Biotin is an essential cofactor for the four carboxylase enzymes propionyl CoA carboxylase, methylcrotonyl CoA carboxylase, pyruvate CoA car-boxylase, and acetyl CoA carboxylase. It is endo-genously derived from lysine and also present in its protein-bound form in small amounts in many foods. Holocarboxylase synthetase (HCS), which forms the inactive parent apoenzyme, is also biotin dependent. Enzyme activation requires free biotin, which is released by the action of biotinidase; this enzyme also plays an essential role in the recycling of biotin for further use. A deficiency of biotinidase, therefore, results in depletion of biotin and a functional defect of the carboxylases. Symptoms include hypotonia, lethargy, vomiting, and ataxia. Recurrent metabolic acidosis may occur. Alopecia and a generalized erythematous rash are common. The symptoms are more severe in HCS deficiency. The characteristic pattern of organic acids is present in both disorders. The diagnosis is made by measuring biotinidase activity in plasma or carboxylase-enzyme activity in leucocytes or fibroblasts. Treatment with pharmacologic doses of biotin is effective.
Multiple defects of cobalamin (vitamin B12) metabolism can occur, involving the transport of vitamin B12 into the cell (defects of the transporter proteins transcobalamin I and II) or subsequent intracellular utilization of the different biologically active forms. These disorders are classified into complementation groups, depending on whether the defect is in ade-nosylcobalamin (Cbl A and B), methylcobalamin (Cbl G and E), or both (Cbl C and D).
Adenosylcobalamin is the cofactor for methyl-malonyl CoA mutase; a defect results in a milder form of methylmalonic acidaemia than that found with a defect of the enzyme itself. Methylcobalamin is the cofactor for methionine synthase; a defect results in low methionine and homocystinuria (distinct from classic homocystinuria due to a defect of cystathionine fi synthase). A defect of both adeno-sylcobalamin and methylcobalamin causes both methylmalonic acidaemia and homocystinuria.
Symptoms vary with the complementation group, but can include metabolic acidosis, hypotonia, developmental delay, macular degeneration, and megaloblastic anemia. Treatment with hydroxo-cobalamin corrects some of the biochemical derangements, especially in Cbl A and B. Treatment is less successful in the other groups.
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