Methylcrotonylglycinuria with 3-hydroxyisovaleric aciduria

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. 

A deficiency of biotin-dependent 3-methylcrotonyl-CoA carboxylase was postulated and this was subsequently demonstrated in leucocytes by a specific assay involving the incorporation of [ Cjbicarbonate into acid-insoluble material in the presence of 3-methylcrotonyl-CoA (Gompertz et ai, 1973a). It is of interest that electron-microscopic examination of fibroblasts from this patient revealed unusual deposits within the mitochondria (McLean and Stewart, 1974). 

The symptoms of the child were similar to those observed in cases of experimental biotin deficiency in humans (Sydenstricker et al.y 1942), and 

Subsequent study of cultured skin fibroblasts from this child have confirmed the existence of deficient activities of both 3-methylcrotonyl-CoA and propionyl-CoA carboxylases (Bartlett and Gompertz, 1976), and a defect in holocarboxylase synthetase (EC 6.3.4.10/11) has been postulated (Sweetman et al,y 1977 Weyler et al., 1977). The greatly increased excretion of lactic acid by the patient (Chalmers et aL, 1974a) supports this concept and could be due to deficient activity of pyruvate carboxylase, which is also dependent on holocarboxylase synthetase. 

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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