Niemann-Pick Type C Disease—Pathophysiology and Future Perspectives for Treatment

Abstract

Niemann-Pick type C (NPC) disease is a rare and fatal inherited metabolic disorder that results in intracellular accumulation of cholesterol and glycolipids within the endosomal/lysosomal system. Central nervous system (CNS) involvement is especially prominent as evidenced by ataxia and progressive decline of motor skills and intellectual function. Defects in either the NPC1 or NPC2 protein, both of which are thought to be involved in the egress of cholesterol and other lipids out of the endosomal/lysosomal system, leads to NPC disease. The pathogenic cascade is not well understood, and currently there is no corrective therapy for NPC patients. However, some compounds tested in animal models of NPC disease have shown promise in slowing disease onset and progression, and administration of these drugs in combination has provided evidence of synergy and enhanced clinical benefit. This favorable outcome indicates that combinatorial therapies using small molecules likely represent the best therapeutic option available to NPC patients at this time.

Niemann-Pick type C disease – the tip of the iceberg? A review of neuropsychiatric presentation, diagnosis and treatment

“…14 The neuropathological sequelae of these defects include Alzheimer's-like neurofibrillary tangles, neuronal degeneration, neuroaxonal dystrophy and demyelination. [6][7][8][9][10][11][12][13][14][15][16][17][18] Also, as endogenously synthesised cholesterol is necessary for axonal membrane maintenance and repair, white matter tracts are severely affected, with the corpus callosum showing the most striking axonal loss. 18,19 Purkinje cells of the cerebellum, basal ganglia and thalamus are characteristically vulnerable in NP-C, leading to the often pronounced cerebellar dysfunction and ataxia in NP-C patients.…”

“…18,19 Purkinje cells of the cerebellum, basal ganglia and thalamus are characteristically vulnerable in NP-C, leading to the often pronounced cerebellar dysfunction and ataxia in NP-C patients. 15…”