Summary
Multiple carboxylase deficiency (pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and methylcrotonyl-CoA carboxylase) is due to either a deficiency or an inherited anomaly in intracellular metabolism of biotin. Biotin is an enzymatic cofactor of these 4 carboxylases. Two genetic diseases have been identified, deficiency in biotinidase and deficiency in holocarboxylase synthetase. Deficiency in biotinidase (the enzyme that catalyses the conversion of biocytin into biotin via liberating residual lysine) presents with an accumulation of cellular biocytin and a deficiency in the 4 above mentioned biotin-dependent carboxylases. Disease usually occurs in the first year of life after age 1 to 3 month(s). The main clinical signs include coma with lactic acidosis and ketosis; various neurological signs, among which encephalopathies of any type, major hypotonia, convulsions, Leigh syndrome. Cutaneous signs (alopecia, conjunctivitis, vesicobullous eruptions) had been described. When not treated, disease results inintelectual deficit and neurosensory hearing loss. The disease is transmitted as an autosomal recessive trait. Diagnosis is suspected by chromatography of organic acids present in urine which reveals a characteristic accumulation of lactate, metabolites of proprionate, methylcrotonic acid and conjugate derivatives of cartinine. Diagnosis is confirmed by dosage of serum biotidinase. Remarkable efficacy of treatment relies on lifelong administration of oral biotin (5 to 10 mg). Holocarboxylase synthetase allows binding of biotin to the various apocarboxylases. Deficiency in this enzyme becomes patent most often at birth or in the first weeks of life due to a clinical picture close to that of biotinidase deficiency and especially due to severe cutaneous features suggesting essential fatty acids deficiency (alopecia, vesiculobullous eruptions and dermatosis). Like for deficiency in biotinidase, diagnosis relies on chromatography of organic acids showing hyperlactacidemia, presence of characteristic organic acids as well as shape of plasma acyl-carnitine. Diagnosis is confirmed by dosage of carboxylases on culture of fibroblasts lacking or supplemented with biotine. Systematic screening of these deficiencies can now be carried out with blood samples on paper (tgp Guthrie test). It is performed a few days after birth and analysed by an electrospray coupled with a double-focusing mass spectrograph. Treatment relies on lifelong administration of pharmacological doses of biotin, first intramuscularly and then orally. *Author: J-M. Saudubray (March 2004)*.
