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 on chromosome 18, and NPC2 on chromosome 14. In NP-C 90% of patients have a mutation on the NPC1 gene.¹

Many different mutations in the NPC1 gene have been identified. Most patients with NPC1 mutations are compound heterozygotes with single-point mutations unique to a family or distinct patient population (e.g. the G992W genotype is mostly found in Acadian patients from Novo Scotia, and the I1061T genotype is present in 15-20% of Western European and USA suffers).² NPC2 mutations vary more than with NPC1, and patients can be either homozygous or compound heterozygous.² Correlations between genotype and phenotype have been established with both NPC1 and NPC2 mutations.²

The NPC1 and NPC2 gene products are important for normal cholesterol trafficking. The NPC1 gene product (NPC1 protein) plays a major role in the trafficking of lipids between the late-stage endosomes, endoplasmic reticulum (ER), and plasma membrane.^2,3 Although much less is known about the role of the NPC2 gene product (NPC2 protein), it is thought to bind and transport cholesterol within late-stage endosomes and lysosomes.^2,3 It is also possible that NPC1 and NPC2 proteins act together to regulate cellular lipid trafficking and sterol homeostasis.² Mutations in the NPC1 and NPC2 genes result in the gene products malfunctioning, disrupting lipid trafficking and leading to lysosomal lipid accumulation (Figure 1).  In NPC1 disease pathogenesis, the storage of sphingosine is an initiating factor that causes altered calcium homeostasis which leads to the secondary accumulation of sphingolipids and cholesterol.⁴

References

1. Patterson MC. Niemann-Pick disease Type C. Gene Reviews 2007a (updated 9 July). Accessible at: www.geneclinics.org. Accessed October 2008.
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. Lloyd-Evans E, Morgan AJ, He X et al. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium.  Nature medicine 2008; 14: 11: 1247-1255