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Type: Journal article
Title: Prediction of neuropathology in mucopolysaccharidosis I patients
Author: Fuller, M.
Brooks, D.
Evangelista, M.
Hein, L.
Hopwood, J.
Meikle, P.
Citation: Molecular Genetics and Metabolism, 2005; 84(1):18-24
Publisher: Academic Press Inc Elsevier Science
Issue Date: 2005
ISSN: 1096-7192
Abstract: 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 mucopolysaccharidosis 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 mucopolysaccharidosis 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 mucopolysaccharidosis I patients.
Keywords: Central Nervous System; Cells, Cultured; Fibroblasts; Skin; Humans; Mucopolysaccharidosis I; Iduronidase; Dermatan Sulfate; Heparitin Sulfate; Oligosaccharides; Genotype; Phenotype; Forecasting; Adolescent; Adult; Child; Child, Preschool; Infant; Mass Spectrometry
RMID: 0020050145
DOI: 10.1016/j.ymgme.2004.09.004
Appears in Collections:Paediatrics publications

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