HOLOCARBOXYLASE SYNTHETASE DEFICIENCY - EARLY DIAGNOSIS AND MANAGEMENT OF A NEW CASE

We present a new case of holocarboxylase synthetase (HCS) deficiency, a rare autosomal recessive metabolic disorder, causing the ''early-ons et'' form of multiple carboxylase deficiency. The patient was born at term of healthy consanguineous parents after an uncomplicated pregnanc y. On the 2nd day of life she refused oral feeding, became tachydyspno eic and showed excessive weight loss. Laboratory studies showed metabo lic acidosis, marked lactic acidaemia, hyperammonaemia and increased u rinary excretion of 3-hydroxyisovaleric acid, 3-methylcrotonylglycine, 3-hydroxypropionic acid and methylcitric acid. Peritoneal dialysis co mbined with oral supplementation of biotin (10 mg/day) started on the 3rd day of life resulted in rapid clincial recovery and normalisation of biochemical parameters. HCS deficiency was established in lymphocyt es and skin fibroblasts. The activities of all biotin-dependent carbox ylases were severely decreased in fibroblasts grown in medium with mod erate biotin concentration (10(-8) mol/l) but normal in a high biotin medium (10(-5) mol/l). Mitochondrial carboxylase activities in lymphoc ytes were 23% -29% of mean normal during therapy with 20 mg of biotin/ day, with the higher dose of 40 mg/day they were within (3-methylcroto ryl-CoA carboxylase, pyruvate carboxylase) or slightly below (propiony l-CoA carboxylase) the normal range. At the age of 3 years the patient 's physical and psychomotor development are normal. Early biotin suppl ementation should be considered in newborns with lactic acidosis and o rganoaciduria until a final diagnosis has been established. Furthermor e, the required individual dose of biotin has to be carefully evaluate d biochemically for the individual patient.