Basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease

Objective: To determine the correlation of clinical and pathologic features with prion protein (PrP) gene polymorphism at codon 129 and with biochemic al characteristics of the protease-resistant PrP (PrPres) in sporadic Creut zfeldt-Jakob disease (CJD), Methods: Clinical data acquisition, determinati on of the codon 129 genotype of the PrP gene, brain pathologic study, and i mmunoblot analysis of crude brain extracts were carried out in 14 patients. Results. The first group of 10 subjects showed the classic clinical triad, with dementia, myoclonus, and periodic sharp waves on EEG. None of the sub jects had amyloid plaques, but PrP immunoreactivity was of diffuse synaptic type in the cerebellar cortex. All subjects were methionine-methionine at codon 129 and the PrPres had a biochemical profile of type 1 (unglycosylate d band of 21.5 kD). A second group of three patients showed cerebellar atax ia and later dementia, Periodic sharp waves on EEG were absent. PrP amyloid plaques predominated in the cerebellar cortex, along with diffuse PrP immu noreactivity. These subjects were valine-valine at codon 129 and had a type 2 PrPres (unglycosylated band of 19.4 kD). In the last patient cerebellar ataxia and dementia appeared simultaneously. Many Kuru-type plaques were pr esent in the cerebellar cortex; many PrP amyloid plaques were present in th e basal ganglia. This patient was methionine-value at codon 129 and the PrP res was of type 1. Conclusions: The codon 129 genotype is only one of the f actors determining CJD phenotype, and the biochemical pattern of PrP has no direct correlation with this phenotype.