Norberg B. Neuropsychiatric disorders caused by vitamin B12 deficiency in the absence of anaemia or macrocytosis – an explaining hypothesis. Rondel 2001; 8:Debate (www.rondellen.net, July – Sept 2001).

Neuropsychiatric disorders caused by vitamin B12 deficiency in the absence of anaemia or macrocytosis – an explaining hypothesis

It is well known that vitamin B12 deficiency leads to megaloblastic anaemia and neuropsychiatric symptoms. Less known is that in 10-15% of patients with vitamin B12 deficiency neuropsychiatric symptoms develop without signs of anaemia. Some years ago Dr Lars Brattström, neurologist at the County Hospital, Kalmar, Sweden, put forward the hypothesis that the latter category of patients is protected against development of anaemia due to a common genetic polymorphism. In 1996 Lars Brattström submitted the hypothesis but it was rejected by two medical journals due to lack of support from own clinical data.

The figure shows the biochemical base for the hypothesis. Vitamin B12 is coenzyme for Reaction 1 and deficiency of the vitamin leads to accumulation of homocysteine and methyltetrahydrofolate (methyl-THF) and deficiency of THF and methionine. THF is the precursor of methylene-THF that is substrate for DNA-synthesis in the haematopoiesis and methionine is the precursor of S-adenosylmethionine (SAM) that is the methyl donor in more than 100 transmethylation reactions (Reaction 2). Lack of methylene-THF is the cause of megaloblastic anaemia and lack of SAM is believed to cause hypomethylation of essential compounds in the central nervous system, which explains the neuropsychiatric symptoms.

The polymorphism (C677T) affects the gene for methylen-THF reductase (Reaction 3). Those about 10% of the population who are homozygotes for the polymorphism have reduced enzyme activity, tend to save methylene-THF, but produce less methyl-THF for the remethylation of homocysteine to methionine. Therefore, owing to Lars Brattström´s hypothesis, homozygotes, in case of vitamin B12 deficiency, have a reduced tendency to develop megaloblastic anaemia but have increased risk to develop neuropsychiatric symptoms.

To find support for his hypothesis, Lars Brattström and co-workers will genotype a large number of Swedish patients with vitamin B12 deficiency and compare the frequency of homozygotes in those who had neuropsychiatric symptoms but no anaemia with those who only had anaemia.

Bo Norberg

Publicerat 2001-09-10