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Tirelli, C.; Rondinone, O.; Italia, M.; Mira, S.; Belmonte, L.A.; De Grassi, M.; Guido, G.; Maggioni, S.; Mondoni, M.; Miozzo, M.R.; et al. Niemann–Pick Disease. Encyclopedia. Available online: (accessed on 16 April 2024).
Tirelli C, Rondinone O, Italia M, Mira S, Belmonte LA, De Grassi M, et al. Niemann–Pick Disease. Encyclopedia. Available at: Accessed April 16, 2024.
Tirelli, Claudio, Ornella Rondinone, Marta Italia, Sabrina Mira, Luca Alessandro Belmonte, Mauro De Grassi, Gabriele Guido, Sara Maggioni, Michele Mondoni, Monica Rosa Miozzo, et al. "Niemann–Pick Disease" Encyclopedia, (accessed April 16, 2024).
Tirelli, C., Rondinone, O., Italia, M., Mira, S., Belmonte, L.A., De Grassi, M., Guido, G., Maggioni, S., Mondoni, M., Miozzo, M.R., & Centanni, S. (2024, February 21). Niemann–Pick Disease. In Encyclopedia.
Tirelli, Claudio, et al. "Niemann–Pick Disease." Encyclopedia. Web. 21 February, 2024.
Niemann–Pick Disease

Niemann–Pick Disease (NPD) is a rare autosomal recessive disease belonging to lysosomal storage disorders. Three types of NPD have been described: NPD type A, B, and C. NPD type A and B are caused by mutations in the gene SMPD1 coding for sphingomyelin phosphodiesterase 1, with a consequent lack of acid sphingomyelinase activity. These diseases have been thus classified as acid sphingomyelinase deficiencies (ASMDs). NPD type C is a neurologic disorder due to mutations in the genes NPC1 or NPC2, causing a defect of cholesterol trafficking and esterification. Although all three types of NPD can manifest with pulmonary involvement, lung disease occurs more frequently in NPD type B, typically with interstitial lung disease, recurrent pulmonary infections, and respiratory failure.

Niemann–Pick Disease acid sphingomyelinase deficiency SMPD1 NPC1 NPC2 Olipudase α miglustat lung transplant

1. Introduction

Niemann–Pick Disease (NPD) is a rare autosomal recessive lysosomal storage disorder. NPD comprises three different pathologies, namely NPD type A, B, and C. NPD type A and B are now most commonly categorized as acid sphingomyelinase deficiencies (ASMDs), as they are caused by mutations in the gene SMPD1, which codes for sphingomyelin phosphodiesterase 1. However, NPD type C is a neurological disorder caused by mutations in the NPC1 or NPC2 genes, leading to defects in cholesterol trafficking and esterification. In ASMD types A and B, defects in sphingomyelin phosphodiesterase 1 result in a lack of acid sphingomyelinase activity, leading to the accumulation of sphingomyelin, cholesterol, and other lipids in lysosomes (Figure 1). 
Figure 1. Molecular pathogenetic mechanisms in ASMD (NPD type A and B) and NPD type C. ASMDs (NPD type A and B) are due to acid sphingomyelinase (ASMase) deficiency. This leads to accumulation of sphingomyelin in lysosomes. As a consequence, a secondary sequestration of cholesterol in lysosomes occurs. ASMase acts as a trigger for endoplasmic reticulum stress. The consequent reduced endoplasmic reticulum stress signaling causes a decrease in reactive oxygen species (ROS) in mitochondria. NPD type C is characterized by defects of NPC1 and NPC2. This leads to accumulation of cholesterol in lysosomes, which is sustained by decreased activity of acid ceramidase (ACDase). As a consequence, via a poorly understood mechanism involving endoplasmic reticulum signals, mitochondrial cholesterol levels increase. The mitochondrial cholesterol accumulation determines an increase in ROS-induced oxidative stress.
Table 1. Main characteristics of ASMD (NPD type A and B) and NPD type C.


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