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: Maria Fuller, Doug A Brooks, Marco Evangelista, Leanne K Hein, John J Hopwood, Peter J Meikle
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 84 Issue 1 Pg. 18-24 (Jan 2005) ISSN: 1096-7192 [Print] United States
• PMID: 15639191 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Oligosaccharides
• Dermatan Sulfate
• Heparitin Sulfate
• Iduronidase

Topics

• Adolescent
• Adult
• Cells, Cultured
• Central Nervous System (pathology)
• Child
• Child, Preschool
• Dermatan Sulfate (metabolism)
• Fibroblasts (enzymology)
• Forecasting
• Genotype
• Heparitin Sulfate (metabolism)
• Humans
• Iduronidase (metabolism)
• Infant
• Mass Spectrometry
• Mucopolysaccharidosis I (metabolism, pathology)
• Oligosaccharides (metabolism)
• Phenotype
• Skin (cytology)