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Objective: To improve diagnostic criteria for sporadic Creutzfeldt–Jakob disease (CJD).Methods: Pooled data on initial and final diagnostic classification of suspected CJD patients were accumulated, including results of investigations derived from a coordinated multinational study of CJD. Prospective analysis for a comparison of clinical and neuropathologic diagnoses and evaluation of the sensitivity and specificity of EEG and 14-3-3 CSF immunoassay were conducted.Results: Data on 1,003 patients with suspected CJD were collected using a standard questionnaire. After follow-up was carried out, complete clinical data and neuropathologic diagnoses were available in 805 cases. In these patients, the sensitivity of the detection of periodic sharp wave complexes in the EEG was 66%, with a specificity of 74%. The detection of 14-3-3 proteins in the CSF correlated with the clinical diagnosis in 94% (sensitivity). The specificity (84%) was higher than that of EEG. A combination of both investigations further increased the sensitivity but decreased the specificity.Conclusions: Incorporation of CSF 14-3-3 analysis in the diagnostic criteria for CJD significantly increases the sensitivity of case definition. Amended diagnostic criteria for CJD are proposed.

Objective: To assess the effect of usage of three different versions of Creutzfeldt-Jakob disease (CJD) diagnostic criteria on estimates of CJD incidence. Methods: A total of 428 patients referred for suspected sporadic CJD between 1991 and 1997 were classified according to different criteria to be compared after analysis of medical records. Specificity, sensitivity, and positive and negative predictive values were calculated for each set of criteria in the subgroup of patients with a postmortem examination. Positive and negative predictive values of the clinical diagnosis were applied to cases without postmortem examination. Subsequently, the true number of cases of CJD among the referred cases was estimated. Results: By comparison with the French and European study criteria, the Masters’ criteria showed higher sensitivity but lower specificity and positive predictive value. Comparison with an estimate of the true total number of CJD cases showed that Masters’ criteria overestimated the incidence by 7%, whereas the French and the European study criteria led to an underestimate of 12%. Detection of the 14-3-3 protein in CSF, considered as an additional diagnostic criterion for clinically probable CJD, resulted in a slight increase in the estimated incidence when the French or European study criteria were applied. Conclusions: Different diagnostic criteria could lead to an under- or overestimation of the true incidence of CJD. Therefore, comparisons of CJD incidence in different countries should rely on diagnostic classifications using identical criteria. Taking into account 14-3-3 protein detection as a criterion for probable CJD will result in a small increase in the estimated CJD incidence.

Inherited prion diseases are characterized by mutations in the PRNP gene encoding the prion protein (PrP). We report a novel missense mutation in the PRNP gene (resulting in a G114V mutation in PrP) in members of a Uruguayan family with clinical and histopathologic features of prion disease. Affected individuals were characterized by an early age at onset, initial neuropsychiatric symptoms, late dementia with prominent pyramidal and extrapyramidal symptoms, and long disease duration.

We performed a study of the distribution of PrP27-30, the proteinase-K-resistant form of prion protein, in the central and peripheral nervous system of a patient with a Glu200Lys mutation of the prion protein gene, cerebellar ataxia, subcortical dementia, rigidity, and demyelinating peripheral neuropathy. In the CNS, there was neuron loss and spongy degeneration, principally in the cerebellum, and with progressively lower density in the caudate nucleus, thalamus, temporal cortex, frontal cortex, and brainstem. Evaluation of the expression of PrP27-30 by Western blot showed that its distribution correlated with the intensity of the lesions in these regions. In contrast, we did not detect PrP27-30 in the peripheral nervous system where lesions consisted of demyelination, and remyelination that predominated in the proximal nerve trunks and roots.

Human prion diseases are characterized by the accumulation in the brain of an abnormal form of the prion protein. Prion protein polymorphisms seem to play a key role in the pathogenesis of these diseases, probably by enhancing the amyloidogenic properties of the protein. We performed prion protein gene (PRNP) coding sequence analysis in 57 French subjects with Creutzfeldt-Jakob disease (CJD) and found a mutation of the PRNP coding sequence in nine subjects (15.8%); the mutation corresponded with a known family history of CJD in only three of these subjects. In 41 definite and probable cases without known PRNP mutations, codon 129 genotyping revealed an excess of the homozygous 129Met/Met genotype corresponding to a 3.4-fold increased risk of developing CJD when compared with the two other genotypes. We also found that the 129Val/Val genotype, which mainly governs susceptibility to iatrogenic CJD, does not seem to predispose to sporadic CJD.

We screened 16 cases of sporadic Creutzfeldt-Jakob disease (CJD) and 28 healthy control subjects to detect possible polymorphisms in their prion protein gene (PRNP). The molecular analysis of the PRNP coding sequence was performed using denaturing gradient gel electrophoresis of polymerase chain reaction products and direct sequencing. We identified (1) a silent mutation at codon 177 in a healthy individual, (2) a codon 200 glutamate-to-lysine substitution in a 48-year-old CJD-affected Libyan Jew, and (3) a G-to-A point substitution at codon 210, leading a valine-to-isoleucine change, in a 63-year-old French CJD patient. This new mutation occurs in a highly conserved part of the PRNP coding sequence, close to the known CJD-associated codon 200 mutation, and might be linked to a symptomatologic and neuropathologic pattern of typical sporadic CJD. This mutation was also present in a sister of the patient who died at the age of 67 without neurologic symptomatology.