Niemann-Pick disease type C: Neuropathology revisited

Niemann-Pick disease type C (NPC) is a neurodegenerative disease characterized by lysosomal accumulation of low-density-lipoprotein (LDL)-derived cholesterol due to defective intracellular transport. The disease-causing gene has been recently identified. The clinical spectrum of NPC is heterogeneous; in general, those who have earlier onset are thought to have a rapidly progressive course with hepatosplenomegaly, while those with later onset show slowly progressive neurological symptoms without significant visceromegaly. However, there are still others with early onset who develop neurological symptoms slowly. In all NPC cases with heterogeneous clinical courses that we examined, the cardinal pathology was neuronal storage and a variable degree of storage in cells of the reticuloendothelial system. In a case with rapid progression, numerous neuroaxonal dystrophies (axonal spheroids) were noted throughout the brain in addition to extensive neuronal storage, while in cases with slow progression, regardless the age of onset, the presence of neurofibrillary tangles was a conspicuous feature in association with variable degrees of neuroaxonal dystrophies. The neurofibrillary tangles in these NPC patients may be somewhat different histologically from those of Alzheimer disease, but ultrastructurally and biochemically they are identical. Thus, there appear to be some differences in the neuropathological features of NPC cases with rapid clinical progression versus slow progression. The underlying mechanism(s) causing such differences in cellular responses is yet to be investigated.