Niemann–Pick disease type C (a cellular cholesterol lipidosis) treated by bone marrow transplantation

Abstract

Summary:Bone marrow transplantation (BMT) has been used for a wide variety of lysosomal storage diseases with encouraging results. We report a 3-year 5-month-old girl with Niemann-Pick type C disease (NPC) who received an allogeneic BMT. The patient presented with repeated lower respiratory tract infections, hepatosplenomegaly, failure to thrive, and developmental delay. Chest computed tomography (CT) revealed diffuse interstitial lung infiltration. Bone marrow and liver biopsies revealed abundant lipid-filled foamy macrophages. Skin fibroblast sphingomyelinase assay revealed partial deficiency. The ability of her skin fibroblasts to esterify cholesterol was very low, and the cells stained brightly for free cholesterol. She received BMT from a healthy HLA-identical male sibling donor at the age of 2 year 6 months. Full engraftment was evidenced by repeated bone marrow sex chromosome studies. Regression of the hepatosplenomegaly, markedly reduced foamy macrophage infiltration in bone marrow, and decreased interstitial lung infiltration was noted 6 months after BMT. Her neurological status, however, deteriorated. Follow-up magnetic resonance image (MRI) revealed progressive, diffuse brain atrophy. We conclude that resolution occurred in the liver, spleen, bone marrow and lung following successful engraftment. Such a response is remarkable since the underlying problem involves a membrane receptor for cholesterol. This positive response might be due to replacement of the monocyte-phagocytic system or it may imply the existence of cross-correction in the NPC membrane receptor defect by BMT approach. Since BMT did not halt the neurological deterioraton, it is unlikely to be an adequate treatment for NPC.

Wolman disease successfully treated by bone marrow transplantation

“…A patient with Niemann-Pick Type C has been treated with bone marrow transplant with engraftment. 15 In this latter report, the expected progression to cirrhosis has not occurred after 2 years.…”

Respiratory manifestations in patients with inherited metabolic diseases

“…In Niemann-Pick disease type B and type C due to NPC2 gene mutation, haematopoietic stem cell transplantation can result in lung disease improvement [32,138]. At present, the substrate reduction therapy with miglustat has been granted marketing authorisation in Europe and several other countries for specific treatment of neurological manifestations of Niemann-Pick disease.…”

“…Diffuse interstitial and nodular infiltrates with basal predominance, as well as honeycombing on chest radiography, or ground-glass opacities on chest high-resolution computed tomography (HRCT), may be regularly found in young children and in adults with type B disease [24,25,29] even in the absence of functional abnormalities [30]. Patients with Niemann-Pick disease type C may have diffuse ILD as a presenting feature, or aspiration pneumonia because of neurological disease [23,31,32]. Finally, it has been reported that a small subset of infants with the severe NPC2 mutation may develop respiratory insufficiency due to pulmonary alveolar proteinosis (PAP) [33].…”

Niemann-Pick Type C Disease—Pathophysiology and Future Perspectives for Treatment

“…However, there were no improvements in neurologic function, consistent with the view that BMT is unlikely to correct the NPC1 defect. 44 A different strategy, chaperone-mediated therapy, relies on the assistance of small molecules or upregulation of endogenous chaperones and related molecules to properly fold, stabilize, and/or traffic partially functioning or misfolded proteins. 46,47 Although there are no harmacologic chaperones currently used for the treatment of NPC disease, there is evidence that some mutated NPC proteins are targeted for endoplasmic reticulum-associated degradation (ERAD) due to protein misfolding.…”

“…BMT was performed in a NPC1 patient who was 2.5 years of age, resulting in full engraftment that led to reduced pathology in the liver, spleen, and lung 44 (likely a reflection of a normalization of macrophages). However, there were no improvements in neurologic function, consistent with the view that BMT is unlikely to correct the NPC1 defect.…”