Journal
MOLECULAR GENETICS AND METABOLISM
Volume 84, Issue 1, Pages 18-24Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2004.09.004
Keywords
mucopolysaccharidosis I; alpha-L-iduronidase; heparan sulphate; dermatan sulphate; oligosaccharides; central nervous system pathology; electrospray-ionisation tandem mass spectrometry
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Mucopolysaccharidosis I is a lysosomal storage disorder caused by a deficiency of the lysosomal hydrolase alpha-(L)-iduronidase, which is required for the degradation of heparan sulphate and dermatan sulphate. Given the wide spectrum of disease severity in mucopolysaccharidosis I patients, one of the challenges for managing the disorder is to accurately predict clinical phenotype. Enzyme replacement therapy by intravenous infusion is unlikely to make a significant impact on central nervous system pathology and patients displaying this clinical manifestation may respond better to bone marrow transplantation. In order to predict whether mucopolysaccharidosis I patients are going to develop central nervous system pathology, we investigated a number of biochemical parameters in cultured skin fibroblasts from patients of different genotype/phenotype. Residual levels of alpha-(L)-iduronidase activity and protein were determined using sensitive immune-quantification assays and fibroblast cell extracts from patients with central nervous system pathology generally had lower levels of alpha-(L)-iduronidase than patients with no evidence of central nervous system disease. A total of 15 oligosaccharides, derived from heparan sulphate and dermatan sulphate, was measured in fibroblast extracts using electrospray-ionisation tandem mass spectrometry and all were shown to discriminate mucopolysacchariclosis I from controls. Of these, two trisaccharides were able to group patients based on the presence/absence of central nervous system disease. Moreover, a ratio of alpha-(L)-iduronidase activity to these trisaccharides provided clear discrimination between mucopolysacchariclosis I patients with and without central nervous system pathology. We suggest that this type of analysis may be very useful for predicting disease severity in mucopolysacchariclosis I patients. (C) 2004 Elsevier Inc. All rights reserved.
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