Lysosomals

Lysosomal storage diseases (LSDs) are a group of more than 50 inherited metabolic disorders that result from defective lysosomal acid hydrolysis of endogenous macromolecules causing their accumulation (Winchester et al 2000). A classification based on the nature of the primary stored material involved is reported in Table 1. Actually it is well known that all LSDs are not simply due to this storage, but they result from the perturbation of complex cell-signaling mechanisms. Generally lysosomal storage disorders occur when the lysosomes do not function properly. All lysosomal storage diseases are single gene/single enzyme disorders resulting in lysosomal dysfunction. Various metabolic substrates are involved: lipids, glycoproteins and mucopolysaccharides. Most of LSDs are autosomal recessively inherited disorders, with only three exceptions: Fabry disease and Hunter disease (MPS II) are X-linked recessive, while Danon disease is X-linked dominant. To date, in the absence of newborn screening programs, true LSDs incidence is not known. Although some pilot projects reported a higher incidence (Spada et al 2006, Chien et al 2008), individual LSDs occur with an incidence of less than 1:100.000, while as a group the incidence is about 1:7700 (Meikle 1999). Comprehensive quali/quantitative analysis of the entire panel of accumulation products is still not available due to the complexity and chemical diversity of the storage products involved in LSDs. Important technological advances in the biological sciences over the past few years have forged a new era of research including the emerging field of systems biology and in particular metabolomics. Metabolomics aims at the comprehensive and qualitative identification and quantification of all metabolites in a biological system. Although in very recent years many papers have been published with very high potentiality, there is no single instrument platform/analytical technique that currently can analyze all metabolites involved in LSDs and the metabolomics approach is still not widely available. This means that LSDs analysis is generally performed on a single category of molecules with classical biochemical tests ranging from thin-layer chromatography, HPLC, electrophoresis, enzyme assays with fluorimetric/spectrophotometric detection and liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, after a diagnosis has been made by biochemical means, mutation analysis may be performed.