No abstract

Isolated deficiency of 3-methylcrotonyl-CoA carboxylase (MCC; McKusick 210200) is a rare disorder of the catabolic pathway for leucine. Only a few subjects from a few families with this enzyme defect have been described (Sweetman and Williams 1995), having a wide range of clinical presentation or being totally asymptomatic. In most patients, after apparently normal health and development during the first or even second year, metabolic stress such as intercurrent infection has precipitated metabolic and neurological decompensation (Reye-like syndrome) and caused complications. Owing to the enzyme block, 3-methylcrotonyl-CoA accumulates within the mitochondria, and, by alternative mechanisms, 3-methyl-crotonylglycine and 3-hydroxyisovaleryl-CoA are formed. Whereas 3-methylcrotonyl-glycine can directly cross mitochondrial membranes, 3-hydroxyisovaleryl-CoA can do this only after deacylation or conjugation with carnitine. After reaching the cytosol, all the compounds are readily excreted in the urine, leading to secondary carnitine deficiency.A 1-year-old boy with mild developmental delay was screened for metabolic disorders and showed in urine the metabolic pattern of isolated 3-methylcrotonyl-CoA carboxylase deficiency. He is the third of four children of healthy unrelated parents. He was born after a 38-week pregnancy with oligohydramnion. Birth weight was 2450 g. The first year of life was uneventful. On clinical investigation he was, except for mild developmental delay, without any neurological symptoms. MRI scan of the brain was normal.Laboratory investigations by gas chromatography-mass spectrometry revealed markedly elevated urinary excretion of 3-methylcrotonylglycine and 3-hydroxyisovaleric acid. On quantitative determination of these metabolites by ~H NMR spectroscopy, the following concentrations were found: 3-methylcrotonylglycine in urine 1.25 mmol/mol creatinine, in plasma and CSF not detectable; 3-hydroxyisovaleric acid in urine 6.3mmol/mol creatinine, in plasma and CSF 600 and 540/~mol/L, respectively. Amino acids in serum were normal while L-carnitine was decreased (free 4/~mol/L, normal >20; total 10/zmol/L, normal >25). Diagnosis of MCC deficiency was established in cultured fibroblasts. Incorporation of [l-laC]isovalerate into trichloroacetic acid precipitable material of the patient's intact fibroblasts was only 3% of controls and was not increased by addition of biotin to the culture medium. In direct measurements, MCC activity was undetectable, while the activities of other carboxylases, propionyl-CoA carboxylase and pyruvate carboxylase, were within the normal range. Culturing the cells in biotin-enriched 643