Fatal familial insomnia with an unusual prion protein deposition pattern: an autopsy report with an experimental...

We recently performed a post-mortem examination on a Japanese patient who had a prion protein gene mutation responsible for fatal familial insomnia (FFI). The patient initially developed cerebellar ataxia, but finally demonstrated insomnia, hyperkinetic delirium, autonomic signs and myoclonus in the late stage of the illness. Histological examination revealed marked neuronal loss in the thalamus and inferior olivary nucleus; however, prion protein (PrP) deposition was not proved in these lesions by immunohistochemistry. Instead, PrP deposition and spongiform change were both conspicuous within the cerebral cortex, whereas particular PrP deposition was also observed within the cerebellar cortex. The abnormal protease-resistant PrP (PrP(res)) molecules in the cerebral cortex of this case revealed PrP(res) type 2 pattern and were compatible with those of FFI cases, but the transmission study demonstrated that a pathogen in this case was different from that in a case with classical FFI. By inoculation with homogenate made from the cerebral cortex, the disease was transmitted to mice, and neuropathological features that were distinguishable from those previously reported were noted. These findings indicate the possibility that a discrete pathogen was involved in the disease in this case. We suggest that not only the genotype of the PrP gene and some other as yet unknown genetic factors, but also the variation in pathogen strains might be responsible for the varying clinical and pathological features of this disease.