keratan-sulfate and Mucopolysaccharidosis-I

Topics: Age of Onset; beta-Galactosidase; Bone Diseases, Developmental; Bone Marrow Examination; Diagnosis, Differential; Facial Bones; Female; Gangliosidosis, GM1; Glycosaminoglycans; Humans; Infant; Keratan Sulfate; Kyphosis; Leukocytes; Mucolipidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis IV; Odontoid Process; Pedigree; Scoliosis

Application of metabolic phenotyping could expand the pathophysiological knowledge of mucopolysaccharidoses (MPS) and may reveal the comprehensive metabolic impairments in MPS. However, few studies applied this approach to MPS.. We applied targeted and untargeted metabolic profiling in urine samples obtained from a French cohort comprising 19 MPS I and 15 MPS I treated patients along with 66 controls. For that purpose, we used ultra-high-performance liquid chromatography combined with ion mobility and high-resolution mass spectrometry following a protocol designed for large-scale metabolomics studies regarding robustness and reproducibility. Furthermore, 24 amino acids have been quantified using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Keratan sulfate, Heparan sulfate and Dermatan sulfate concentrations have also been measured using an LC-MS/MS method. Univariate and multivariate data analyses have been used to select discriminant metabolites. The mummichog algorithm has been used for pathway analysis.. The studied groups yielded distinct biochemical phenotypes using multivariate data analysis. Univariate statistics also revealed metabolites that differentiated the groups. Specifically, metabolites related to the amino acid metabolism. Pathway analysis revealed that several major amino acid pathways were dysregulated in MPS. Comparison of targeted and untargeted metabolomics data with in silico results yielded arginine, proline and glutathione metabolisms being the most affected.. This study is one of the first metabolic phenotyping studies of MPS I. The findings might help to generate new hypotheses about MPS pathophysiology and to develop further targeted studies of a smaller number of potentially key metabolites.

Topics: Adolescent; Adult; Aged; Algorithms; Amino Acids; Arginine; Case-Control Studies; Child; Child, Preschool; Chromatography, High Pressure Liquid; Dermatan Sulfate; Female; Glutathione; Heparitin Sulfate; Humans; Infant; Keratan Sulfate; Male; Mass Spectrometry; Metabolome; Metabolomics; Middle Aged; Mucopolysaccharidosis I; Multivariate Analysis; Phenotype; Proline

Corneal opacification associated with glycosaminoglycan (GAG) deposition occurs in canine mucopolysaccharidosis I (MPS I), a deficiency of the lysosomal enzyme alpha-L-iduronidase. In affected dogs corneal lesions appear similar to those in children with the same disease. Transplantation of bone marrow from unaffected littermates was performed in 5 MPS I affected dogs at 5 months of age. In three recipients that became long-term survivors corneal clouding was largely alleviated compared to affected control dogs. In no case, however, did the corneas remain totally clear throughout the course of the study (594, 628 and 1425 days). Light and electron microscopic findings correlated with the clinical impression of partial improvement. Glycosaminoglycan analysis of corneal tissue from two transplant recipients, one normal littermate, and one MPS I-affected, untransplanted dog showed quantitative and qualitative changes in stored GAG following bone marrow transplantation.

Topics: Animals; Bone Marrow Transplantation; Corneal Opacity; Dermatan Sulfate; Dogs; Electrophoresis; Glycosaminoglycans; Keratan Sulfate; Mucopolysaccharidosis I; Time Factors

Acidic glycosaminoglycans (GAGs) and gangliosides were analyzed in the brains from control fetuses, fetal Hurler syndrome, control children and three patients affected by genetic mucopolysaccharidosis (Hurler, Hunter and Morquio syndromes). GAGs contents in the brains from patients with Hurler and Hunter syndromes were approximately 1.5-3.0-fold greater as compared with those controls, and most of the GAGs were much more degraded than those from controls. Dermatan sulfate (DS), which was not identified in the control brains, comprised about 20--40% of the total GAGs. On the other hand, GAGs content and molecular weight distribution in the brain from the patient affected by Morquio syndrome were similar to those in the control brains. GAGs content in the brain from fetal Hurler syndrome was also 2.0-fold greater and DS, which was not detected in the control fetal brains, comprised 1.6% of the total GAGs. However, the molecular weight distribution of the GAGs was similar to those of the control fetal brains. The total amount of the brain gangliosides in all patients assayed here was similar to those in the control brains. However, a greater amount of GM1- and Gm2-gangliosides was observed in the brains from patients with Hurler and Hunter syndromes.

Topics: Adolescent; Brain; Brain Chemistry; Child; Child, Preschool; Dermatan Sulfate; Fetus; Gangliosides; Glycosaminoglycans; Humans; Infant; Keratan Sulfate; Mucopolysaccharidosis I; Mucopolysaccharidosis II; Mucopolysaccharidosis IV