Genetic Creutzfeldt-Jakob disease-M232R with the cooccurrence of multiple prion strains, M1 + M2C + M2T: Report of an autopsy case.

Genetic Creutzfeldt-Jakob disease (gCJD) with a methionine to arginine substitution at codon 232 of the prion protein gene (gCJD-M232R) is rare and has only been reported in Japan. We report an autopsy case of gCJD-M232R showing alleles of codon 129 that were homozygous for methionine and the presence of multiple strains of the protease-resistant, abnormal isoform of prion protein (PrPSc ), M1 + M2C + M2T. The patient, a 54-year-old Japanese man, died after a clinical course of 21 months characterized by slowly progressive dementia and sleep disturbance. At autopsy, the neuropil of the cerebral neocortex showed a widespread and severe spongiform change. Grape-like clusters of large confluent vacuoles were admixed with fine vacuoles. Neuronal loss was moderate, but reactive astrocytosis was mild. The dorsomedial nucleus of the thalamus and the inferior olivary nucleus showed moderate and severe neuronal loss, respectively. Many amyloid plaques were present in the cerebellar molecular layer. PrPSc deposition pattern was predominantly the synaptic type in the cerebrum and corresponded to the plaques in the cerebellum. Perivacuolar deposition was also seen. Western blot analysis of PrPSc revealed the predominance of type 2. Moreover, by employing Western blot analysis in combination with the protein misfolding cyclic amplification (PMCA) method, which selectively amplifies the minor M2T prion strain, we demonstrated the presence of M2T, in addition to M1 and M2C strains, in the brain of the patient. PMCA was a powerful method for demonstrating the presence of the M2T strain, although the amount is often small and the transmission is difficult.