Cobalamin deficiency may cause bilateral peripheral neuropathy or degeneration (demyelination) of the posterior and pyramidal tracts of the spinal cord and, less frequently, optic atrophy or cerebral symptoms.
The patient classically presents with paraesthesiae, muscle weakness or difficulty in walking and sometimes dementia, psychotic disturbances or visual impairment. Long-term nutritional cobalamin deficiency in infancy leads to poor brain development and impaired intellectual development. Folate deficiency may cause mental changes such as depression and slowness and has been suggested to cause organic nervous disease, but this is uncertain. Methotrexate injected into the cerebrospinal fluid may, however, cause brain or spinal cord damage. Neural tube defects in the fetus are discussed above.
The biochemical basis for cobalamin neuropathy, however, remains obscure. Its occurrence in the absence of methyl-malonic aciduria in transcobalamin (TC) deficiency, and in monkeys given nitrous oxide, suggests that the neuropathy is related to the defect in homocysteine-methionine conversion. Accumulation of S-adenosylhomocysteine in the brain, resulting in inhibition of transmethylation reactions, has been suggested. Measurements of methylation of arginine in myelin basic protein in fruit bats with cobalamin neuropathy, or in rats exposed to N2O, however, show no defect of methylation.
Psychiatric disturbance is common in both folate and cobal-amin deficiencies. This, like the neuropathy, has been attributed to a failure of the synthesis of S-adenosylmethionine (SAM), due to reduced conversion of homocysteine to methionine. SAM is needed in methylation of biogenic amines (e.g. dopamine), as well as of proteins, phospholipids and neurotransmitters in the brain (Figure 5.3). A reduced ratio of SAM to S-adenosylhomo-cysteine is postulated to result in reduced methylation. In cobalamin deficiency there is an intriguing inverse correlation between the degree of anaemia, on the one hand, and the severity of the myeloneuropathy on the other hand. Moreover, although pernicious anaemia is more frequent in women, the neuropathy is more frequent in men.
Plasma homocysteine is a risk factor for dementia and Alzheimer's disease, shown in a median follow-up period of 8 years in one study of 1092 subjects. Studies showing an association between lower serum levels of folate or cobalamin and higher homocysteine levels with Alzheimer's disease have been reported, subjects with the vitamin deficiencies being more likely to develop Alzheimer's disease in subsequent years than control subjects.
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