1. The case is described of a child with retarded physical and mental development, recurrent megaloblastic anaemia, methylmalonic aciduria and abnormal homocysteine metabolism resulting from an inborn error in the metabolism of cobalamins. She died at the age of 7 years. At autopsy there was pulmonary fibrosis and the brain showed lesions typical of those seen in subacute combined degeneration of the cord.
2. A metabolic abnormality was present which resulted in an inability to maintain normal tissue concentrations of the two coenzyme forms of vitamin B12, methylcobalamin and adenosylcobalamin. Lack of methylcobalamin led to deficient activity of N5-methyltetrahydrofolate-homocysteine methyltransferase with reduced ability to methylate homocysteine, and lack of adenosylcobalamin to deficient activity of methylmalonyl-CoA mutase, which accounted for the methylmalonic aciduria.
3. Analyses of total vitamin B12 and of individual cobalamins by a chromatobioautographic technique showed that in organs sampled at autopsy, the content of total vitamin B12 and of methylcobalamin, adenosylcobalamin and hydroxocobalamin were all greatly reduced. The plasma had a high normal total vitamin B12 content, but showed a gross abnormality in the distribution of individual cobalamins, methylcobalamin being decreased and adenosylcobalamin and hydroxocobalamin increased. The erythrocytes showed a reduction in cobalamins resembling that in the solid organs, though less severe.
4. The underlying abnormality in this patient appeared to be either a defect in cellular uptake of vitamin B12, or a defect in a metabolic pathway leading to the formation of a common precursor of methylcobalamin and adenosylcobalamin. Abnormalities in transcobalamins I and II, plasma factors involved in plasma transport and cellular uptake of vitamin B12, were excluded.
5. The clinical and biochemical findings in the patient are compared with those described in three patients previously reported, who had methylmalonic aciduria and homocystinuria, and who were in some respects similar to this patient. The present case is unusual in that previous examples of errors in cobalamin metabolism have not had megaloblastosis or neurological changes typical of vitamin B12 deficiency. It is also the first case in which direct estimations of individual cobalamins have been made.