ArticlesNeonatal screening for lysosomal storage disorders: feasibility and incidence from a nationwide study in Austria
Introduction
Starting in the early 1960s, neonatal screening was the first organised nationwide effort to identify inborn errors of metabolism and endocrine defects at a presymptomatic stage. It was revolutionised by the introduction of electrospray ionisation tandem mass spectrometry (ESI-MS) in 1993,1 which enabled for the first time the identification of several disorders by simultaneous measurement of aminoacids and acylcarnitines.2 The increased technological capacity means that expanded neonatal screening programmes can now identify a broad range of disorders in which early detection and presymptomatic treatment result in clinical benefit. A further and more controversial benefit of such expanded programmes is the opportunity to inform parents of future reproductive risks.3
Lysosomal storage disorders are an attractive candidate for an expanded neonatal screening programme. These disorders result in the accumulation of macromolecular substrates that would normally be degraded by enzymes involved in lysosomal metabolism.4 Although individual lysosomal storage disorders are believed to be rare, their combined incidence has been estimated at 1 per 7700 livebirths for white people,5 and a third of inborn errors of metabolism in the Arabic population are attributed to these disorders.6 Progressive lysosomal substrate deposition can occur in cells throughout the body and results in gradual deterioration of renal function to end-stage renal disease, cerebrovascular, cardiovascular, or neurological disease, muscle weakness, and cardiomyopathy among others.7, 8, 9 Management by a multidisciplinary team is necessary. Lysosomal storage disorders have a progressive course, and can present at any age and affect any number of tissues and organ systems.10 In most cases, treatment is directed toward symptomatic care of secondary complications. Haemopoietic stem-cell transplantation and enzyme-replacement therapy are effective in some patients, although these therapies still have limitations.11 Nonetheless, early diagnosis and treatment are essential for optimum outcomes, which encourages the incorporation of lysosomal storage disorders into the neonatal screening panel.12
The technology for simultaneous screening of several enzyme activities related to lysosomal storage disorders from one blood punch was initially complicated, time-consuming, and laborious but new protocols and technologies are now available that allow simplified screening.13, 14, 15 Experience of nationwide screening for these disorders is scarce.16, 17, 18 We implemented a multiplex high-throughput screening assay 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.
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Study design and population
Blood spot samples from 34 736 newborn babies were collected consecutively from January, 2010, to July, 2010, during the national Austrian newborn screening programme. In Austria, neonatal screening is routine and centralised with more than 99% coverage (8·3 million inhabitants, mean 77 496 births per year, SD 1183 in the past 10 years). We analysed all samples that were screened successfully with the regular screening panel for endocrine and metabolic disorders, including cystic fibrosis,
Results
Minimum values for normal activity are above 4·0 μmol/L per h for Gaucher's disease, 2·0 μmol/L per h for Pompe's disease, 2·8 μmol/L per h for Fabry's disease, and 1·3 μmol/L per h for Niemann-Pick disease types A and B, according to the 0·1 percentile of 5000 samples of each enzyme's activity. The coefficient of variation was less than 12% for GAA, GBA, and ASM, and less than 15% for GLA with low and medium quality controls.
The adapted biochemical multiplex screening assay was successful for
Discussion
Lysosomal storage disorders are only one of a new category of disorders that will confront clinicians with difficult decisions for nationwide neonatal screening programmes. Our results showed an unexpectedly high number of babies with enzyme deficiencies in a predominantly white population in a central European country (panel). We confirmed 15 cases with pathogenetic mutations in addition to low lysosomal enzyme activities, showing a high overall incidence of 1 per 2315 births among the
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TPM and SS contributed equally