Background: Since 1975 cells lines from patients with suspected inborn errors of vitamin B12 metabolism have been referred to our laboratory because of elevations of homocysteine, methylmalonic acid, or both.
Design: Cultured fibroblasts from patients were subjected to a battery of tests: incorporation of labelled propionate and methyltetrahydrofolate into cellular macromolecules, to test the functional integrity of methylmalonyl-CoA mutase and methionine synthase, respectively; uptake of labelled cyanocobalamin and synthesis of adenosylcobalamin and methylcobalamin; and, where applicable, complementation analysis.
Results: This approach has allowed for the discovery of novel steps in the cellular transport and metabolism of vitamin B12, including those involving cellular uptake, the efflux of vitamin B12 from lysosomes, and the synthesis of adenosylcobalamin and methylcobalamin. For all of these disorders, the responsible genes have been discovered.
Conclusion: The study of highly selected patients with suspected inborn errors of metabolism has consistently resulted in the discovery of previously unknown metabolic steps and has provided new lessons in biology.
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