Identification Of Specific Lysosomal Storage Diseases 477

Pick A/B, and Pompe diseases [ 14] because of the recognition that simple and reliable diagnostic markers for patient identification were needed with the imminent and/or probable availability of specific therapies in these diseases. This methodological advance highlights the importance of using an easily obtainable patient sample (and in this case in small quantities) that can be transported without damage without special handling and which is highly reproducible. For the majority of the enzymes above, the filter paper system is reliable; however, in Pompe disease, for example, measured a-glucosidase activity may be a composite of other activities, making this specific assay less reliable. In its stead, and in similar cases where inhibition of nonspecific (substrate) activities cannot be totally suppressed, other assays, such as immunocapture, can be used [15] [ There is also proof of principle for the use of diagnostic biomarkers from amniotic fluid in lysosomal disorders, with the express purpose of distinguishing normal from affected and even correlation with specific storage material in some of the disorders [16] . Within the past few years the list of diseases that can be profiled on the basis of various proteins, oligosaccharides, and glycolipids includes six MPS disorders and at least eight other diseases. Of note is a urinary measure of oligo-sacchirides (glycosaminoglycan derivatives) which has met the criteria of sensitivity and specificity in identifying persons with MPS disorders and, based on unique profiles, can differentiate among (all but MPS IIIB and MPS IIIC) subtypes [17].

Generally, to be useful as true biomarkers, some correlation with clinical disease expression (i.e., predictive or prognostic value) must be proven. A urinary diagnostic test that may be an appropriate marker of both disease progression and response to therapy is urinary globotriaosylceramide (Gb3 ) in Fabry disease [18], although residual enzyme activity in the blood is a poorer marker of disease status. Similarly, in Gaucher disease, the most common lysosomal storage disorder, which has a range of clinical expression from virtually asymptomatic octogenarians to lethal neonatal forms, residual activity is a poor predictor of disease severity [19]. Therefore, in other diseases, a combination of analyses of enzyme activity with genotype or molecular phenotypes has been recommended [20] [e.g., in MPS II (Hunter disease)] to improve predictability. In summary, within the past few decades various specific assays have been developed that identify patients with enzyme deficiencies and can even quantify residual enzyme activity (relative to normal controls) based on the kinetics model of Conzelmann and Sandhoff [21] of a correlation between lipid accumulation and deficient enzyme activity [22], but residual activity is not always correlated with clinical status. Alternatively, improper or "derailed" processing of the enzyme may be indicative of disease severity since these enzymes undergo trafficking from endosome to Golgi to lysosome. This thinking has been applied in estimates of lysosomal-associated membrane proteins (LAMP-1 and LAMP-2) with the expectation of uncovering a processing defect common to all lysosomal disorders that would also be predictive of disease severity [23] . but this was not proven [24] . It has also been suggested that mutant enzyme variants may be retained in the endoplas-mic reticulum and that this may be one of the factors that determine disease severity [25]. Accumulation of lipid in the endosomes or lysosomes was shown to characterize variants of type C Niemann-Pick disease because of the presence of cholesterol [26], thereby making this a good marker, but again, this was true only for a highly specific variant of this rare disorder. It should be noted that one ramification from these and similar findings is that response to therapy, even if the modality is identical for more than one lysosomal disease, may not be uniquely or sensitively monitored using non-disease-specific markers.

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