Abstract
Mucopolysaccharidoses (MPS) are characterized by mental retardation constantly present in the severe forms of Hurler (MPS I), Hunter (MPS II) and Sanfilippo (MPS III) diseases. On the contrary, mental retardation is absent in Morquio (MPS IV) and Maroteaux-Lamy (MPS VI) diseases and absent or only minimal in the attenuated forms of MPS I, II and III. Considering that MPS patients affected by mental disease accumulate heparan sulfate (HS) due to specific enzymatic defects, we hypothesized a possible correlation between urinary HS-derived glucosamine (GlcN) accumulated in tissues and excreted in biological fluids and mental retardation. 83 healthy subjects were found to excrete HS in the form of fragments due to the activity of catabolic enzymes that are absent or impaired in MPS patients. On the contrary, urinary HS in 44 patients was observed to be composed of high molecular weight polymer and fragments of various lengths depending on MPS types. On this basis we correlated mental retardation with GlcN belonging to high and low molecular weight HS. We demonstrate a positive relationship between the accumulation of high molecular weight HS and mental retardation in MPS severe compared to attenuated forms. This is also supported by the consideration that accumulation of other GAGs different from HS, as in MPS IV and MPS VI, and low molecular weight HS fragments do not impact on central nervous system disease.
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Acknowledgments
The authors are grateful to Fondazione Mancini for its continuous support.
Grant support
Partially supported by MIUR, Ministero dell’Istruzione, dell’Università e della Ricerca, for the project PRIN 2012 National Research Program, Prot. 20122EK9SZ_002, entitled “Comprehensive approach to mucopolysaccharidoses: application of highly specific methods for neonatal diagnosis and assessment of therapeutic efficacy in patients and in experimental animals” to O.G. and N.V.
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N.V. developed the applied methodologies. F.M., V.M., L.Z., T.G. and F.G. performed the experimental procedures and analyses. N.V., G.V.C. and O.G. designed and developed the experimental design, performed data analysis and wrote the manuscript.
All authors reviewed and approved the study.
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Coppa, G.V., Gabrielli, O., Zampini, L. et al. Mental retardation in mucopolysaccharidoses correlates with high molecular weight urinary heparan sulphate derived glucosamine. Metab Brain Dis 30, 1343–1348 (2015). https://doi.org/10.1007/s11011-015-9684-y
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DOI: https://doi.org/10.1007/s11011-015-9684-y