Basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease

To determine the correlation of clinical and pathologic features with prion protein (PrP) gene polymorphism at codon 129 and with biochemical characteristics of the protease-resistant PrP (PrPres) in sporadic Creutzfeldt-Jakob disease (CJD).

Clinical data acquisition, determination of the codon 129 genotype of the PrP gene, brain pathologic study, and immunoblot analysis of crude brain extracts were carried out in 14 patients.

The first group of 10 subjects showed the classic clinical triad, with dementia, myoclonus, and periodic sharp waves on EEG. None of the subjects 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 (unglycosylated band of 21.5 kD). A second group of three patients showed cerebellar ataxia and later dementia. Periodic sharp waves on EEG were absent. PrP amyloid plaques predominated in the cerebellar cortex, along with diffuse PrP immunoreactivity. 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 present in the cerebellar cortex; many PrP amyloid plaques were present in the basal ganglia. This patient was methionine-valine at codon 129 and the PrPres was of type 1.

The codon 129 genotype is only one of the factors determining CJD phenotype, and the biochemical pattern of PrP has no direct correlation with this phenotype.