Prediction of neuropathology in mucopolysaccharidosis I patients

Maria Fuller, Doug A. Brooks, Marco Evangelista, Leanne K. Hein, John J. Hopwood, Peter J. Meikle

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)

Abstract

Mucopolysaccharidosis I is a lysosomal storage disorder caused by a deficiency of the lysosomal hydrolase α-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 α-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 α-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 α-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.

Original languageEnglish
Pages (from-to)18-24
Number of pages7
JournalMolecular Genetics and Metabolism
Volume84
Issue number1
DOIs
Publication statusPublished or Issued - Jan 2005

Keywords

  • Central nervous system pathology
  • Dermatan sulphate
  • Electrospray- ionisation tandem mass spectrometry
  • Heparan sulphate
  • Mucopolysaccharidosis I
  • Oligosaccharides
  • α-l-Iduronidase

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

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