Prion disease are characterized by cerebral deposition of an abnormal protease-resistant isoform of a membrane-bound glycoprotein called prion protein. Sporadic Creutzfeldt-Jakob disease (CJDs) is the most frequent, accounting for approximately 85% of all human prion disease. The identification of a new variant of Creutzfeldt-Jakob disease has reinforced the need for a detailed analysis of phenotypic variability of CJDs. CJDs is typically characterized by rapidly progressive dementia, myoclonus, periodic sharp-wave electroencephalographic activity, and wide-spread spongiform degeneration. However, variations in clinical presentation, disease duration, as well as type and distribution of lesion have been consistently observed. The physicochemical properties of PrPsc in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability. Continued attention to clinically atypical cases is required to monitor the real incidence of CJDs. To reach this goal neuropathological examination, including the search for PrPsc, and molecular genetic analysis of human prion protein gene (PRNP) should be increasingly applied to atypical neurodegenerative diseases.