THE BIOCHEMICAL BASIS OF THE NEUROPATHY IN COBALAMIN DEFICIENCY

The neurological disease associated with cobalamin deficiency has recently been receiving renewed interest due to some recent developments. (1) Neuropsychiatric disorders have been shown to be caused by cobalamin deficiency in the absence of anaemia or macrocytosis (Lindenbaum et al, 1988; Stabler et al, 1990). This may be associated with only a moderate reduction in serum cobalamin concentrations, and when diagnosed at this relatively early stage is reversible by cobalamin therapy (Lindenbaum et al, 1988). (2) The observation that deficiencies of the vitamins cobalamin, folate and pyridoxal phosphate (vitamin B-6) are relatively frequent in elderly people; as judged by the elevation of the substrates of the enzymes to which they act as co-factors namely, homocysteine, methylmalonic acid and cystathionine. These substrates accumulate to a much greater extent than would be expected by what is presently considered to be serum vitamin levels indicative of deficiency (Joosten et al, 1993). (3) The recent observation that folic acid given periconceptually to pregnant women will significantly reduce the prevalence of neural tube defective fetuses (MRC Vitamin Study Research Group, 1991). This begs the question of how best to ensure that all women are supplied with adequate amounts of dietary folic acid. This has to be given periconceptually as the neural tube closes at day 24-26 of the pregnancy and before the mother is aware that she is pregnant. Fortification of food with folic acid is an obvious answer, but this in turn poses the question as to whether such a global increase of folic acid intake could itself precipitate and/or mask the early symptoms of the neurological sequelae of cobalamin deficiency, especially in the elderly (Savage and Lindenbaum, 1994). At present 12% of pernicious anaemia patients present with neuropathy alone, and extra dietary folic acid might increase this incidence (Scott et al, 1994a). Nevertheless it seems illogical to rely on the presence of megaloblastosis to signal the potential development of subacute combined degeneration of the cord (SCD) (Wald and Bower, 1994).