PHENOTYPE-GENOTYPE STUDIES IN KURU - IMPLICATIONS FOR NEW VARIANT CREUTZFELDT-JAKOB-DISEASE

The PRNP polymorphic (methionine/valine) codon 129 genotype influences the phenotypic features of transmissible spongiform encephalopathy. A ll tested cases of new variant Creutzfeldt-Jakob disease (nvCJD) have been homozygous for methionine, and it is conjectural whether differen t genotypes, if they appear, might have distinctive phenotypes and imp lications for the future ''epidemic curve'' of nvCJD, Genotype-phenoty pe studies of kuru, the only other orally transmitted transmissible sp ongiform encephalopathy, might be instructive in predicting the answer s to these questions. We therefore extracted DNA from blood clots or s era from 92 kuru patients, and analyzed their codon 129 PRNP genotypes with respect to the age at onset and duration of illness and, in nine cases, to detailed clinical and neuropathology data. Homozygosity at codon 129 (particularly for methionine) was associated with an earlier age at onset and a shorter duration of illness than was heterozygosit y, but other clinical characteristics were similar for all genotypes. In the nine neuropathologically examined cases, the presence of histol ogically recognizable plaques was limited to cases carrying at least o ne methionine allele (three homozygotes and one heterozygote). If nvCJ D behaves like kuru, future cases (with longer incubation periods) may begin to occur in older individuals with heterozygous codon 129 genot ypes and signal a maturing evolution of the nvCJD ''epidemic.'' The cl inical phenotype of such cases should be similar to that of homozygous cases, but may have less (or at least less readily identified) amyloi d plaque formation.