Neonatal screening for lysosomal storage disorders: feasibility and incidence from a nationwide study in Austria

Background The interest in neonatal screening for lysosomal storage disorders has increased substantially because of newly developed enzyme replacement therapies, the need for early diagnosis, and technical advances. We tested for Gaucher's disease, Pompe's disease, Fabry's disease, and Niemann-Pick disease types A and B in an anonymous prospective nationwide screening study that included genetic mutation analysis to assess the practicality and appropriateness of including these disorders in neonatal screening panels. Methods Specimens from dried blood spots of 34 736 newborn babies were collected consecutively from January, 2010 to July, 2010, as part of the national routine Austrian newborn screening programme. Anonymised samples were analysed for enzyme activities of acid beta-glucocerebrosidase, alpha-galactosidase, alpha-glucosidase, and acid sphingomyelinase by electrospray ionisation tandem mass spectrometry. Genetic mutation analyses were done in samples with suspected enzyme deficiency. Findings All 34 736 samples were analysed successfully by the multiplex screening assay. Low enzyme activities were detected in 38 babies. Mutation analysis confirmed lysosomal storage disorders in 15 of them. The most frequent mutations were found for Fabry's disease (1 per 3859 births), followed by Pompe's disease (1 per 8684), and Gaucher's disease (1 per 17 368). The positive predictive values were 32% (95% CI 16-52), 80% (28-99), and 50% (7-93), respectively. Mutational analysis detected predominantly missense mutations associated with a late-onset phenotype. Interpretation The combined overall proportion of infants carrying a mutation for lysosomal storage disorders was higher than expected. Neonatal screening for lysosomal storage disorders is likely to raise challenges for primary health-care providers. Furthermore, the high frequency of late-onset mutations makes lysosomal storage disorders a broad health problem beyond childhood.