Abstract
Niemann–Pick disease type C2 (NPC2) is caused by the inherited deficiency of a lysosomal cholesterol transport protein, NPC2 protein. Many cases of NPC2 present in early infancy with inflammatory lung disease, with subsequent severe neurological disease and death in early childhood. This disease is theoretically correctable by bone marrow transplantation (BMT), as the NPC2 protein is small and soluble and secreted and recaptured by the mannose-6-phosphate pathway. In this report we describe the first successful allogeneic bone marrow transplantation for this condition in a 16-month-old boy homozygous for the NPC2 p.E20X mutation, which has hitherto been reported to cause disease with a severe phenotype. During BMT there was an initial improvement of the established respiratory illness, with the immune suppression associated with transplant conditioning, but there was subsequent marked deterioration at the time of immune reconstitution and donor cell engraftment. This ‘graft versus substrate’ reaction was managed with intensive immune suppressant therapy, and it gradually resolved as the substrate was cleared by the engrafted donor macrophages. All immune suppression was withdrawn 18 months after transplantation, and his respiratory illness has resolved. He walked independently at 24 months and is continuing to reach developmental milestones after receiving his transplant. We conclude that the successful treatment of Niemann–Pick C2 therefore seems likely to be associated with a severe post-transplantation ‘graft versus substrate’ reaction that requires intense immune suppression before eventual resolution.
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Elleder M, Houstkova H, Zeman J, Ledvinova J, Poupetova H (2001) Pulmonary storage with emphysema as a sign of Niemann-Pick type C2 disease (second complementation group). Report of a case. Virchows Arch 439:206–211
Ferrara JL, Levine JE, Reddy P, Holler E (2009) Graft-versus-host disease. Lancet 373:1550–1561
Kennedy DW, Abkowitz JL (1998) Mature monocytic cells enter tissues and engraft. Proc Natl Acad Sci U S A 95:14944–14949
Kolb HJ (2008) Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 112:4371–4383
Millat G, Chikh K, Naureckiene S, Sleat DE, Fensom AH, Higaki K, Elleder M, Lobel P, Vanier MT (2001) Niemann–Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. Am J Hum Genet 69:1013–1021
Neufeld EF (1983) The William Allan Memorial Award address: cell mixing and its sequelae. Am J Hum Genet 35:1081–1085
Valayonnopoulos V, Neven B, Aboutaam R, De Blic J, Vanier MT, Fischer A, de Lonlay P (2007) Bone marrow transplantation for Niemann Pick C2 disease. J Inherit Metab Dis 30(Suppl 1):122
Vanier MT, Millat G (2003) Niemann–Pick disease type C. Clin Genet 64:269–281
Verot L, Chikh K, Freydiere E, Honore R, Vanier MT, Millat G (2007) Niemann–Pick C disease: functional characterization of three NPC2 mutations and clinical and molecular update on patients with NPC2. Clin Genet 71:320–330
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Communicated by: Olaf Bodamer
Competing interest: None declared.
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Bonney, D.K., O’Meara, A., Shabani, A. et al. Successful allogeneic bone marrow transplant for Niemann–Pick disease type C2 is likely to be associated with a severe ‘graft versus substrate’ effect. J Inherit Metab Dis 33 (Suppl 3), 171–173 (2010). https://doi.org/10.1007/s10545-010-9060-3
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DOI: https://doi.org/10.1007/s10545-010-9060-3