NEUROFIBRILLARY TANGLES IN NIEMANN-PICK DISEASE TYPE-C

Niemann-Pick disease type C (NPC) is an autosomal recessive disease, b elonging to a clinically heterogeneous group of lipid storage diseases , distinguished by a unique error in cellular trafficking of exogenous cholesterol, associated with lysosomal accumulation of unesterified c holesterol. Unlike Niemann-Pick disease types A and B, there is no pri mary genetic defect in sphingomyelinase in NPC. During the routine neu ropathological study of NPC patients, we found neurofibrillary tangles (NFT) in a series of cases with a slowly progressive chronic course. These were not associated with P-amyloid deposits. The NFT were most f requent in the orbital gyrus, cingulate gyrus and entorhinal region of the cerebral cortex, but were also frequently found in the basal gang lia, thalamus and hypothalamus. In one of the most severely affected c ase, the NFT were even found in the neurons in the inferior olivary nu cleus and in the spinal cord. The NFT were immunostained with Alz 50, and consisted of paired helical filaments. The distribution of the neu rons bearing the NFT was generally similar to that of the swollen stor age neurons, and storage neurons often contained NFT in their perikary a and/or in the meganeurites. However, neurons with NFT could be noted without swollen perikarya. The coexistence of neuronal storage and NF T in NPC without amyloid deposits suggests that perturbed cholesterol metabolism and/or lysosomal membrane trafficking may play a role in th e formation of NFT, and that amyloid deposits are not necessarily the prerequisite for NFT formation. The results of our study also suggest that NFT formation may be a rather nonspecific cellular reaction of ne urons to certain slowly progressive metabolic perturbations of an as y et undefined nature.