar JJ, Mansvelt EP, Bouwens CS, Carr J, Stander I, du Plessis L (2001) Analysis of the NRAMP1 gene implicated in iron transport: association with multiple sclerosis and age effects. Blood Cells Mol Dis 27:44–53

    Article  PubMed  CAS  Google Scholar 

  • Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452

    PubMed  CAS  Google Scholar 

  • Kwik-Uribe CL, Gietzen D, German JB, Golub MS, Keen CL (2000). Chronic marginal iron intakes during early development in mice result in persistent changes in dopamine metabolism and myelin composition. J Nutr 130:2821–2830

    PubMed  CAS  Google Scholar 

  • LeVine SM, Chakrabarty A (2004) The role of iron in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis. Ann N Y Acad Sci 1012:252–266

    Article  PubMed  CAS  Google Scholar 

  • McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127

    Article  PubMed  CAS  Google Scholar 

  • Nordvik I, Myhr KM, Nyland H, Bjerve KS (2000) Effect of dietary advice and n-3 supplementation in newly diagnosed MS patients. Acta Neurol Scand 102:143–149

    Article  PubMed  CAS  Google Scholar 

  • Oloyede OB, Folayan AT, Odutuga AA (1992) Effects of low-iron status and deficiency of essential fatty acids on some biochemical constituents of rat brain. Biochem Int 27:913–922

    PubMed  CAS  Google Scholar 

  • Ortiz E, Pasquini JM, Thompson K, Felt B, Butkus G, Beard J, Connor JR (2004) Effect of manipulation of iron storage, transport, or availability on myelin composition and brain iron content in three different animal models. J Neurosci Res 77:681–689

    Article  PubMed  CAS  Google Scholar 

  • Poser CM, Brinar VV (2004) Diagnostic criteria for multiple sclerosis: an historical review. Clin Neurol Neurosurg 106:147–58

    Article  PubMed  Google Scholar 

  • Reynolds EH (1992) Multiple sclerosis and vitamin B12 metabolism. J Neuroimmunol 40:225–30

    Article  PubMed  CAS  Google Scholar 

  • Rooney RN, Kotze MJ, de Villiers JN, Hillermann R, Cohen JA (1999) Multiple sclerosis, porphyria-like symptoms, and a history of iron deficiency anemia in a family of Scottish descent. Am J Med Genet 86:194–196

    Article  PubMed  CAS  Google Scholar 

  • Saleh MC, Espinosa de los Monteros A, de Arriba Zerpa GA, Fontaine I, Piaud O, Djordjijevic D, Baroukh N, Garcia Otin AL, Ortiz E, Lewis S, Fiette L, Santambrogio P, Belzung C, Connor JR, de Vellis J, Pasquini JM, Zakin MM, Baron B, Guillou F (2003) Myelination and motor coordination are increased in transferrin transgenic mice. J Neurosci Res 72:587–594

    Article  PubMed  CAS  Google Scholar 

  • Selzer RR, Rosenblatt DS, Laxova R, Hogan K (2003) Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N Engl J Med 349:45–50

    Article  PubMed  Google Scholar 

  • Shukla VK, Jensen GE, Clausen J (1977) Erythrocyte glutathione perioxidase deficiency in multiple sclerosis. Acta Neurol Scand 56:542–550

    Article  PubMed  CAS  Google Scholar 

  • Steinman L (1993) Autoimmune disease. Scientific American 269:75–83

    Article  Google Scholar 

  • Surtees R, Leonard J, Austin S (1991) Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 338:1550–1554

    Article  PubMed  CAS  Google Scholar 

  • Syburra C, Passi S (1999) Oxidative stress in patients with multiple sclerosis. Ukr Biokhim Zh 71:112–115

    PubMed  CAS  Google Scholar 

  • Szeinberg A, Golan R, Ben Ezzer J, Sarova Pinhas I, Sadeh M, Braham J (1979) Decreased erythrocyte glutathione peroxidase activity in multiple sclerosis. Acta Neurol Scand 60:265–271

    Article  PubMed  CAS  Google Scholar 

  • Toshniwal PK, Zarling EJ (1992) Evidence for increased lipid peroxidation in multiple sclerosis. Neurochem Res 17:205–207

    Article  PubMed  CAS  Google Scholar 

  • Valberg LS, Flanagan PR, Kertesz A, Ebers GC (1989) Abnormalities in iron metabolism in multiple sclerosis. Can J Neurol Sci 16:184–186

    PubMed  CAS  Google Scholar 

  • Van Rensburg SJ, van Zyl JM, Hon D, Daniels WMU, Hendricks J, Potocnik FCV, Erasmus R (2004) Biochemical model for inflammation of the brain: the effect of iron and transferrin on monocytes and lipid peroxidation. Metabolic Brain Disease 19:97–112

    Article  PubMed  CAS  Google Scholar 

  • Vrethem M, Mattsson E, Hebelka H, Leerbeck K, Osterberg A, Landtblom AM, Balla B, Nilsson H, Hultgren M, Brattstrom L, Kagedal B (2003) Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid. Mult Scler 9:239–245

    Article  PubMed  CAS  Google Scholar 

  • Wikstrom J, Westermarck T, Palo J (1976) Selenium, vitamin E and copper in multiple sclerosis. Acta-Neurol-Scand 54:287–290

    Article  PubMed  CAS  Google Scholar 

  • Yu GS, Steinkirchner TM, Rao GA, Larkin EC (1986) Effect of prenatal iron deficiency on myelination in rat pups. Am J Pathol 125:620–624

    PubMed  CAS  Google Scholar 

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Acknowledgements

We gratefully acknowledge the financial support given by the National Health Laboratory Service, the Medical Research Council of South Africa and the University of Stellenbosch. The Multiple Sclerosis Society of the Western Cape is acknowledged for distribution of the Raphah Regimen free of charge, for recruiting study participants, distribution of questionnaires to MS patients and data collection. Study participants are acknowledged for their willingness and cooperation to participate in this study. Blood samples were analysed in the laboratory of Drs. Whittaker and Taljaard, Pinelands, South Africa. Dr Johan Keyter is acknowledged for providing the MRI scans and Dr Frank Melonas of radiologists Schnetler and Partners for interpreting the scans. The consultant for the statistical analysis was Dr Martin Kidd of the Centre for Statistical Consultation, University of Stellenbosch. Dr Carel Meyer is thanked for photographing the MRI scan. This paper is dedicated to the memory of Prof Louis de Villiers and Dr David Horrobin, who insisted that a lot could be done to combat MS.

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Authors and Affiliations

  1. Chemical Pathology, National Health Laboratory Service and the University of Stellenbosch, Tygerberg Hospital, PO Box 19113, 7505, Tygerberg, South Africa

    S. J. van Rensburg, D. Hon, T. Matsha & R. T. Erasmus

  2. Genecare Molecular Genetics, Christiaan Barnard Memorial Hospital, Cape Town, South Africa

    M. J. Kotze

  3. Department of Neurology, University of Stellenbosch, Stellenbosch, South Africa

    P. Haug

  4. Panorama Medi Clinic, Panorama, South Africa

    J. Kuyler

  5. Department of Psychiatry, University of Stellenbosch, Stellenbosch, South Africa

    M. Hendricks & F. C. V. Potocnik

  6. University of Stellenbosch Rehabilitation Unit, Stellenbosch, South Africa

    J. Botha

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  1. S. J. van Rensburg
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  3. D. Hon
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Correspondence to S. J. van Rensburg.

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van Rensburg, S.J., Kotze, M.J., Hon, D. et al. Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis. Metab Brain Dis 21, 117–133 (2006). https://doi.org/10.1007/s11011-006-9019-0

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  • DOI: https://doi.org/10.1007/s11011-006-9019-0

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