Abstract
Intracellular cobalamin is converted to adenosylcobalamin, coenzyme for methylmalonyl-CoA mutase and to methylcobalamin, coenzyme for methionine synthase, in an incompletely understood sequence of reactions. Genetic defects of these steps are defined as cbl complementation groups of which cblC, cblD (described in only two siblings), and cblF are associated with combined homocystinuria and methylmalonic aciduria. Here we describe three unrelated patients belonging to the cblD complementation group but with distinct biochemical phenotypes different from that described in the original cblD siblings. Two patients presented with isolated homocystinuria and reduced formation of methionine and methylcobalamin in cultured fibroblasts, defined as cblD-variant 1, and one patient with isolated methylmalonic aciduria and deficient adenosylcobalamin synthesis in fibroblasts, defined as cblD-variant 2. Cell lines from the cblD-variant 1 patients clearly complemented reference lines with the same biochemical phenotype, i.e. cblE and cblG, and the cblD-variant 2 cell line complemented cells from the mutant classes with isolated deficiency of adenosylcobalamin synthesis, i.e. cblA and cblB. Also, no pathogenic sequence changes in the coding regions of genes associated with the respective biochemical phenotypes were found. These findings indicate heterogeneity within the previously defined cblD mutant class and point to further complexity of intracellular cobalamin metabolism.
Highlights
Intracellular cobalamin is converted to adenosylcobalamin, coenzyme for methylmalonyl-CoA mutase and to methylcobalamin, coenzyme for methionine synthase, in an incompletely understood sequence of reactions
The values for patients 1, 2, and 3 are the means of duplicate determinations from three individual experiments, the values for the original cblD cell line are the means of duplicate determinations from a representative experiment, and the values for the different cbl mutant cell lines and control cell lines are the mean and range of results obtained in each cell line in a representative experiment with duplicate determinations
Enzyme Activities, cbl Uptake, and cbl Coenzyme Synthesis— Activities of enzymes related to MMA and homocysteine metabolism are shown in Tables I and II, respectively, and total cbl uptake and coenzyme synthesis results are given in Table III, in fibroblasts of the three patients, in reference cell lines belonging to different cbl complementation groups, and in control fibroblasts
Summary
Patient 1, born after uneventful pregnancy, was of Irish origin. Family relationships were complicated and suggested high grade consanguinity. At 6 years of age he presented with global developmental delay, severe learning difficulties and spastic ataxia, absence of ankle jerks, and rapid deterioration of gait His weight and head circumference were at the 50th percentile. At 16 years of age, compliance with medication was good, weight and height were between the 10th and 25th, and head circumference was at the 10th percentile He had nearly normal gait, could speak a number of single words, but required help with dressing and washing; he could finger-feed and drink from a cup but is incontinent. Non-protein-bound homocystine was not detected in the plasma, and later normal plasma total homocysteine (8.9 M) was found even when treatment compliance was poor.
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