Neurological Degeneration in Vitamin B2 Deficiency

Vitamin B12 deficiency is accompanied by neurological degeneration in about two-thirds of cases - either peripheral neuropathy or subacute combined degeneration of the spinal cord. Folic acid deficiency is only rarely associated with similar neurological damage.

Subacute combined degeneration of the spinal cord is from demyelination of the corticospinal tracts and posterior columns of the spinal cord, leading to gait ataxia and loss of position sense and vibratory sense. Peripheral neuropathy leads to loss of cutaneous sensation and tendon reflexes (Savage and Lindenbaum, 1995).

Demyelination is because of failure of the methylation of arginine107 of myelin basic protein. The nervous system is especiallyvulnerable to depletion of S-adenosylmethionine in vitamin B12 deficiency because, unlike other tissues, it contains only methionine synthetase, which is vitamin B12 -dependent and not vitamin B12-independent homocysteine methyltransferase that uses betaine as the methyl donor (Section 10.3.4; Weir and Scott, 1995).

Vitamin B12 deficiency is associated with increased synthesis of tumor necrosis factor-a and decreased synthesis of epidermal growth factor in the spinal cord; in experimental animals, injection of tumor necrosis factor-a causes spinal cord lesions. The role of vitamin B12 is unclear, but there is some evidence that methylcobalamin has a role in regulation of the expression of cytokine genes in nerve tissue (Buccellato et al., 1999; Scalabrino et al., 2000; Peracchiet al., 2001).

Although the accumulation of methylmalonic acid can lead to increased synthesis of odd-carbon andbranched-chainfatty acids (Section 10.8.2), which might become incorporated into myelin lipids, this does not seem to be responsible for neuropathy. Methylmalonic aciduria can also occur without any evidence of vitamin B12 deficiency, as a result of a genetic defect of either methylmalonyl CoA mutase or the synthesis of adenosylcobalamin. In some cases, the condition is a vitamin dependency syndrome and responds to very high intakes of vitamin B12. Although patients show mental retardation, failure to thrive, intermittent hypo- or hyperglycemia, and protein intolerance, they do not developeither megaloblastic anemia or neurological degeneration. Similarly, in the rare condition of combined methylmalonic aciduria with ho-mocystinuria, caused by a failure of the synthesis of both adenosylmethionine and methylcobalamin, although there is megaloblastic anemia with failure to thrive and mental retardation, there is no evidence of neurological degeneration. This suggests that neither the accumulation of methylmalonyl CoA and methylmalonic acid nor the formation of odd-carbon and branched-chain fatty acids has any significant effect on myelin synthesis.

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