Niemann-Pick Disease Type C: from molecule to clinic.

1. Niemann-Pick Type C disease (NPC) is an incurable cholesterol-storage disorder that stems from inherited deficiencies of lysosomal proteins involved in intracellular lipid-trafficking proteins. The condition manifests as progressive neurological impairment and leads to death at an early age. 2. To improve clinical recognization and investigate therapeutic strategies, recent studies using molecular and genetic approaches have led to significant advances in the creation of animal models of NPC, as well as in the understanding of the cellular and molecular mechanisms underlying the pathogenesis of NPC. 3. Patients with NPC are divided into four groups based on age at presentation, whereas the clinical features of NPC can be divided into five categories based on the severity of the disease. Progressive neuronal loss, especially of cerebellar Purkinje cells, is a hallmark of NPC. Ballooned neurons, axonal abnormalities and astroglyosis are among the pathological changes seen. Severe demyelination is also present in the mouse model of NPC. 4. Mutations in the NPC1 gene cause approximately 95% of cases of NPC, whereas mutations in the NPC2 gene account for the remainder of cases. NPC1 is a transmembrane protein and NPC2 is a soluble protein involved in lipid trafficking in lysosomes. Loss-of-function mutations in the NPC1 gene lead to a failure of the calcium-mediated fusion of endosomes with lysosomes, resulting in the accumulation of cholesterol and other lipids in late endosomes and lysosomes. 5. The present review updates the disorders of NPC from clinical features to animal models and molecular mechanisms.