Lysosomal storage disorders: Molecular basis and laboratory testing

Although the first clinical descriptions of patients with lysosomal storage disorders (LSDs) were reported at the end of the nineteenth century by Warren Tay (1881)[1] and Bernard Sachs (1887; Tay-Sachs disease),[2] and by Phillipe Gaucher (1882) (Gaucher disease),[3] the biochemical nature of the accumulated products was only elucidated some 50 years later (1934) in the latter, as glucocerebroside [4]. Considerably more time was then required for the demonstration by Hers (1963) that there was a link between an enzyme deficiency and a storage disorder (Pompe disease) [5]. In the following years, the elucidation of several enzyme defects led to the initial classification of the various types of LSDs according to their clinical pictures, pathological manifestations and the biochemical nature of the undegraded substrates. Although part of this classification is still maintained, it is continually updated on the basis of newly acquired knowledge on the underlying molecular pathology.At present, more than 50 LSDs are known. The majority of these result from a deficiency of specific lysosomal enzymes. In a few cases, non-enzymatic lysosomal proteins or non-lysosomal proteins involved in lysosomal biogenesis are deficient.The common biochemical hallmark of these diseases is the accumulation of undigested metabolites in the lysosome. This can arise through several mechanisms as a result of defects in any aspect of lysosomal biology that hampers the catabolism of molecules in the lysosome, or the egress of naturally occurring molecules from the lysosome. Lysosomal accumulation activates a variety of pathogenetic cascades that result in complex clinical pictures characterised by multi-systemic involvement [6-10]. Phenotypic expression is extremely variable, as it depends on the specific macromolecule accumulated, the site of production and degradation of the specific metabolites, the residual enzymatic expression and the general genetic background of the patient. Many LSDs h