Brain (1995), 118, 119-129 Neurofibrillary tangles in Niemann-Pick disease type C Seth Love, 1 Leslie R. Bridges 3 and C. Patrick Case 2 * Department of Neuropathology, Frenchay Hospital, the 2 Departinent of Pathology, Southmead Hospital, Bristol and the ^Department of Neuropathology, University of Leeds, Leeds, UK Correspondence to: Dr S. Love, Department of Neuropathology, Frenchay Hospital, Bristol BS16 1LE, UK Summary Post-mortem neuropathological examination of five cases of Niemann-Pick disease type C revealed neurofibrillary tangles in many parts of the brain. Tangles were a consistent finding in the hippocampus, hypothalamus, substantia innominata, midbrain pons and medulla. Other regions of the brain in which tangles were present included neocortex, basal ganglia, thalamus, cerebellar cortex in one case, and dentate nucleus in another. The tangles were argyrophilic, fluoresced under ultraviolet light when stained with thioflavin S, and reacted strongly with antibody to tau protein. Some of the tangles could be immunostained for ubiquitin. Electron microscopy, performed in one of the cases, showed the tangles to consist of paired helical filaments ultrastructurally identical to those of Alzheimer's disease. The distribution of the tangles in the central nervous system as a whole and also within many individual neurons corresponded fairly closely with that of the abnormal storage material. Both the tangles and the storage material extended into, and distended, the proximal parts of many dendrites and axons. No A4/§ protein, either in the form of plaques or in the walls of blood vessels, was detected in any of the cases. Our findings suggest that neurofibrillary tangles are a common feature of Niemann- Pick disease type C and that their formation may be a reaction to the abnormal storage material. Keywords: Niemann-Pick disease type C; neurofibrillary tangles; paired helical filaments; tau protein Introduction The term Niemann-Pick disease includes several clinically and biochemically distinct disorders. These were subdivided by Crocker (1961) into types A, B, C and D on the basis of the tempo of the disease and the pattern of organ involvement. These different types of Niemann-Pick disease have been further subclassified into group I, in which there is sphingomyelinase deficiency, and group II, in which total sphingomyelinase activity is normal. Group I includes types A and B, and group II types C and D. Synonyms for Type C Niemann-Pick disease include juvenile dystonic lipidosis, ophthalmoplegic lipidosis, neurovisceral storage disease with vertical supranuclear ophthalmoplegia and juvenile Niemann- Pick disease with sea-blue histiocytes. This disorder corresponds to Niemann-Pick disease type IIS in the scheme of Spence and Callahan (1989). The onset of Niemann- Pick disease type C may be in infancy, early childhood, adolescence or, occasionally, in adulthood (Fink et ai, 1989; Turpin et al., 1991). Clumsiness, ataxia, supranuclear gaze paresis, seizures and psychomotor retardation are the commonest neurological manifestations (Fink et at., 1989; © Oxford University Press 1995 Spence and Callahan, 1989; Turpin et al., 1991). Other features include myoclonus, narcolepsy and cataplexy. Turpin et al. (1991) noted that a psychosis may be the only manifestation of Niemann-Pick disease type C for several years. Hepatosplenomegaly is usually present and may be marked or, particularly in older-onset cases, mild or even absent (Turpin et al., 1991; Hulette et al., 1992). Neuropathological examination in cases of Niemann-Pick disease type C reveals marked neuronal distension by weakly or non-sudanophilic material that stains moderately well with periodic acid-Schiff reagent (Lake, 1992). Other histological features include the presence of swollen axons, particularly in the brainstem and spinal cord, and foam cells in the bone marrow, spleen and hepatic sinusoids. Horoupian and Yang (1978), described a patient with type C Niemann-Pick disease in whom Alzheimer-like neuro- fibrillary tangles were found at autopsy. The tangles were most numerous in the frontal and temporal lobes, insula and basal ganglia, and were shown by electron microscopy to consist of paired helical filaments.