Creutzfeldt-Jakob disease with an M232R substitution: report of a patient showing slowly progressive disease with abundant plaque-like PrP deposits in the cerebellum

Patients with genetic Creutzfeldt-Jakob disease in which arginine is substituted for methionine at codon 232 (M232R) of the prion protein gene (CJD232) have been described in Japan, and a recent study has revealed the presence of two clinical phenotypes: a rapidly progressive type (rapid-type) and a slowly progressive type (slow-type). Although the former is known to show pathologic features similar to those of classical CJD, the neuropathology of the latter still remains unclear. We report the autopsy findings of slow-type CJD232 of 37 months' duration in a 73-year-old man who had methionine homozygosity at codon 129 of the prion protein gene (129MM). His initial symptoms included agraphia and memory disturbance, followed by relatively slowly progressive dementia. Myoclonus and akinetic mutism became evident 5 and 23 months after disease onset, respectively. The electroencephalogram revealed periodic sharp wave complexes at 7 months before death. The neuropathologic features were partly reminiscent of those of MM2-cortical-type sporadic CJD, showing spongiform change of the large confluent vacuole type, neuronal loss with gliosis, and coarse, perivacuolar prion protein deposits, which were later shown to consist of protease-resistant type 2 prion protein, in the cerebral cortex and striatum. It was of considerable interest that not only was the medial thalamus severely involved, but also that the cerebellar cortex showed loss of Purkinje cells and abundant plaque-like prion protein deposits. These findings are not a feature of MM2-cortical-type sporadic CJD. Whether or not the M232R substitution, in combination with the genetic polymorphism and the molecular type of pathological prion protein, really participates in the development of CJD232 and its different phenotypes awaits further studies.