Hydroxocobalamin Acetate

The use of hydroxocobalamin (OH-B12), betaine, carnitine, and folinic acid were studied in two children with the cobalamin C form of methylmalonic acidemia and homocystinuria. When daily injections of 1 mg OH-B12 were discontinued for 3 weeks, there was no significant change in total plasma homocysteine or methionine levels and only a modest increase in methylmalonate. Orally administered OH-B12 1 mg/d in one patient was associated with an increase in plasma homocystine and a decrease in methionine within 1 month. Withdrawal of betaine 250 mg/kg/d was also associated with a rise in plasma homocystine and a fall in methionine levels. Carnitine 100 mg/kg/d lead to an increase in urinary excretion of propionylcarnitine, but did not affect plasma methylmalonate levels. No beneficial biochemical effect of folinic acid could be documented at a dose of 25 mg/d. Our results suggest that daily injections of OH-B12 are not necessary to maintain metabolic control and that orally administered OH-B12 is unlikely to be effective. Betaine appears to act synergistically with OH-B12 and should be part of the treatment regimen. Although there are theoretical reasons for using L-carnitine and folinic acid, we could not document their effectiveness in these two patients.

A child presented early in life with homocystinuria and megaloblastic anaemia which responded to hydroxocobalamin (OH-B12) therapy. Mental development has been subnormal since birth. Fibroblasts from this patient contained low levels of methylcobalamin (CH3-B12) and incorporated less 14C from labelled 5-methyltetrahydrofolate (14CH3H4PteGlu) into methionine. Methionine synthase activity was more thiol-dependent in the patient's fibroblasts than it was in normal cells. Studies on fibroblasts from the parents confirmed that both are heterozygous for this disorder. When the mother became pregnant again, prenatal diagnosis was attempted by use of cultured amniocytes obtained at 16 weeks' gestation. Values for incorporation of 14CH3H4PteGlu into methionine by intact cells and the thiol requirement of methionine synthase were abnormal in these amniocytes but these features did not conclusively identify the fetus at risk as being homozygous for the abnormality. Only 8% of the 57Co vitamin B12 incorporated by the fetal amniocytes was present as CH3-B12 compared with 29% and 40% in two control amniocyte lines and 37% and 32% in fibroblasts from the parents who are obligate heterozygotes. These studies suggested that the fetus had CH3-B12 deficiency. The mother was treated with OH-B12 (1 mg twice weekly, intramuscularly) from 25 weeks' gestation. The baby was clinically normal at birth without any evidence of homocystinuria or anaemia, and has been maintained on OH-B12 (1 mg twice weekly). Studies on fibroblasts from the baby confirmed the diagnosis of CH3-B12 deficiency (cobalamin E disease). At 6 months of age, growth and development remain normal.