http://www.researchgate.net/publication ... _sclerosis Metabolic Brain Disease
September 2006, Volume 21, Issue 2, pp 117-133Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis
S.J. van Rensburg, M.J. Kotze, D. Hon, P. Haug, J. Kuyler, M. Hendricks, J. Botha, F.C.V. Potocnik, T. Matsha, R.T. Erasmus
Received: 31 July 2005 / Accepted: 18 November 2005
© Springer Science+Business Media, Inc. 2006Abstract
Some subjects with multiples 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 significant weight 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 Kurtzke 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 (Kurtzke 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.Introduction
Multiple sclerosis (MS) is a disorder in which autoreactive immune responses are involved in the attack on myelinated axons, thereby interfering with the conduction of signals to the periphery (Steinman, 1993). The disease process is often progressive, leading to chronic disability. The diagnosis of MS is extremely stressful for patients and care-givers alike because at diagnosis neurologists cannot deduce from the severity of the symptoms what the disease outcome will be. After an initial remission, some subjects experience few symptoms for long periods of time, while others deteriorate rapidly. The diagnosis of MS is mainly clinical (Poser and Brinar, 2004), assisted by cerebrospinal fluid analysis (Friedman et al
., 2005), while magnetic resonance imaging (MRI) is gaining importance in diagnosis and follow-up (McDonald et al
The aetiology of MS is complex and multi-factorial, involving genetic and environmental factors, while a viral component is also implicated (De Villiers et al
., 2006). Furthermore, a combination of different factors may cause disease in different patients. Metals have previously been implicated in the aetiology of MS (Clausen, 1993). The role of excess iron has been investigated, but three clinical trials attempting to remove excess iron by chelation with desferrioxamine have been inconclusive (LeVine and Chakrabarty, 2004). A study by Grant et al
. (2003) showed that low iron concentrations in food protected mice against developing experimental autoimmune encephalomyelitis (EAE), a mouse model for studying autoimmunity in MS. Contrary to these findings, a single patient study demonstrated stabilisation of the MS disease process with no further degeneration when a patient took iron supplements daily together with other nutrients (Rooney et al
., 1999). The role of iron in the aetiology and pathology of MS has thus not been elucidated.
Since myelin regeneration is a prerequisite for remission, it is important to note that iron is indispensable for myelin synthesis. Iron deficiency during early postnatal life as well as in later life, results in a reduced amount of myelin in the spinal cord and white matter of rat pups (Yu et al
., 1986; Beard et al
., 2003). In mice, the disruption of iron availability, either by limiting dietary iron intake or by altering iron storage capacity, resulted in decreased myelin proteins and lipids (Ortiz et al
., 2004). Proteolipid protein was most consistently affected, suggesting that limiting iron to oligodendrocytes results not only in hypomyelination but also in a decrease in myelin compaction, i.e. in the structure of the myelin. Electron microscopic studies have revealed high concentrations of iron in the cytoplasm of oligodendrocytes and within myelin (Connor and Menzies, 1996). Many of the enzymes involved in the biosynthetic pathways that produce myelin utilize iron as part of their catalytic center (LeVine and Chakrabarty, 2004). Myelinogenesis is a highly energy-intensive process resulting in a high metabolic demand for iron. Hulet et al
. (1999) found ferritin receptors on oligodendrocytes and suggested that the significance of a cellular ferritin receptor was that ferritin was capable of delivering 2,000 times more iron per mole of protein than transferrin to the oligodendrocytes.
Iron enrichment within both oligodendrocytes and myelin raises the possibility that an imbalance in the management of iron during the disease process could lead to the production of iron-catalyzed free radicals that would cause oxidative damage. Toshniwal and Zarling (1992) found that the inflammation during an acute exacerbation causes so much lipid peroxidation that pentane can be measured in the breath of the patients, but during remission exhaled pentane was similar to values recorded for control subjects.
Vascular damage in MS is implicated in the finding of higher homocysteine levels in MS subjects (Vrethem et al
., 2003). Interestingly, iron deficiency may also be linked to increased homocysteine levels. Prolonged iron deficiency anaemia is associated with gastritis and atrophy of glands producing intrinsic factor in the stomach (Davidson and Markson, 1955, 1959). Optimal functioning of the folate-vitamin B12-methyl transfer cycle continuously providing activated methyl groups, is a prerequisite for myelin production and maintenance, and long-term deficiencies of this pathway cause demyelinating diseases of the brain and spinal cord (Selzer et al
., 2003). Inborn errors of metabolism involving the genes of the methyl transfer pathway are known to cause inadequate myelination and serious disability from childhood, but supplementation with the chemical metabolite following each metabolic block was found to restore the myelin as well as some of the functional deficiencies (Surtees et al
Polymorphisms in the genes of the methyl transfer pathway may occur without having an effect on the phenotype under normal circumstances, but when the substrates or co-factors of this pathway are depleted, demyelination may follow (Selzer et al
., 2003). The latter case study illustrates this principle. The authors describe extensive demyelination of the brain and subsequent death of a child after anesthesia with nitrous oxide, which irreversibly oxidizes the cobalt in cobalamine (vitamin B12). The activity of methionine synthase (the enzyme which utilizes cobalamine) is reduced to zero after 2 h of anaesthesia (Selzer et al
., 2003). This adverse effect was amplified in the patient by the fact that he had two polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) which reduced the activity of this enzyme as well, effectively blocking the production of active methyl groups. Importantly, in the deceased patient normal vitamin B12 levels were measured (403 pg/mL) even though the activity of the enzyme was zero, i.e. in this study the vitamin B12 assay did not distinguish between active and inactive (oxidized) vitamin B12. This may explain the results of Vrethem et al. (2003) who found increased homocysteine levels in MS subjects, but without decreased vitamin B12. Other researchers have found decreased levels of vitamin B12 and folic acid in serum and CSF of MS subjects (Reynolds et al
., 1992; Frequin et al
., 1993; Kolesar, 2000).
The aims of the present open-label pilot study were to determine iron parameters, as well as folate and homocysteine concentrations in a group of MS subjects, and to correct deficiencies while observing possible effects on MS symptoms.