Biotinidase deficiency is a rare inherited metabolic disorder that can cause severe neurological symptoms. To prevent severe clinical presentations, it was included in the Dutch neonatal screening programme in 2007. Since then the number of cases detected has been high. This study set out to describe the incidence of the disease, the clinical and demographic characteristics of the neonates identified and the type of mutations found. In the south-western Netherlands, 304 982 neonates were screened between 2007 and 2012; and 92 were identified for further testing. Confirmatory testing revealed 6 (7%) with a profound biotinidase deficiency (<10% enzyme activity), 44 (48%) with a partial deficiency (10-30%) and 42 (46%) with normal activity (>30%). All six patients whose profound deficiency was confirmed had enzyme activities below 15% on neonatal screening. Mutation analysis was performed in 61 neonates: 5 'profound', 35 'partial' and 21 'normal'. All five 'profound' cases had two severe mutations. Comparison with the northern Netherlands showed that the frequency and types of mutation were representative for the Netherlands as a whole. The most common mutation detected was c.{1330G>C} (p.(Asp444His); 34%), which is considered to be mild, followed by three severe mutations c.{1368A>C}, c.{1595C>T} and c.{1330G>C;511G>A}. Seven new mutations were identified. We conclude that neonatal screening for profound biotinidase produces a high number of false positives. Biotinidase deficiency was profound in less than 10% of cases identified. As biotinidase activity lay below 15% on neonatal screening in all such cases, the screening threshold might be reduced to 15%.,
European Journal of Human Genetics
Department of Pediatrics

Wiltink, R.C. (Rachel C), Kruijshaar, M., Thornton, A., Onkenhout, W., Verheijen, F., Kemper, E.A. (Evelien A), … Williams, M. (2016). Neonatal screening for profound biotinidase deficiency in the Netherlands: Consequences and considerations. European Journal of Human Genetics, 24(10), 1424–1429. doi:10.1038/ejhg.2016.65