title: Prediction of neuropathology in mucopolysaccharidosis I patients.
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.
authors.affiliation: Lysosomal Diseases Research Unit, Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, SA 5006, Australia. maria.fuller@adelaide.edu.au
authors.forename: Maria
authors.initials: M
authors.lastname: Fuller
authors.forename: Doug A
authors.initials: DA
authors.lastname: Brooks
authors.forename: Marco
authors.initials: M
authors.lastname: Evangelista
authors.forename: Leanne K
authors.initials: LK
authors.lastname: Hein
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D003871:Dermatan Sulfate / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology; D005544:Forecasting; D005838:Genotype; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D007068:Iduronidase / Q000378:metabolism; D007223:Infant; D013058:Mass Spectrometry; D008059:Mucopolysaccharidosis I / Q000378:metabolism* / Q000473:pathology*; D009844:Oligosaccharides / Q000378:metabolism; D010641:Phenotype; D012867:Skin / Q000166:cytology
chemical_list: D003871:Dermatan Sulfate; D006497:Heparan Sulfate; D007068:Iduronidase; D009844:Oligosaccharides