Long term survival and cardiopulmonary outcome in children with Hurler syndrome after haematopoietic stem cell transplantation


Premature death in untreated children with Hurler syndrome (HS) in the first decade of life is largely due to life-threatening cardiopulmonary complications. We examined the long-term survival and cardiopulmonary outcome in 54 children undergoing haematopoietic stem cell transplantation (HSCT) at the Royal Manchester Children’s Hospital from 1985 to 2008. The median age at first HSCT was 15.1 months. Eighteen had graft failure and nine died after first HSCT. Of 18 patients with graft failure, 17 underwent second HSCT and the remaining one was lost to follow-up (LOF). Twelve were alive-and-engrafted after second HSCT. The overall survival at one year and 20-years was the same at 73.7%. Six children were followed up at the referral centers and excluded from cardiopulmonary endpoint review. Of the 33 evaluable children for the cardiopulmonary endpoints, nine (27.3%) had normal cardiac assessment. Of the four children on angiotensin-converting-enzyme inhibitors, two had mild cardiomyopathy and two had aortic valvular replacement. Twenty (60%) had mild/moderate mitral and/or aortic insufficiencies. Two had overnight hypoxia needing nocturnal non-invasive support. Enzyme level and donor chimerism are important predictors of long-term cardiac outcome.

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

Fig. 1
Fig. 2



Angiotensin converting enzyme inhibitors


Aortic regurgitation


Blood-brain barrier




Central nervous system


Enzyme replacement therapy


Epstein-Barr virus




Human leucocyte antigen


Hurler syndrome


Haematopoietic stem cell transplantation


Lost to follow-up


Post-transplant lymphoproliferative disease


∝-L-iduronidase deficiency




Mitral regurgitation


Overall survival


Royal Manchester Children’s Hospital


Supraventricular tachycardia


  1. Aldenhoven M, Jones SA, Bonney D, Borrill RE, Coussons M, Mercer J, Bierings MB, Versluys B, van Hasselt PM, Wijburg FA, van der Ploeg AT, Wynn RF, Boelens JJ (2015) Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: results after implementation of international guidelines. Biol Blood Marrow Transplant 21(6):1106–1109

    CAS  Article  PubMed  Google Scholar 

  2. Bigger BW, Wynn RF (2014) Novel approaches and mechanisms in hematopoietic stem cell gene therapy. Discov Med 17(94):207–215

    PubMed  Google Scholar 

  3. Bijarnia S, Shaw P, Vimpani A, Smith R, Pacey V, O’Grady H, Christodoulou J, Sillence D (2009) Combined enzyme replacement and haematopoietic stem cell transplantation in Hurler syndrome. J Paediatr Child Health 45(7-8):469–472

    Article  PubMed  Google Scholar 

  4. Boelens JJ, Wynn RF, O’Meara A, Veys P, Bertrand Y, Souillet G, Wraith JE, Fischer A, Cavazzana-Calvo M, Sykora KW, Sedlacek P, Rovelli A, Uiterwaal CS, Wulffraat N (2007) Outcomes of hematopoietic stem cell transplantation for Hurler’s syndrome in Europe: a risk factor analysis for graft failure. Bone Marrow Transplant 40(3):225–233

    CAS  Article  PubMed  Google Scholar 

  5. Boelens JJ, Rocha V, Aldenhoven M, Wynn R, O’Meara A, Michel G, Ionescu I, Parikh S, Prasad VK, Szabolcs P, Escolar M, Gluckman E, Cavazzana-Calvo M, Kurtzberg J, I. e. W. P. o. E. Eurocord and U. Duke (2009) Risk factor analysis of outcomes after unrelated cord blood transplantation in patients with hurler syndrome. Biol Blood Marrow Transplant 15(5):618–625

    Article  PubMed  Google Scholar 

  6. Boelens JJ, Aldenhoven M, Purtill D, Ruggeri A, Defor T, Wynn R, Wraith E, Cavazzana-Calvo M, Rovelli A, Fischer A, Tolar J, Prasad VK, Escolar M, Gluckman E, O’Meara A, Orchard PJ, Veys P, Eapen M, Kurtzberg J, Rocha V, Eurocord B, Inborn Errors Working Party of European, g. Marrow Transplant, B. Duke University, P. Marrow Transplantation, B. Centre for International and R. Marrow (2013) Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning. Blood 121(19):3981–3987

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Cox-Brinkman J, Boelens JJ, Wraith JE, O’Meara A, Veys P, Wijburg FA, Wulffraat N, Wynn RF (2006) Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome. Bone Marrow Transplant 38(1):17–21

    CAS  Article  PubMed  Google Scholar 

  8. Eisengart JB, Rudser KD, Tolar J, Orchard PJ, Kivisto T, Ziegler RS, Whitley CB, Shapiro EG (2013) Enzyme replacement is associated with better cognitive outcomes after transplant in Hurler syndrome. J Pediatr 162(2):375–380.e1

    CAS  Article  PubMed  Google Scholar 

  9. Fratantoni JC, Hall CW, Neufeld EF (1968) Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science 162(3853):570–572

    CAS  Article  PubMed  Google Scholar 

  10. Fratantoni JC, Hall CW, Neufeld EF (1969) The defect in Hurler and Hunter syndromes. II. deficiency of specific factors involved in mucopolysaccharide degradation. Proc Natl Acad Sci U S A 64(1):360–366

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Grewal SS, Wynn R, Abdenur JE, Burton BK, Gharib M, Haase C, Hayashi RJ, Shenoy S, Sillence D, Tiller GE, Dudek ME, van Royen-Kerkhof A, Wraith JE, Woodard P, Young GA, Wulffraat N, Whitley CB, Peters C (2005) Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome. Genet Med 7(2):143–146

    CAS  Article  PubMed  Google Scholar 

  12. Krivit W, Sung JH, 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(4):385–392

    CAS  Article  PubMed  Google Scholar 

  13. Meikle PJ, Hopwood JJ, Clague AE, Carey WF (1999) Prevalence of lysosomal storage disorders. JAMA 281(3):249–254

    CAS  Article  PubMed  Google Scholar 

  14. Moore D, Connock MJ, Wraith E, Lavery C (2008) The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the UK. Orphanet J Rare Dis 3:24

    Article  PubMed  PubMed Central  Google Scholar 

  15. Platt FM, Boland B, van der Spoel AC (2012) The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J Cell Biol 199(5):723–734

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Scott HS, Ashton LJ, Eyre HJ, Baker E, Brooks DA, Callen DF, Sutherland GR, Morris CP, Hopwood JJ (1990) Chromosomal localization of the human alpha-L-iduronidase gene (IDUA) to 4p16.3. Am J Hum Genet 47(5):802–807

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Tolar J, Grewal SS, Bjoraker KJ, Whitley CB, Shapiro EG, Charnas L, Orchard PJ (2008) Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome. Bone Marrow Transplant 41(6):531–535

    CAS  Article  PubMed  Google Scholar 

  18. Wynn T, Brunetti S (2009) Compounding naltrexone for the treatment of autism. Int J Pharm Compd 13(4):296–299

    PubMed  Google Scholar 

  19. Wynn RF, Wraith JE, Mercer J, O’Meara A, Tylee K, Thornley M, Church HJ, Bigger BW (2009) Improved metabolic correction in patients with lysosomal storage disease treated with hematopoietic stem cell transplant compared with enzyme replacement therapy. J Pediatr 154(4):609–611

    CAS  Article  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Robert Wynn.

Ethics declarations

Conflict of interest


Details of funding


Additional information

Communicated by: Frits Wijburg

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lum, S.H., Stepien, K.M., Ghosh, A. et al. Long term survival and cardiopulmonary outcome in children with Hurler syndrome after haematopoietic stem cell transplantation. J Inherit Metab Dis 40, 455–460 (2017). https://doi.org/10.1007/s10545-017-0034-6

Download citation


  • Enzyme Replacement Therapy
  • Haematopoietic Stem Cell Transplantation
  • Donor Chimerism
  • Hurler Syndrome
  • National Health Service Foundation