Neonatal screening for biotinidase deficiency in Hungary: Clinical, biochemical and molecular studies

From 1989 to 2001, 1 336 145 newborns were screened for biotinidase deficiency in Hungary. Fifty-eight children with the disorder were identified as enzyme-deficient. We have characterized the clinical and biochemical features and mutations of 20 of these children. Eleven children had profound biotinidase deficiency, 7 had partial biotinidase deficiency, and 2 were found to be heterozygous for profound deficiency by mutation analysis. Seventeen different mutations were identified in this population including seven novel mutations. Six of these new mutations are missense, 245C>A, 334G>A, 652G>C, 832C>G, 1253G>C, 1511T>A, and one is a unique allelic double mutation [212T>C;236G>A]. Of five Romanian Gypsies, four were homozygous for the 1595C>T mutation and one was heterozygous for this mutation. Most of the children with profound deficiency have been asymptomatic on therapy; however, four exhibited minimal brain abnormalities, motor delay and abnormal blood chemistries. Compliance with therapy must be questioned in these cases. Of clinical importance, all of the children with partial deficiency exhibited mild symptoms at the time of diagnosis, at several weeks to months of age. These symptoms resolved following biotin therapy. This is in contrast to the experience in the United States, where the children with partial deficiency have been asymptomatic at the time of diagnosis. This finding further indicates that children with partial deficiency should be treated. The incidence of biotinidase deficiency in Hungary is more than twice that observed in a worldwide survey. These results indicate that newborn screening in Hungary is effective and warranted. Biotin is a water-soluble vitamin that is covalently bound to the four known human carboxylases, propionyl-CoA, 3-methylcrotonyl-CoA, pyruvate carboxylase and acetyl-CoA carboxylase (Wolf 2001). After the carboxylases are proteolytically degraded, the biotin is still attached to the E-amino group of a lysine, forming biocytin. Biotinidase (EC 3.5.1.12) catalyses the cleavage of biocytin resulting in the recycling and reutilization of biotin. Biotinidase deficiency (McKusick 253260) is an autosomal recessively inherited disorder that can result in neurological and cutaneous symptoms (Wolf 2001). The symptoms can be improved or prevented by treating the individual with oral biotin. Biotinidase deficiency meets the criteria for inclusion in newborn screening programmes and, in fact, is currently screened for in over 25 countries (Wolf 1991). Two different centres, the Budapest Screening Centre and the East-Hungarian Screening Centre, perform the newborn screening in Hungary. The results of a pilot newborn screening programme in Hungary were published previously (Havass 1991). We now report the clinical, biochemical and mutation analysis of 20 of the 58 children suspected of having biotinidase deficiency of the 1 336 145 newborns screened between 1989 and 2002.