About Niemann-Pick type C disease

Niemann-Pick type C disease (NP-C) is a very serious, life-threatening neurological condition belonging to a clinically heterogeneous group of lipid storage disorders.¹ NP-C is characterized by a unique defect in cellular lipid trafficking that leads to lysosomal lipid accumulation that varies between tissues.² In peripheral tissues such as skin, the accumulation of unesterified cholesterol predominates.³ In the liver and spleen several lipids accumulate including unesterified cholesterol, glycosphingolipids, phospholipids and sphingomyelin.² Glycosphingolipid accumulation primarily occurs in the central nervous system (CNS), including the brain.³

Cholesterol trafficking in peripheral cells is shown in Figure 1. In normal cells, low density lipoprotein (LDL) cholesterol enters cells via endocytosis at the LDL receptor and is digested within the late-stage endosomes and lysosomes (Figure 1).^2,4 Unesterified cholesterol is then transported to the endoplasmic reticulum (ER) and Golgi apparatus for recycling within the cell.¹ However in NP-C, the LDL-cholesterol becomes trapped within perinuclear lysosomes and lysosome-like storage organelles (LSOs), resulting in considerably reduced transport of unesterified cholesterol (Figure 1).^2,5 Consequently, lipids accumulate to toxic levels, damaging cells and tissues.²

Most NP-C patients have severely impaired cellular lipid trafficking (‘classic' biochemical phenotype), while others have relatively mild impairment but still exhibit clinical symptoms (variant biochemical phenotype).²

References

1. Suzuki K, Parker CC, Pentchev PG et al. Neurofibrillary tangles in Niemann-Pick disease type C. Acta Neuropathol (Berl) 1995; 89: 227-38.
2. Wraith JE, Imrie J. Understanding Niemann-Pick disease type C and its potential treatment. UK Blackwell Publishing, 2007.
3. Patterson MC. A riddle wrapped in a mystery: understanding Niemann-Pick disease, type C. Neurologist 2003; 9: 301-10.
4. Brady RO, Filling-Katz MR et al. Niemann-Pick disease C and D. Neurol clin 1989; 7: 75-88.
5. Mukherjee S, Maxfield FR. Lipid and cholesterol trafficking in NPC. Biochim Biophys Acta 2004; 1685: 28-37.