Early Umbilical Cord Blood-Derived Stem Cell Transplantation Does Not Prevent Neurological Deterioration in Mucopolysaccharidosis Type III

  • Lindsey Welling
  • Jan Pieter Marchal
  • Peter van Hasselt
  • Ans T. van der Ploeg
  • Frits A. WijburgEmail author
  • Jaap Jan Boelens
Case Report
Part of the JIMD Reports book series (JIMD, volume 18)


Mucopolysaccharidosis type III (MPS III), or Sanfilippo disease, is a neurodegenerative lysosomal storage disease (LSD) caused by defective lysosomal degradation of heparan sulfate (HS). No effective disease-modifying therapy is yet available. In contrast to some other neuronopathic LSDs, bone marrow-derived hematopoietic stem cell transplantation (HSCT) fails to prevent neurological deterioration in MPS III patients. We report on the 5-year outcome of early transplantation, i.e., before onset of clinical neurological disease, in combination with the use of umbilical cord blood-derived hematopoietic stem cells (UCBT), in two MPS III patients. Both patients had a normal developmental quotient at the time of UCBT. One patient had a combination of mutations predicting a classical severe phenotype (MPS IIIA), and one patient (MPS IIIB) had mutations predicting a very attenuated phenotype. Transplantation was uncomplicated with full engraftment of donor cells in both.

Both patients showed progressive neurological deterioration with regression of cognitive skills and behavioral disturbances during 5 years after successful UCBT, comparable to the natural history of patients with the same combination of mutations. The concentration of HS in CSF in the patient with the attenuated phenotype of MPS IIIB 2 years after UCBT was very high and in the range of untreated MPS III patients.

We conclude that the course of cognitive development, behavioral problems, and absence of biochemical correction in CSF demonstrate the absence of relevant effect of UCBT in MPS III patients, even when performed before clinical onset of CNS disease.


Hematopoietic Stem Cell Transplantation Central Nervous System Disease Lysosomal Storage Disease Developmental Quotient Umbilical Cord Blood Transplantation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. De Bildt AA, Kraijer DW (2003) Vineland-Z (Handleiding). PITS BV, LeidenGoogle Scholar
  2. Boelens JJ, Prasad VK, Tolar J et al (2010) Current international perspectives on hematopoietic stem cell transplantation for inherited metabolic disorders. Pediatr Clin North Am 57:123–145. doi: 10.1016/j.pcl.2009.11.004 CrossRefPubMedGoogle Scholar
  3. Buhrman D, Thakkar K, Poe M, Escolar ML (2014) Natural history of Sanfilippo syndrome type A. J Inherit Metab Dis 37:431–437. doi: 10.1007/s10545-013-9661-8 CrossRefPubMedGoogle Scholar
  4. Griffiths R (1970) The abilities of young children. Child Development Research Center, LondonGoogle Scholar
  5. De Jong JG, Wevers RA, Liebrand-van Sambeek R (1992) Measuring urinary glycosaminoglycans in the presence of protein: an improved screening procedure for mucopolysaccharidoses based on dimethylmethylene blue. Clin Chem 38:803–807PubMedGoogle Scholar
  6. Klein K, Krivit W, Whitley C et al. (1995) Poor cognitive outcome of eleven children with Sanfilippo syndrome after bone marrow transplantation and successful engraftment. Bone Marrow Trans 15(SUPPL):S176–S181Google Scholar
  7. Krivit W, Ho Sung J, Shapiro EG, Lockman LA (1995) Microglia: the effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases. Cell Transplant 4:385–392CrossRefPubMedGoogle Scholar
  8. Langford-Smith A, Wilkinson FL, Langford-Smith KJ et al (2012) Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice. Mol Ther 20:1610–1621. doi: 10.1038/mt.2012.82 CrossRefPubMedCentralPubMedGoogle Scholar
  9. Lawrence R, Lu H, Rosenberg R et al (2008) Disaccharide structure code for the easy representation of constituent oligosaccharides from glycosaminoglycans. Nat Methods 5:291–292CrossRefPubMedGoogle Scholar
  10. Van der Meulen B, Ruiter S, Lutje Spelberg H, Smrkovskỳ M (2002) BSID-II-NL, Dutch manual. Swets, LisseGoogle Scholar
  11. Meyer A, Kossow K, Gal A et al (2008) The mutation p.Ser298Pro in the sulphamidase gene (SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis type IIIA (Sanfilippo a syndrome). Hum Mutat 29:770CrossRefPubMedGoogle Scholar
  12. Moore C, O’Keefe S, Lawhown D, Tellegen P (1998) Concurrent validity of the Snijders-Oomen nonverbal intelligence test 2 1/2-7-revised with the Wechsler Preschool and primary scale of intelligence-revised. Psychol Rep 82:619–625CrossRefGoogle Scholar
  13. Peters C, Balthazor M, Shapiro EG et al (1996) Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood 87:4894–4902PubMedGoogle Scholar
  14. Peters C, Shapiro EG, Anderson J et al. (1998) Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. 2601–2608Google Scholar
  15. Prasad VK, Mendizabal A, Parikh SH et al (2008) Unrelated donor umbilical cord blood transplantation for inherited metabolic disorders in 159 pediatric patients from a single center: influence of cellular composition of the graft on transplantation outcomes. Blood 112:2979–2989. doi: 10.1182/blood-2008-03-140830 CrossRefPubMedCentralPubMedGoogle Scholar
  16. De Ru MH, Boelens JJ, Das AM et al (2011) Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure. Orphanet J Rare Dis 6:55. doi: 10.1186/1750-1172-6-55 CrossRefPubMedCentralPubMedGoogle Scholar
  17. De Ru MH, van der Tol L, van Vlies N et al (2013) Plasma and urinary levels of dermatan sulfate and heparan sulfate derived disaccharides after long-term enzyme replacement therapy (ERT) in MPS I: correlation with the timing of ERT and with total urinary excretion of glycosaminoglycans. J Inherit Metab Dis 36:247–255. doi: 10.1007/s10545-012-9538-2 CrossRefPubMedGoogle Scholar
  18. Scholte E, Van Duijn G, Dijkxhoorn Y et al (2008) Vineland screener 0–6 years: manual of the Dutch adaptation. PITS, LeidenGoogle Scholar
  19. Shapiro EG, Lockman LA, Balthazor M, Krivit W (1995) Neuropsychological outcomes of several storage diseases with and without bone marrow transplantation. J Inherit Metab Dis 18:413–429CrossRefPubMedGoogle Scholar
  20. Sivakumur P, Wraith JE (1999) Bone marrow transplantation in mucopolysaccharidosis type IIIA: a comparison of an early treated patient with his untreated sibling. J Inherit Metab Dis 22:849–850CrossRefPubMedGoogle Scholar
  21. Valstar MJ, Bruggenwirth HT, Olmer R et al (2010a) Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype. J Inherit Metab Dis 33:759–767. doi: 10.1007/s10545-010-9199-y CrossRefPubMedCentralPubMedGoogle Scholar
  22. Valstar MJ, Neijs S, Bruggenwirth HT et al (2010b) Mucopolysaccharidosis type IIIA: clinical spectrum and genotype-phenotype correlations. Ann Neurol 68:876–887. doi: 10.1002/ana.22092 CrossRefPubMedGoogle Scholar
  23. Valstar MJ, Ruijter GJG, van Diggelen OP et al (2008) Sanfilippo syndrome: a mini-review. J Inherit Metab Dis 31:240–252. doi: 10.1007/s10545-008-0838-5 CrossRefPubMedGoogle Scholar
  24. Vellodi A, Young E, New M et al (1992) Bone marrow transplantation for Sanfilippo disease type B. J Inherit Metab Dis 15:911–918CrossRefPubMedGoogle Scholar
  25. Weber B, Guo XH, Kleijer WJ et al (1999) Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes. Eur J Hum Genet 7:34–44. doi: 10.1038/sj.ejhg.5200242 CrossRefPubMedGoogle Scholar
  26. Weber B, Guo XH, Wraith JE et al (1997) Novel mutations in Sanfilippo A syndrome: implications for enzyme function. Hum Mol Genet 6:1573–1579CrossRefPubMedGoogle Scholar
  27. Wynn RF, Wraith JE, Mercer J et al (2009) Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy. J Pediatr 154:609–611. doi: 10.1016/j.jpeds.2008.11.005 CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Lindsey Welling
    • 1
  • Jan Pieter Marchal
    • 2
  • Peter van Hasselt
    • 3
  • Ans T. van der Ploeg
    • 4
  • Frits A. Wijburg
    • 1
    Email author
  • Jaap Jan Boelens
    • 5
  1. 1.Division of Metabolic Diseases (H7-270), Department of Pediatrics and Amsterdam Lysosome Center “Sphinx”Academic Medical Center (AMC), University of AmsterdamAmsterdamThe Netherlands
  2. 2.Psychosocial DepartmentAcademic Medical Center, University of AmsterdamAmsterdamThe Netherlands
  3. 3.Department of Pediatric Gastroenterology and Metabolic DiseasesWilhelmina Children’s Hospital, University Medical Center UtrechtUtrechtThe Netherlands
  4. 4.Department of Pediatrics and Center for Lysosomal and Metabolic DiseasesErasmus MC University Medical CenterRotterdamThe Netherlands
  5. 5.Pediatric Blood and Marrow Transplantation ProgramWilhelmina Children’s Hospital, University Medical Center UtrechtUtrechtThe Netherlands

Personalised recommendations