Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H

Abstract

Mucopolysaccharidosis (MPS) type-IH is a lysosomal storage disease that results from mutations in the IDUA gene causing the accumulation of glycosaminoglycans (GAGs). Historically, children with the severe phenotype, MPS-IH (Hurler syndrome) develop progressive neurodegeneration with death in the first decade due to cardio-pulmonary complications. New data suggest that inflammation may play a role in MPS pathophysiology. To date there is almost no information on the pathophysiologic changes within the cerebral spinal fluid (CSF) of these patients. We evaluated the CSF of 25 consecutive patients with MPS-IH. While CSF glucose and total protein were within the normal range, we found a significantly mean elevated CSF opening pressure at 24 cm H2O (range 14–37 cm H2O). We observed a 3-fold elevation in CSF heparan sulfate and a 3–8 fold increase in MPS-IH specific non-reducing ends, I0S0 and I0S6. Cytokine analyses in CSF of children with MPS-IH showed significantly elevated inflammatory markers including: MCP-1 SDF-1a, IL-Ra, MIP-1b, IL-8, and VEGF in comparison to unaffected children. This is the largest report of CSF characteristics in children with MPS-IH. Identification of key biomarkers may provide further insight into the inflammatory-mediated mechanisms related to MPS diseases and perhaps lead to improved targeted therapies.

Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients

“…In addition to showing lysosomal dysfunction, MPS II mouse brains (as well MPS I and III) show widespread neuroinflammation and astrogliosis, as indicated by increased markers of gliosis [ 11 , 12 , 13 ], and increased inflammatory cytokines [ 12 ]. This is in agreement with the observation that plasma and CSF from MPS I patients showed significantly elevated inflammatory cytokines, including IL-1b, TNF-a, MCP-1 SDF-1a, IL-Ra, MIP-1b, IL-8, and VEGF [ 14 , 15 , 16 ].…”

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology

“…TLR-4 activation results in the increased expression and release of pro-inflammatory cytokines, chemokines, and matrix metalloproteinases [104,105]. TLR-4-mediated TNF-α release is central to the inflammatory immune response observed in MPS I [104], with major impacts on synovial inflammation and joint disease [193,194], neuroinflammation [132,133], cardiovascular disease [195], and chronic pain [196]. Polgreen et al followed up their initial finding of elevated TNF-α levels in MPS I patients with chronic pain and limited physical function [196] with a small pilot study, where MPS patients received TNF-α inhibitor adalimumab [197].…”

Fast, sensitive method for trisaccharide biomarker detection in mucopolysaccharidosis type 1

“…Sample volumes of 10 µl were sufficient for our assay. The full study on these patients will be presented elsewhere; here the purpose was to assess the sensitivity our LC-mass spec method and to compare the results to those obtained with the I0S6 Sensi pro method (Arup, Salt Lake City, Utah, also mentioned in 25 , 26 ). In the I0S6 approach, non-reducing end disaccharides containing iduronic acid and sulfated glucose amine at position 6 are conjugated with a fluorescent label and quantified.…”