LATE-ONSET HOLOCARBOXYLASE SYNTHETASE-DEFICIENCY - PRE-NATAL AND POSTNATAL DIAGNOSIS AND EVALUATION OF EFFECTIVENESS OF ANTENATAL BIOTIN THERAPY

The clinical and biochemical findings in a family with late-onset holo carboxylase synthetase (HCS) deficiency are described. The index patie nt had two life-threatening episodes of metabolic decompensation at th e age of 13 and 18 months with ketotic hypoglycaemia, vomiting and pro gressive loss of consciousness. The child recovered without biotin the rapy. Organic aciduria characteristic of multiple carboxylase deficien cy (MCD) was found, however. the key metabolites were only slightly el evated in some samples. Biotinidase deficiency was considered but excl uded by the finding of normal plasma biotinidase activity. The correct diagnosis was made only at the age of 19 months when severe MCD was f ound in lymphocytes in the presence of normal plasma biotin concentrat ion. HCS deficiency was confirmed by fibroblast studies. Biotin therap y (20 or 40 mg/day) prevented further episodes and normalized biochemi cal parameters with so far normal development. During two subsequent p regnancies, 10 mg biotin/day was administered to the mother from the 2 0th week of gestation. At delivery plasma biotin in cord blood samples was 3-4 times higher than in maternal plasma. The 2nd child was unaff ected. In the 3rd pregnancy prenatal diagnosis was performed at 16 wee ks of gestation. The concentration of methylcitrate in amniotic fluid was within the normal range and that of 3-hydroxyisovalerate only slig htly elevated. However; enzyme assays in cultured amniotic fluid cells were consistent with an affected fetus. At birth, carboxylase activit ies in lymphocytes of this newborn were only moderately decreased to 3 7% of mean normal. HCS deficiency was confirmed postnatally in fibrobl asts. Development remains normal on biotin therapy (20 mg/day). Conclu sion Prenatal diagnosis in families with milder forms of HCS deficienc y has to be performed by enzyme assays in cultured amniotic cells sinc e organic acid analysis of amniotic fluid may be inconclusive in affec ted fetuses. Biotin administered prenatally is effectively taken up by the fetus and prevents functional deficiency of the carboxylases in a n affected newborn.