Lysosomal diseases: diagnostic update

Technological developments in newborn and population screening, biomarker discovery for monitoring treatment and rapid high throughput DNA sequencing are having a great impact on the diagnostic procedure for symptomatic patients with lysosomal storage diseases. The use of dried blood spots, initially for newborn screening, has stimulated the introduction of automated, rapid and more sensitive methods for the assay of lysosomal enzymes, including the synthesis of novel substrates. Storage products and secondary metabolites in urine and cells can be identified and measured very accurately and sensitively by high performance liquid chromatography and tandem mass spectrometry. This has enhanced the preliminary metabolite screen for LSDs and facilitated the diagnosis of transport defects. Fast, reliable and affordable high throughput DNA sequencing, such as whole or selected exome sequencing, is helping to make diagnoses in difficult cases, to reveal novel gene defects, to widen the clinical spectrum of diseases and possibly to identify modifying genetic factors. Bioinformatics will be necessary to handle the data generated by these new technologies. Notwithstanding, these technical innovations, accurate and reliable diagnosis will still depend on the knowledge and experience of skilled laboratory staff.