Skip to main content
Log in

Mental retardation in mucopolysaccharidoses correlates with high molecular weight urinary heparan sulphate derived glucosamine

  • Research Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Ahmed A, Whitley CB, Cooksley R, et al (2014) Neurocognitive and neuropsychiatric phenotypes associated with the mutation L238Q of the α-L-iduronidase gene in Hurler-Scheie syndrome. Mol Genet Metab 111:123–127

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bruyère J, Roy E, Ausseil J, et al (2015) Heparan sulfate saccharides modify focal adhesions: implication in mucopolysaccharidosis neuropathophysiology. J Mol Biol 427:775–791

    Article  PubMed  Google Scholar 

  • Coppa GV, Galeotti F, Zampini L, et al (2011a) High-throughput determination of urinary hexosamines for diagnosis of mucopolysaccharidoses by capillary electrophoresis and high-performance liquid chromatography. Anal Biochem 411:32–42

    Article  CAS  PubMed  Google Scholar 

  • Coppa GV, Buzzega D, Zampini L, et al (2011b) Agarose-gel electrophoresis for the diagnosis of mucopolysaccharidoses. Clin Chem Lab Med 50:589–592

    PubMed  Google Scholar 

  • Coppa GV, Galeotti F, Zampini L, et al (2013) Mild mental retardation and low levels of urinary heparan sulphate in a patient with attenuated phenotype of mucopolysaccharidosis type IIIA. Clin Biochem 46:688–690

    Article  CAS  PubMed  Google Scholar 

  • de Ruiter J, Ijlist L, Kulik W, et al (2013) Heparan sulfate derived disaccharides in plasma and total urinary excretion of glycosaminoglycans correlate with disease severity in Sanfilippo disease. J Inherit Metab Dis 36:271–279

    Article  Google Scholar 

  • Hopwood JJ, Elliott H (1985) Urinary excretion of sulphated N-acetylhexosamines in patients with various MPS. Biochem J 229:579–586

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jackson RJ, Busch SJ, Cardin AD (1991) Glycosaminoglycans: molecular properties, protein interactions, and role in physiological processes. Physiol Rev 71:481–539

    CAS  PubMed  Google Scholar 

  • Komosinska-Vassev K, Blat D, Olczyk P, et al (2014) Urinary glycosaminoglycan (uGAG) excretion in healthy pediatric and adolescent population. Clin Biochem 47:1341–1343

    Article  CAS  PubMed  Google Scholar 

  • Lamanna WC, Lawrence R, Sarrazin S, et al (2011) Secondary storage of dermatan sulfate in Sanfilippo disease. J Biol Chem 286:6955–6962

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lehman TJA, Miller N, Norquist B, et al (2011) Diagnosis of the mucopolysaccharidoses. Rheumatol 50:v41–v48

    Article  CAS  Google Scholar 

  • Lokeshwar VB, Selzer MG, Cerwinka WH, et al (2005) Urinary uronate and sulfated glycosaminoglycan levels: markers for interstitial cystitis severity. J Urol 174:344–349

    Article  CAS  PubMed  Google Scholar 

  • Neufeld EF, Muenzer J (2007) The mucopolysaccharidoses. In: Valle D, Beaudet AL, Vogelstein B, et al (eds). The online metabolic and molecular bases of inherited disease. McGraw-Hill, New York, Chapter 136

    Google Scholar 

  • Rumsey RK, Rudser K, Delaney K, et al (2014) Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J Pediatr 164:1147–1151.e1

    Article  PubMed Central  PubMed  Google Scholar 

  • Stone JE (1998) Urine analysis in the diagnosis of mucopolysaccharide disorders. Ann Clin Biochem 35:207–225

    Article  CAS  PubMed  Google Scholar 

  • Tomatsu S, Okamura K, Maeda H, et al (2012) Keratan sulphate levels in mucopolysaccharidoses and mucolipidoses. J Inherit Metab Dis 28:187–202

    Article  Google Scholar 

  • Wilkinson FL, Holley RJ, Langford-Smith KJ, et al (2012) Neuropathology in mouse models of mucopolysaccharidosis type I, IIIA and IIIB. PLoS One 7:e35787

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

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.

Contributors

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.

Conflict of interest

We declare no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N. Volpi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-015-9684-y

Keywords

Navigation