Organic aciduria, biotin

On rare occasions an organic aciduria occurs not because of an enzyme deficiency but from a failure to transport or activate a water-soluble vitamin that serves as a cofactor for the reaction in question. Thus, congenital deficiencies in the metabolism of vitamin B12 commonly give rise to methylmalonic aciduria (Fig. 40-1, Table 40-2). Similarly, deficiencies of biotin metabolism can cause a severe organic aciduria (Table 40-2). It is very important to be aware of the defects of vitamin metabolism because the administration of large doses of these cofactors may completely prevent brain damage. 

Biotinidase activity in cerebrospinal fluid and the brain is very low. This suggests that the brain may not recycle biotin effectively and depends on biotin transported across the blood-brain barrier. Several symptomatic children who have failed to exhibit peripheral lactic acidosis or organic aciduria have had elevated lactate or organic acids in their cerebrospinal fluid. This compartmentalization of the biochemical abnormalities may explain why the neurological symptoms usually appear before other symptoms. Peripheral metabolic ketoacidosis and organic aciduria subsequently occur with prolonged metabolic compromise. 

The condition is a biotin-responsive genetic disease, and patients can be maintained in good health with supplements of high doses of biotin. Doses of biotin of the order of 1 mg per day prevent clinical signs in most patients, but 10 mg per day or more is required to correct the organic aciduria. 

Propionyl-CoA is an intermediary product in the metabo-hsm of four essential amino acids (isoleucine, valine, threonine, and methionine), the aliphatic side-chain of cholesterol, pyrimidines (uracd and thymine), and the final product of the [3-oxidation of odd-chain fatty acids. Under normal circumstances, propionyl-CoA first is converted by a biotin-dependent carboxylase to methylmalonyi-CoA, then to succinyl-CoA by an adenosylcobalamin-dependent mutase, leading to oxidation in the tricarboxylic acid cycle. Primary or secondary defects of these two enzymes were among the first organic acidurias to be discovered, and their natural history has been characterized perhaps better than any other inborn error of organic acid metabolism. 

Biotinidase deficiency A failure of biotin recycling results in an organic aciduria, developmental delay, seizures, alopecia, hypotonia and hearing loss... 

Biotin deficiency causes disturbances in a variety of carboxylase-mediated metabolic reactions. As a result, such a deficiency may induce ketolactic acidosis and organic aciduria (Zempleni et al. 2008). Organic acids such as 3-methylcrotonylglycine, 3-hydroxyvaleric acid or methylcitric acid are excreted in urine in case of biotin deficiency (Figure 43.2). 

Mock DM, Mock Nf, Weintraub S. Abnormal organic aciduria in biotin deficiency the rat is similiar to the humaiL J Lab Clin Med 1988 112(2) 240-247. 

It is apparent that several abnormalities in this system may lead to deficient metabolism of 3-methylcrotonyl-CoA and hence an associated abnormal organic aciduria. Defects of the apocarboxylase affecting either active site could produce an isolated 3-methylcrotonyl-CoA carboxylase deficiency. Deficient activity of holocarboxylase synthetase would lead to multiple carboxylase deficiency and a similar disorder would be expected if a defect occurred in biotin uptake by the cell or transport into the mitochondria. It would be surprising, however, if the patients with the latter disorders would be responsive in vivo to biotin therapy and the molecular basis for the response in other cases and hence of the exact nature of the underlying primary defects remains to be elucidated by further study. 

Saunders, M., Sweetman, L., Robinson, B., Roth, K., Cohn, R. and Gravel, R.A. (1979), Biotin responsive organic aciduria. Multiple carboxylase defects and complementation studies with propionic acidemia in cultured fibroblasts. J. Clin. Invest., 64, 1695. 

Inborn errors of metabolism may be due to propionyl-CoA carboxylase deficiency, defects in biotin transport or metabolism, methylmalonyl-CoA mutase deficiency, or defects in adenosylcobalamin synthesis. The former two defects result in propionic acidemia, the latter two in methylmalonic acidemia. All cause metabolic acidosis and developmental retardation. Organic acidemias often exhibit hyperammonemia, mimicking ureagenesis disorders, because they inhibit the formation of N-acetylglutamate, an obligatory cofactor for carbamoyl phosphate synthase (Chapter 17). Some of these disorders can be partly corrected by administration of pharmacological doses of the vitamin involved (Chapter 38). Dietary protein restriction is therapeutically useful (since propionate is primarily derived from amino acids). Propionic and methylmalonyl acidemia (and aciduria) results from vitamin B12 deficiency (e.g., pernicious anemia Chapter 38). 

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