Niemann-Pick disease type C (NPC) is caused by mutations in NPC1 or NPC2 proteins involved in intracellular cholesterol trafficking. The biochemical defect in NPC is FUNDAMENTALLY different from NPC type A/B because:

• A NPC type C has defective acid sphingomyelinase (ASM), causing sphingomyelin accumulation in lysosomes
• B NPC type C has normal ASM activity but impaired lysosomal cholesterol export by NPC1/NPC2 proteins, causing cholesterol (and secondarily sphingomyelin) to accumulate in late endosomes/lysosomes ✓
• C NPC type C involves defective glucocerebrosidase causing glucosylceramide accumulation similar to Gaucher disease
• D NPC type C involves defective LDL receptor recycling causing extracellular cholesterol accumulation

Explanation

Niemann-Pick type A and B are both caused by acid sphingomyelinase (ASM/SMPD1) deficiency, leading to sphingomyelin accumulation. NPC type C is a lipid trafficking disorder caused by mutations in NPC1 (a membrane protein in late endosomes/lysosomes, ~95% of cases) or NPC2 (a soluble lysosomal cholesterol-binding protein). NPC1/NPC2 work together to export unesterified cholesterol from lysosomes to the ER and other organelles; their dysfunction traps cholesterol (and secondarily glycosphingolipids) in late endosomes/lysosomes. NPC presents with vertical gaze palsy, ataxia, and progressive neurodegeneration, distinguishing it from NPC A/B.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.