Disease-Specific Markers for the Mucopolysaccharidoses

Abstract

Unprecedented demands are now placed on clinicians for early diagnosis as we enter into an era of advancing treatment opportunities for the mucopolysaccharidoses (MPS). Biochemical monitoring of any therapeutic avenue will also be prerequisite. To this end, we aimed to identify a range of urinary oligosaccharides that could be used to identify and characterize patients with MPS. We analyzed 94 urine samples from 68 patients with MPS and 26 control individuals for oligosaccharides derived from glycosaminoglycans using electrospray ionization-tandem mass spectrometry. The oligosaccharide profile for each patient group was compared with that of the control group. The Mann-Whitney U test was used to measure the difference between each patient group and the controls for each analyte. Urine samples from patients before and at successive times after bone marrow transplantation were also evaluated. A number of oligosaccharides were identified in the urine of each MPS subtype, and for each of these, specific oligosaccharide profiles were formulated. These profiles enabled the identification of all 68 patients and their subtypes with the exception of MPS IIIB and IIIC. Selected oligosaccharides were used to assess three individuals after a bone marrow transplant, and, in each case, a substantial reduction in the level of diagnostic oligosaccharides, posttransplantation, was observed. The identification and measurement of glycosaminoglycan-derived oligosaccharides in urine provides a sensitive and specific screen for the early identification of individuals with MPS. The resulting oligosaccharide profiles not only characterize subtype but also provide a disease-specific fingerprint for the biochemical monitoring of current and proposed therapies. The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders characterized by a deficiency in one of the lysosomal enzymes required to degrade glycosaminoglycans (GAG). There are 11 known enzyme deficiencies that give rise to seven distinct types of MPS, with a combined incidence of~1 in 16,000 (1). In all MPS subtypes, partially degraded GAG accumulate in the lysosomes of affected cells and/or are excreted in the urine. The lysosomal storage of GAG leads to the chronic and progressive deterioration of cells, tissues, and organs (2). The MPS share many clinical manifestations, including organomegaly, abnormal facial features, and dysostosis multiplex. Impaired hearing, vision, and joint mobility, as well as abnormal airway and cardiovascular function, are common, although there is wide clinical heterogeneity within each enzyme deficiency. Profound mental retardation is characteristic of the severe forms of MPS I, II, and VII and all subtypes of MPS III. Similar and severe skeletal and joint abnormalities are present in MPS I, II, VI, and VII, whereas MPS IV develops different skeletal pathology.The clinical management for MPS is changing, as new treatment options, such as enzyme replacement therapy, that will complement and replace bone marrow transplantatio...

Mucopolysaccharidosis Type I, Unique Structure of Accumulated Heparan Sulfate and Increased N-Sulfotransferase Activity in Mice Lacking α-l-iduronidase

“…Previous methods identifying diagnostic oligosaccharides in the urine of MPSIH patients required extensive GAG purification followed by MS for visualization (39,40). Our quick purification, labeling, and RP-HPLC method to analyze small amounts of material from in vivo samples in just a few days, represents a significant advance in the analysis of primary tissues and clinical specimens.…”

Reliability of a visual test for the rapid detection of mucopolysaccharidoses: GAG-test®

“…Sometimes, there can be a delay in the diagnosis of MPS owing to the late onset of less progressive phenotypes. This has prompted the publication of guidelines for their diagnosis and management (26) and the possibility of neonatal screening is being developed (27). It should be borne in mind that during the first periods of the disease, physicians can detect few signs or no specific symptoms within a wide range of presentations (neurological, rheumatological, cardiorespiratory, dermatological, ophthalmological, etc.)…”

Establishment of glycosaminoglycan assays for mucopolysaccharidoses

“…After digestion, the samples are loaded into the LC-MS/MS for quantitation, and the results are compared with control samples (Figure 2). The LC-MS/MS method for analysis of disaccharides not only shows sensitivity and specificity for detecting all subtypes of MPS but also can monitor therapeutic efficacy in MPS patients and animal models [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. This method has an advantage of being both GAG-specific and quantitative.…”