Methionine auxotrophy in inborn errors of cobalamin metabolism

Several of the inborn errors of vitamin B12 (cobalamin, Cbl) metabolism (cblC, cblD, cblE, cblF, cblG) are associated with homocystinuria and hypomethioninemia due to a functional deficiency of the cytoplasmic enzyme methionine synthase which requires methylcobalamin (MeCbl) as a cofactor. We compared the growth of cultured fibroblasts from controls, from patients with a selective deficiency of MeCbl (cblE and cblG), with those with a defect in both MeCbl and adenosylcobalamin (AdoCbl) (cblC, cblD and cblF), in methionine and folic acid-free media to their growth in fully supplemented medium. Control cells were able to grow in deficient medium supplied with homocysteine, cobalamin and folate, while mutant cells were not, due to their inability to synthesize methionine from its immediate metabolic precursor, homocysteine. This differential growth is useful in screening for genetic defects of methionine biosynthesis.