Cultured diploid fibroblasts from a patient with a previously undescribed inborn error of cobalamin metabolism accumulate unmetabolized, nonprotein-bound vitamin B12 in lysosomes. These cells are able to endocytose the transcobalamin II-B12 complex and to release B12 from transcobalamin II. The freed vitamin B12 is not released from lysosomes into the cytoplasm of the cell. This suggests that there is a specific lysosomal transport mechanism for vitamin B12 in the human.
Low serum vitamin B-12 concentrations after gastric bypass (GB) surgery for obesity were observed in 11 of 28 patients without detectable impairment of crystalline vitamin B-12 absorption. This was observed in 2 of 19 patients with vertical banded gastroplasty (VBG). In contrast, protein-bound vitamin B-12 absorption was markedly impaired, as demonstrated in eight of these patients after GB (n = 7) and VBG (n = 1). Correction of this impaired absorption occurred when protein-bound vitamin B-12 was incubated with an enzyme mixture before consumption. Simultaneous ingestion of the enzyme mixture with protein-bound vitamin B-12 did not improve absorption of the vitamin. In a separate experiment, 10 patients with a normal result from the Schilling test failed to correct low serum vitamin B-12 concentrations with a quantity of oral crystalline vitamin B-12 equal to the recommended dietary allowance of 2 micrograms, taken twice daily for 3 mo. Serum total homocysteine values declined during this interval. An oral daily dose of 350 micrograms crystalline vitamin B-12 raised the average serum vitamin B-12 concentration to an amount greater than the lower reference limit. A dose > 350 micrograms/d was required to raise all patients' vitamin B-12 concentrations above this concentration rather than just above the population mean. We conclude that because concentrations of oral crystalline vitamin B-12 were required to normalize serum vitamin B-12 concentrations, that a mechanism other than formation of a vitamin B-12 intrinsic factor complex is responsible for crystalline vitamin B-12 absorption after GB for obesity.
A s bstract. Cultured fibroblasts from a recently described patient with homocystinuria and megaloblastic anemia of infancy without methylmalonic aciduria were previously shown to have normal cobalamin uptake and a specific decrease in the proportion of intracellular methylcobalamin. As in control cells but unlike in those from patients with combined homocystinuria and methylmalonic aciduria (cobalamin C and cobalamin D), accumulated 57Co-labeled cobalamin was bound in appropriate amounts and proportion to intracellular binders which are known to be the two vitamin B12-dependent enzymes, methionine synthetase and methylmalonylCoA mutase. Despite the association of a normal quantity of intracellular cobalamin with methionine synthetase, the proportion of intracellular cobalamin which was methyl-B12 was below normal and in the range observed in cobalamin C and D cells. This methyl-B12 was decreased by exposure of fibroblasts in culture to nitrous oxide as was observed with control cells. Exposure of control fibroblasts during culture, but not of fibroblasts from this patient, to nitrous oxide significantly reduced
We describe two brothers with 5,10-methylene tetrahydrofolate reductase (MTHFR) deficiency. The younger patient first developed limb weakness, incoordination, paresthesiae, and memory lapses at age 15 years, and by his early twenties he was wheelchair bound. His older brother remains asymptomatic at age 37 years. Both had homocystinuria and homocystinemia and low plasma levels of methionine. MTHFR activities in cultured skin fibroblasts of both patients were < 10% control and residual enzyme activities were markedly reduced on heating. The parents had intermediate enzyme activities and the reductase in the father (who had unexplained paraparesis and homocystinemia), but not in the mother, was also thermolabile. Both patients were treated with oral folate and betaine which improved, but did not totally correct, their biochemical abnormality. MTHFR deficiency should be considered in the differential diagnosis of unexplained neurologic disease in adolescents and adults.
Inborn errors of vitamin B12 (cobalamin) metabolism are associated with homocystinuria and methylmalonic aciduria, either alone or in combination. A number of these disorders have provided the first evidence for the existence of important steps in the transport or metabolism of cobalamin in eukaryotic cells. Eight complementation classes have been defined on the basis of somatic cell hybridization studies. Although the majority of patients present in infancy or early childhood, some are not diagnosed until adolescence or later. For some of these disorders, prenatal diagnosis and therapy with cobalamin during pregnancy has been attempted. Although only males have been described with cblE disease, all of these disorders are presumed to be autosomal recessive in inheritance. The clinical and laboratory aspects of the different complementation classes (cblA-cblG) are reviewed here.
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