Clinicopathological phenotype of codon 129 valine homozygote sporadic Creutzfeldt-Jakob disease

The naturally occurring polymorphism at codon 129 of the human prion protei n gene (PRNP) influences susceptibility to sporadic Creutzfeldt-Jakob Disea se (CJD); the majority of the patients are methionine homozygotes at this l ocus, while valine homozygotes represent only 10% of cases. The aim was to study the clinical and neuropathological phenotype of sporadic CJD in valin e homozygotes, to estimate the reliability of current clinical diagnostic c riteria, and to identify any consistent and distinct features. Twelve cases of sporadic CJD with a codon 129 valine homozygote genotype were identifie d at the National CJD Surveillance Unit in Edinburgh. In addition to a retr ospective clinical analysis, tissue blocks were stained by conventional tec hniques and by immunocytochemistry for prion protein. Frozen brain tissue w as available from five cases for Western blot analysis of PrPRES, which in all cases showed a type 2 mobility. The cases included four males and eight females, average age 63.6 years, with a mean duration of illness of 6 mont hs. Eleven patients presented with ataxia, and none had the characteristic EEG changes found in sporadic CJD. The neuropathological phenotype comprise d spongiform change and prion protein immunopositivity most marked in the s ubcortical grey matter and cerebellum, prion protein positive plaque-like d eposits in all regions, laminar deposition of prion protein in the cerebral cortex, and hippocampal involvement (which is seldom reported in sporadic CJD). In conclusion, these cases exhibited a fairly uniform phenotype, whic h is relatively distinct from sporadic CJD in methionine homozygotes, and t hus diagnosis may be difficult using existing clinical criteria.