Journal of Inherited Metabolic Disease

, Volume 33, Supplement 3, pp 123–127

The effects of early and late bone marrow transplantation in siblings with alpha-mannosidosis. Is early haematopoietic cell transplantation the preferred treatment option?

Case Report


This article documents both the neurological and physical outcomes of the first published set of siblings undergoing transplantation at differing ages for α-mannosidosis. The older brother, the index case, was diagnosed at the age of 3 years and underwent transplantation at 13 years for the treatment of increasing somatic problems and recurrent infections. The younger brother had undergone transplantation pre-symptomatically at 6 months of age. Their clinical, radiological and developmental outcomes are documented and compared with the previous published cases, with the case for early transplantation being weighted against other potential therapies.



enzyme replacement therapy


haematopoietic cell transplantation


human leukocyte antigen


magnetic resonance imaging


computed tomography


mucopolysaccharidosis type 1


central nervous system


  1. Abraham D, Muir H, Olsen I, Winchester B (1985) Direct enzyme transfer from lymphocytes corrects a lysosomal storage disease. Biochem Biophys Res Commun 129:417–425PubMedCrossRefGoogle Scholar
  2. Albert MH, Schuster F, Peters C et al (2003) T cell depleted peripheral blood stem cell transplantation for α-mannosidosis. Bone Marrow Transplant 32:443–446PubMedCrossRefGoogle Scholar
  3. Ara JR, Mayayo E, Marzo ME, Guelbenzu S, Chabis A, Pina MA, Calderon C (1999) Neurological impairment in α-mannosidosis: a longitudinal clinical and MRI study of a brother and sister. Childs Nerv Syst 15:369–371PubMedCrossRefGoogle Scholar
  4. Bahr BA, Bendiske J (2002) The neuropathogenic contributions of lysosomal dysfunction. J Neurochem 83:481–489PubMedCrossRefGoogle Scholar
  5. Berg T, Riise HM, Hansen GM, Malm D, Tranebbjarg L, Tollersrud OK (1999) Spectrum of mutations in alpha-mannosidosis. Am J Hum Genet 64:77–88PubMedCrossRefGoogle Scholar
  6. Blanz J, Stroobants S, Lullmann-Rauch R et al (2008) Reversal of peripheral and central neuronal storage and ataxia after recombinant enzyme replacement therapy in α-mannosidosis mice. Hum Mol Genet 17:3437–3445PubMedCrossRefGoogle Scholar
  7. Boelens JJ, Wynn RF, O’Meara A et al (2007) Outcomes of hematopoietic stem cell transplantation for Hurler’s syndrome in Europe: a risk factor analysis for graft failure. Bone Marrow Transplant 40:225–233PubMedCrossRefGoogle Scholar
  8. Chester MA, Lundblad A, Ockerman PA, Autio S (1982) Mannosidosis. In: Durand P, O’Brien JS (eds) Genetic errors in glycoprotein metabolism. Springer, Berlin, p 89CrossRefGoogle Scholar
  9. Clark GF, Patankar MS (1998) Response to a letter to Glyco-Forum entitled “Hypothesis: immunodeficiencies ina-mannosidosis, mycosis, AIDS and cancer—acommon mechanism of inhibition of the functionof the lectin interleukin 2 by oligomannosides”. Glycobiology 8:iii–ivGoogle Scholar
  10. Crawley AC, Walkley SU (2007) Developmental analysis of CNS pathology in the lysosomal storage disease α-mannosidosis. J Neuropathol Exp Neurol 66:687–697PubMedCrossRefGoogle Scholar
  11. Dietmann JL, Flippi de la Palavesa MM, Tranchant C, Kastler B (1990) MR findings in mannosidosis. Neuroradiology 32:485–487, PMID 2287376CrossRefGoogle Scholar
  12. Dobrenis K (1992) Mechanisms underlying successful treatment of neuronal storage disease. Abstract 034 of the 7th International Congress of Inborn Errors of Metabolism, Vienna, AustriaGoogle Scholar
  13. Futerman AH, van Meer G (2004) The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol 5:554–565PubMedCrossRefGoogle Scholar
  14. Grewal SS, Shapiro EG, Krivit W et al (2004) Effective treatment of α-mannosidosis by allogeneic haematopoietic stem cell transplantation. J Pediatr 144:569–573PubMedCrossRefGoogle Scholar
  15. Hansen MD, Filipovich AH, Davies SM et al (2008) Allogeneic hematopoietic cell transplantation (HCT) in Hurler’s syndrome using a reduced intensity preparative regimen. Bone Marrow Transplant 41:349–353PubMedCrossRefGoogle Scholar
  16. Hickey WF, Kimura H (1998) Perivascular microglial cells of the CNS are bone derived and present in vivo. Science 239:290–292CrossRefGoogle Scholar
  17. Hoffmann B, Keshav S (2007) Gastrointestinal symptoms in Fabry disease: everything is possible, including treatment. Acta Paediatr Suppl 96:84–86, PMID 17391450PubMedCrossRefGoogle Scholar
  18. Jeyakumar M, Dwek RA, Butters TD, Platt FM (2005) Storage solutions treating lysosomal disorders of the brain. Nat Rev Neurosci 6:713–725PubMedGoogle Scholar
  19. Kakkis ED, Muenzer J, Tiller GE, Waber L et al (2001) Enzyme replacement therapy in mucopolysaccharidosis. N Eng J Med 344:1831–1888CrossRefGoogle Scholar
  20. Kennedy DW, Abkowitz JL (1997) Kinetics of central nervous system miroglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model. Blood 90:986–993PubMedGoogle Scholar
  21. Kharbanda S, Panoskaltis-Moratari A, Haddad IY et al (2006) Inflammatory cytokines and the development of Pulmonary complications after allogeneic Hematopoietic Cell transplantation in patients with inherited metabolic storage disorders. Biol Blood Marrow Transplant 12:430–437PubMedCrossRefGoogle Scholar
  22. Knoll RB, Kulkarni R, Netzloff ML (1986) Follow up of language and cognitive development in patients with mannosidosis. Arch Neurol 43:157–159CrossRefGoogle Scholar
  23. Malm D, Pantel J, Linaker OM (2005) Psychiatric symptoms in alpha-mannosidosis. J Intellect Disabil Res 49:865–871PubMedCrossRefGoogle Scholar
  24. Miano M, Labopin M, Hartmann O et al (2007) Haematopoietic stem cell transplantation trends in children over the last three decades: a survey by the paediatric diseases working party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 39:89–99PubMedCrossRefGoogle Scholar
  25. Michalski JC, Klein A (1999) Glycoprotein lysosomal storage disorders: α- and β-mannosidosis, fucosidosis and α-N-acetylgalactosaminidase deficiency. Biochem Biophys Acta 1455:69–84PubMedCrossRefGoogle Scholar
  26. Mitchell ML, Erickson RP, Schmid D, Hieber V, Poznanski AK, Hicks SP (1981) Mannosidosis: two brothers with different degrees of disease severity. Clin Genet 20:191–202PubMedCrossRefGoogle Scholar
  27. O’Brien T, Eastlund T, Peters C, Neglia JP, Defor T, Ramsay NKC, Baker KS (2004) Autoimmune haemolytic anaemia complicating haematopoietic cell transplantation in paediatric patients: high incidence and significant mortality in unrelated transplants for non-malignant diseases. Br J Haematol 127:67–75PubMedCrossRefGoogle Scholar
  28. Peters CJ (2003) Effective treatment of the central nervous system in lysosomal storage diseases: save that brain. J Lab Clin Med 142:361–363PubMedCrossRefGoogle Scholar
  29. Roces DP, Lüllmann-Rauch R, Peng J et al (2004) Efficacy of enzyme replacement therapy in α-mannosidosis mice: a preclinical animal study. Hum Mol Genet 13:1979–1988PubMedCrossRefGoogle Scholar
  30. Spranger J, Gehler J, Cantz M (1976) The radiographic features of α-mannosidosis. Radiology 119:401PubMedGoogle Scholar
  31. Staba SL, Escolar ML, Poe M et al (2004) Cord-blood transplants from unrelated donors in patients with Hurler’s syndrome. N Engl J Med 350:1932–1934CrossRefGoogle Scholar
  32. Sun H, Wolfe JH (2001) Recent progress in lysosomal α-mannosidosis and its deficiency. Exp Mol Med 33:1–7PubMedCrossRefGoogle Scholar
  33. Thomas G (2001) Disorders of glycoprotein degradation: α-mannosidosis, β-mannosidosis, fucosidosis and sialidosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B (eds) The metabolic and molecular bases of inherited metabolic disease, 8th edn. McGraw-Hill Medical, pp 3507–3516Google Scholar
  34. Vite CH, McGowan JC, Niogi SN, Passini MA, Drobatz KJ, Haskins ME, Wolfe JH (2005) Effective gene therapy for an inherited metabolic disease in a large animal model. Ann Neurol 57:355–364PubMedCrossRefGoogle Scholar
  35. Walkley SU (2004) Pathogenic cascades and brain dysfunction. In: Platt FM, Walkley SU (eds) Lysosomal disorders of the brain. Oxford University Press, New York, p 290–324CrossRefGoogle Scholar
  36. Walkley SU (2007) Pathological mechanisms in lysosomal disease: a reappraisal of the role of the lysosome. Acta Paediatr 96:26–32CrossRefGoogle Scholar
  37. Walkley SU, Dobrenis K (1995) Bone marrow transplantation for the treatment of lysosomal storage disorders. Lancet 345:1398–1402CrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  • A. A. Broomfield
    • 1
    • 3
  • A. Chakrapani
    • 2
  • J. E. Wraith
    • 1
  1. 1.Department of Genetic MedicineRoyal Manchester Children’s HospitalManchesterUK
  2. 2.Birmingham Children’s HospitalBirminghamUK
  3. 3.Department of Metabolic DiseaseGreat Ormond Street Hospital for Children NHS TrustLondonUK

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