Niemann-Pick Disease Type C

Niemann-Pick Disease Type C results from mutations in NPC1 gene (95% of cases) or NPC2 gene (5% of cases), which encode proteins essential for intracellular lipid trafficking and metabolism. These proteins are required for proper movement of cholesterol and other lipids from lysosomes to other cellular compartments. Loss of NPC1 or NPC2 function impairs this lipid transport, leading to lysosomal accumulation of unesterified cholesterol, glycosphingolipids, and other lipids. This accumulation particularly affects neurons and hepatocytes. The mechanism of neuronal dysfunction involves impaired autophagy, mitochondrial dysfunction, calcium signaling abnormalities, oxidative stress, and neuroinflammation. NPC manifests in several forms depending on age of presentation. The infantile form presents with neonatal cholestasis, hepatosplenomegaly, and failure to thrive, with neurological signs appearing by age 2. The early-childhood form presents with neurological symptoms including ataxia, gaze palsy (downward worse than upward), developmental delay, and cognitive decline between ages 2-6 years. The juvenile form presents between 6-15 years with ataxia, cognitive decline, and psychiatric symptoms. The adult form presents after age 15 with progressive ataxia, cognitive decline, and other neurological features. Hepatosplenomegaly can be severe in some patients. Vertical supranuclear gaze palsy is characteristic, though not present in all patients. The disease is relentlessly progressive, with neurological decline eventually leading to severe disability and death.