In Niemann–Pick disease type C, which protein is defective, and what is the primary consequence of this defect?

## Niemann–Pick Disease Type C: Protein Defect and Pathophysiology **Key Point:** Niemann–Pick disease type C (NP-C) is caused by mutations in NPC1 (chromosome 18) or NPC2 (chromosome 14) genes, which encode proteins essential for intracellular cholesterol and lipid trafficking, not enzymatic degradation. ### Mechanism of Defect Unlike most lysosomal storage disorders, NP-C is NOT caused by enzyme deficiency but by a **transport defect**: 1. NPC1 and NPC2 proteins are involved in cholesterol and lipid transport from lysosomes to other cellular compartments 2. When these proteins are defective, cholesterol and sphingolipids accumulate within lysosomes and late endosomes 3. This leads to impaired intracellular lipid homeostasis and secondary accumulation of multiple lipid species ### Pathological Features | Feature | Details | |---------|----------| | **Primary accumulation** | Cholesterol and sphingolipids in lysosomes | | **Secondary accumulation** | Sphingomyelin, glycosphingolipids | | **Affected cells** | Macrophages ("sea-blue histiocytes"), neurons, hepatocytes | | **Enzyme activity** | Sphingomyelinase is NORMAL (distinguishes from NP-A/B) | **High-Yield:** NP-C is the only lysosomal storage disorder caused by a transport defect rather than enzyme deficiency — this distinction is frequently tested. ### Clinical Presentation - **Neonatal form**: Cholestasis, hepatosplenomegaly, respiratory distress - **Infantile form**: Progressive neurological decline, ataxia, vertical supranuclear gaze palsy (pathognomonic) - **Juvenile/Adult form**: Slower progression with psychiatric and cognitive symptoms **Clinical Pearl:** Vertical supranuclear gaze palsy (inability to move eyes upward) is a hallmark neurological sign of NP-C and helps distinguish it from other lysosomal storage disorders. [cite:Robbins 10e Ch 5]