Phenotypic heterogeneity in sporadic Creutzfeldt‐Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease‐resistant prion protein (PrPSc) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrPSc properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrPSc deposition. Seventy percent of subjects showed the classic CJD phenotype, PrPSc type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru‐plaque variants, associated to PrPSc type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrPSc type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrPSc type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrPSc in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants. Ann Neurol 1999;46:224–233

We present a synthesis of clinical, neuropathological, and biological details of the National Institutes of Health series of 300 experimentally transmitted cases of spongiform encephalopathy from among more than 1,000 cases of various neurological disorders inoculated into nonhuman primates during the past 30 years. The series comprises 278 subjects with Creutzfeldt-Jakob disease, of whom 234 had sporadic, 36 familial, and 8 iatrogenic disease; 18 patients with kuru; and 4 patients with Gerstmann-Strüssler-Scheinker syndrome. Sporadic Creutzfeldt-Jakob disease, numerically by far the most important representative, showed an average age at onset of 60 years, with the frequent early appearance of cerebellar and visual/oculomotor signs, and a broad spectrum of clinical features during the subsequent course of illness, which was usually fatal in less than 6 months. Characteristic spongiform neuropathology was present in all but 2 subjects. Microscopically visible kuru-type amyloid plaques were found in 5% of patients with Creutzfeldt-Jakob disease, 75% of those with kuru, and 100% of those with Gerstmann-Sträussler-Scheinker syndrome; brain biopsy was diagnostic in 95% of cases later confirmed at autopsy, and proteinase-resistant amyloid protein was identified in Western blots of brain extracts from 88% of tested subjects. Experimental transmission rates were highest for iatrogenic Creutzfeldt-Jakob disease (100%), kuru (95%), and sporadic Creutzfeldt-Jakob disease (90%), and considerably lower for most familial forms of disease (68%). Incubation periods as well as the durations and character of illness showed great variability, even in animals receiving the same inoculum, mirroring the spectrum of clinical profiles seen in human disease. Infectivity reached average levels of nearly 10(5) median lethal doses/gm of brain tissue, but was only irregularly present (and at much lower levels) in tissues outside the brain, and, except for cerebrospinal fluid, was never detected in bodily secretions or excretions.

Fatal familial insomnia (FFI) and a subtype of familial Creutzfeldt-Jakob disease (CJD), two clinically and pathologically distinct diseases, are linked to the same mutation at codon 178 (Asn178) of the prion protein gene. The possibility that a second genetic component modified the phenotypic expression of the Asn178 mutation was investigated. FFI and the familial CJD subtype segregated with different genotypes determined by the Asn178 mutation and the methionine-valine polymorphism at codon 129. The Met129, Asn178 allele segregated with FFI in all 15 affected members of five kindreds whereas the Val129, Asn178 allele segregated with the familial CJD subtype in all 15 affected members of six kindreds. Thus, two distinct disease phenotypes linked to a single pathogenic mutation can be determined by a common polymorphism.

The causes and geographic distribution of 267 cases of iatrogenic Creutzfeldt-Jakob disease (CJD) are here updated at the millennium. Small numbers of still-occurring cases result from disease onsets after longer and longer incubation periods following infection by cadaveric human growth hormone or dura mater grafts manufactured and distributed before the mid-1980s. The proportion of recipients acquiring CJD from growth hormone varies from 0.3 to 4.4% in different countries, and acquisition from dura mater varies between 0.02 and 0.05% in Japan (where most cases occurred). Incubation periods can extend up to 30 years, and cerebellar onsets predominate in both hormone and graft recipients (in whom the site of graft placement had no effect on the clinical presentation). Homozygosity at codon 129 of the PRNP gene is over-represented in both forms of disease; it has no effect on the incubation period of graft recipients, but may promote shorter incubation periods in hormone cases. Knowledge about potential high-risk sources of contamination gained during the last quarter century, and the implementation of methods to circumvent them, should minimize the potential for iatrogenic contributions to the current spectrum of CJD.