Abstract
Extract: Methylmalonyl-CoA carbonylmutase (mutase) activity was measured in fibroblast extracts from 15 patients with methylmalonic acidemia and in extracts of postmortem tissues from 6 of these children. Propionate oxidation and synthesis of 5′-deoxyadenosylcobalamin (AdoCbl, the vitamin B12 coenzyme that is part of the mutase holoenzyme) were measured in intact fibroblasts. Mutase activity was low in the absence of added AdoCbl in fibroblast extracts from both control subjects and patients. When the assay included supplemental AdoCbl, mutase activity increased in the control subjects (to 24.0 pmol succinate/mg protein/mini and in extracts from eight of the patients (20.8 pmol/mg protein/min), but showed almost no change in extracts from the other seven patients (0.16 pmol/mg protein/min). We have defined the eight fibroblast lines that showed normal mutase activity in the presence of AdoCbl as “responsive lines” and the other seven lines as “nonresponsive.” In the liver or kidney extracts of postmortem tissues, mutase activity responded to AdoCbl supplementation if fibroblast mutase activity from that patient had responded, and failed to respond if fibroblast activity failed to respond. Mean propionate oxidation in intact fibroblasts was much higher in control lines than in either responsive or nonresponsive lines (0.728 vs 0.097 vs 0.080 nmol CO2/106 cells/hr, respectively). AdoCbl synthesis was normal (0.27 pg AdoChl/mg cells wet weight) in nonresponsive fibroblasts but was undetectable (<0.005 pg/mg cells) in the responsive lines. Thus, the deficiency of mutase activity in responsive fibroblast lines is due to the failure to synthesize significant amounts of AdoCbl, whereas the deficiency in nonresponsive lines is due to some other abnormality, presumably a defect in the mutase apoenzyme.
Speculation: Fibroblasts can be used to define whether patients with methylmalonic acidemia have an error of vitamin B12 metabolism if both mutase activity and AdoCbl synthesis are measured. The response of fibroblast mutase activity to the addition of AdoCbl reflects accurately the responsiveness of the enzyme in other tissues of the body. If an error of vitamin B12 metabolism is diagnosed with cultured fibroblasts, a prolonged trial of vitamin B12 therapy is warranted in the patient to seek evidence of in vivo responsiveness and clinical benefit from vitamin therapy.
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Morrow, G., Mahoney, M., Mathews, C. et al. Studies of Methylmalonyl Coenzyme A Carbonylmutase Activity in Methylmalonic Acidemia. I. Correlation of Clinical, Hepatic, and Fibroblast Data. Pediatr Res 9, 641–644 (1975). https://doi.org/10.1203/00006450-197508000-00006
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DOI: https://doi.org/10.1203/00006450-197508000-00006
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