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Causes of Niemann-Pick type C disease

Niemann-Pick type C disease (NP-C) is an inherited, autosomal recessive condition linked to two genes; NPC1 (located on chromosome 18; q11-q12) and NPC2 (located on chromosome 14; q24.3). NP-C can be caused by a mutation on either gene.1 Approximately 95% of patients have a mutation on the NPC1 gene and 5% have a mutation on the NPC2 gene.1,2

There are thought to be almost 300 different mutations in the NPC1 gene and more than 60 polymorphisms have been described.1

Genotype-phenotype studies are limited but show good correlation between mutations and the severity of neurological disease. However, studies of large multiplex families show there to be no correlation with systemic manifestation of the disease.1

NPC1 and NPC2 proteins
The NPC1 and NPC2 gene products – NPC1 and NPC2 proteins – are important for normal cholesterol trafficking.

  • The NPC1 protein, a large membrane glycoprotein, plays a major role in the movement of lipids between the late-stage endosomes, endoplasmic reticulum (ER), and plasma membrane.1,2
  • The NPC2 protein, a small soluble lysosomal protein, is thought to bind and transport cholesterol with high affinity within late-stage endosomes and lysosomes.1,2
  • It is also possible that NPC1 and NPC2 proteins act together to regulate cellular lipid trafficking and sterol homeostasis.2


It is thought that mutations in the NPC1 and NPC2 genes result in protein malfunction and impairment in the processing and utilization of endocytosed cholesterol. Subsequent accumulation of cholesterol, glycolipids and free sphingosine/sphinganine in extra-neural tissues and accumulation of GM2 and GM3 gangliosides in the brain might also be a result of these mutations. The accumulation of lipids eventually becomes toxic, damaging the cells and tissues and causing the neurological symptoms of NP-C.1,2


  1. Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis 2010;5:16.
  2. Wraith JE, Imrie J. Understanding Niemann-Pick disease type C and its potential treatment UK Blackwell Publishing, 2007.