5 PATIENTS WITH A BIOTIN-RESPONSIVE DEFECT IN HOLOCARBOXYLASE FORMATION - EVALUATION OF RESPONSIVENESS TO BIOTIN THERAPY IN-VIVO AND COMPARATIVE BIOCHEMICAL-STUDIES IN-VITRO

Biochemical studies in five patients with a defect in biotin-responsiv e holocarboxylase synthesis are reported. The age of onset (2 d to 6 y ) as well as the severity of illness varied considerably. In all patie nts diagnosis was established by the finding of organic aciduria typic al for multiple carboxylase deficiency in a catabolic state. In four p atients the response to biotin therapy was evaluated by measurement of mitochondrial carboxylase activities in lymphocytes and by monitoring urinary organic acid excretion. In three patients clinical symptoms d isappeared with 10-20 mg biotin/d, whereas normalization of the bioche mical parameters required higher doses (20-40 mg/d). The fourth patien t required a dose of 100 mg biotin/d before her skin rash disappeared. She remains mentally retarded and shows slightly elevated urinary org anic acid excretion. Carboxylase activities were clearly deficient in fibroblasts grown in the commonly used medium which contains 10 nmol/L biotin (contributed by FCS in medium) in two patients. Fibroblasts of the other three patients became deficient only in a low biotin medium (0.1 nmol/L). Reactivation of deficient carboxylase activities in rel ation to time and biotin concentration correlated well with the severi ty and age of onset of illness in four patients. In one patient, howev er, carboxylase reactivation followed a more complex pattern requiring the longest incubation time but only a moderately increased biotin co ncentration of 19 nmol/L compared with 3-5 nmol/L in normal cells and 34-400 nmol/L in the other four patients. The results in the five pati ents are in accordance with a primary defect of holocarboxylase synthe tase due to a decreased affinity for biotin, in one patient combined w ith a decreased V-max.