Holocarboxylase synthetase deficiency

1 Holocarboxylase Synthetase Deficiency Genetic deficiency of holocarboxylase synthetase leads to the neonatal form of multiple carboxylase 

Arising from impaired activity of acetyl CoA carboxylase 2-Ethyl-3-hydroxyhexanoic acid 

Arising from impaired activity of methylcrotonyl CoA carboxylase 

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Weiner DL, Grier RE, Wolf (1985) A bioassay for determining biotinidase activity and for discriminating biocytin from biotin using holocarboxylase synthetase-deficient cultured fibroblasts. J Inherit Metab Dis 8 101-102... 

Figure 12-2. Metabolic pathways involving the four biotin-dependent carboxylases. The solid rectangular blocks indicate the locations of the enzymes ACC, acetyl-CoA carboxylase PMCC, P-methylcrotonyl-CoA carboxylase PC, pyruvate carboxylase PCC, propionyl-CoA carboxylase. Isolated deficiencies of the first three carboxylases (mitochondrial) have been established (isolated ACC deficiency has not been confirmed). At least the activities of the three mitochondrial carboxylases can be secondarily deficient in the untreated multiple carboxylase deficiencies, biotin holocarboxylase synthetase deficiency and biotinidase deficiency. Lowercase characters indicate metabolites that are frequently found at elevated concentrations in urine of children with both multiple carboxylase deficiencies. The isolated deficiencies have elevations of those metabolites directly related to their respective enzyme deficiency.

Both multiple carboxylase deficiencies are characterized by deficient activities of the three mitochondrial carboxylases in peripheral blood leukocytes prior to biotin treatment. The carboxylase activities increase to near normal or normal after treatment with pharmacological doses of biotin. Patients with biotin holocarboxylase synthetase deficiency have deficient activities of the three mitochondrial carboxylases in fibroblasts incubated in medium with low biotin concentrations (containing only the biotin contributed by fetal calf serum added to the medium for cell growth), whereas patients with biotinidase deficiency have normal carboxylase activities under these conditions. The activities of the carboxylases in biotin holocarboxylase synthetase deficiency become near normal to normal when cultured in medium supplemented with high concentrations of biotin. 

Biotinidase deficiency and biotin holocarboxylase synthetase deficiency can be definitively diagnosed by direct enzymatic assay. Biotinidase activity in plasma or serum is usually determined by using the artificial substrate, biotinyLp-aminobenz< >ate. If biotinidase activity is present, then biotin is cleaved, releasing jD-aminobenzoatc. The / -aminobenzoate then is reacted with reagents that result in the development of purple color that can be quantitated colorimetrically. In the absence of biotinidase activity,/ -aminobenzoate is not liberated. Biotinidase activity in patients with an isolated carboxylase deficiency or biotin holocarboxylase synthetase deficiency is normal. 

MetabolicaUy, biotin is of central importance in lipogenesis, gluconeogen-esis, and the catabolism of branched-chain (and other) amino acids. There are two well-characterized biotin-responsive inborn errors of metabolism, which are fatal if untreated holocarboxylase synthetase deficiency and biotinidase deficiency. In addition, biotin induces a number of enzymes, including glu-cokinase and other key enzymes of glycolysis. Biotinylation of histones may be important in regulation of the cell cycle. 

Holocarboxylase synthetase deficiency can be diagnosed prenatally by assessing the response of carboxylase activity in cultured amniocytes (obtained by amniocentesis) to the addition of biotin, or by the detection of methylcitric and hydroxyisovaleric acids in the amniotic fluid. Prenatal therapy, by giving the mother 10 mg of biotin per day, results in sufficiently elevated fetal blood concentrations of biotin to prevent the development of organic acidemia at birth. 

Biotinidase Deficiency Genetic lack of biotinidase results in the late-onset variant of multiple carboxylase deficiency. Patients generally present later in life than those with holocarboxylase synthetase deficiency (Section 11.2.2.1) and have a lower than normal blood concentration of biotin. Culture of fibroblasts in media containing low concentrations of biotin results in normal activities of carboxylases, and holocarboxylase synthetase activity is normal. 

Thuy, L.P., Belmont, J., and Nyhan, W.L., 1999. Prenatal diagnosis and treatment of holocarboxylase synthetase deficiency. Prenatal Diagnosis. 19 108-112. 

Holocarboxylase synthetase deficiency [3, 4] is the classic infantile form of multiple carboxylase deficiency. Untreated it is uniformly fatal, while early diagnosis and treatment with biotin usually lead to the disappearance of all of the manifestations of the disease. Life-threatening illness is associated with massive ketosis and metabolic acidosis. A bright red cutaneous eruption may cover the body, and there is alopecia totalis. Immune function, both T and B cell, may be defective. 

Since this first case report, some 12 patients who have shown features of 3-methylcrotonyl-CoA carboxylase deficiency have been reported in the literature. The majority (7) of these patients appear to have multiple carboxylase deficiencies probably due to holocarboxylase synthetase deficiency and are responsive to D-biotin therapy. Early diagnosis is essential in order to avoid the possible fatal consequences of the diseases. The number of cases now reported permit some degree of classification, but the degree of heterogeneity of presentation necessitates their description in some detail and the important features are given below. 

The observation of other cases of multiple carboxylase deficiencies due to apparent holocarboxylase synthetase deficiency has now shown this to be the major cause of apparent 3-methylcrotonylglycinuria. 

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