Methylcobalamin is an essential cofactor in the conversion of homocysteine to methionine. An impairment of this reaction caused by a deficiency of cobalamin is thought to cause a failure of DNA synthesis, accounting for the hematologic abnormalities, particularly for the production of megaloblasts. However, because neurons do not divide, this sequence of chemical events does not explain the central nervous system abnormalities. One of the better-understood functions of vitamin B12 is its role as a coenzyme in the methylmalonyl-CoA mutase reaction. In this reaction, which is a key step in propionate metabolism, methylmalonyl-CoA is transformed to succinyl-CoA, which subsequently enters the Krebs cycle. A lack of the cobalamin-dependent enzyme methylmalonyl-CoA mutase leads to the accumulation of methylmalonyl-CoA and its precursor, propionyl-CoA. According to this mechanism, propionyl-CoA displaces succinyl-CoA, which is the usual primer for the synthesis of even-chain fatty acids; this results in the anomalous insertion of odd-chain fatty acids into membrane lipids, such as are found in myelin sheaths. Conceivably, this biochemical abnormality underlies the lesions of myelinated fibers that characterize the disease. However, Carmel and associates described a hereditary form of cobalamin deficiency in which methylmalonyl-CoA mutase activity was normal, despite the presence of typical neurologic abnormalities. In their view, the primary failure is one of methylation of homocysteine to methionine, that is, a failure of the methionine synthetase reaction, for which the coenzyme methylcobalamin is necessary.
Evidence for the latter view comes also from the observations, mentioned earlier, that prolonged administration of nitrous oxide (N2O) may produce not only megaloblastic changes in the marrow (Amess et al), but also a sensorimotor polyneuropathy, often combined with signs of involvement of the posterior and lateral columns of the spinal cord (Layzer). Probably N2O produces its effects by inactivating the methylcobalamin-dependent enzyme, methionine synthetase. These and other hypotheses are discussed by Jandl, Carmel and colleagues, and by Beck (1988).
The role of folate deficiency in the genesis of SCD is less certain. One known clinical mistake has been to treat pernicious anemia by giving folic acid; this corrects the anemia but may worsen or even evoke the spinal cord lesions. Nevertheless, there have been a few reported examples of cerebral and spinal cord lesions indistinguishable from those caused by vitamin B12 deficiency in patients with defective folate metabolism, both in adults with acquired deficiency (Pincus) and in children with an inborn metabolic error (Clayton et al). The current view, however, is that folate deficiency alone does not produce SCD.