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(American Journal of Pathology. 2005;167:1729-1738.)
© 2005 American Society for Investigative Pathology

Creutzfeldt-Jakob Disease (CJD) with a Mutation at Codon 148 of Prion Protein Gene

Relationship with Sporadic CJD

Manuela Pastore^*, Steven S. Chin, Karen L. Bell, Zhiqian Dong^*, Qiwei Yang^*, Lizhu Yang^*, Jue Yuan^*, Shu G. Chen^*, Pierluigi Gambetti^* and Wen-Quan Zou^*

From the Department of Pathology, Case Western Reserve University^* and National Prion Disease Pathology Surveillance Center, Cleveland, Ohio; the University of Utah Health Science Center, Salt Lake City, Utah; and Columbia University College of Physicians & Surgeons, New York, New York

Creutzfeldt-Jakob disease (CJD), the most common human prion disease, includes sporadic (s) and familial (f) forms. Regardless of etiology, both forms are thought to share the pathogenic mechanism whereby the cellular prion protein (PrP^C) converts into its pathogenic isoform (PrP^Sc). While PrP^C conversion is thought to be random in sCJD, conversion in fCJD is facilitated by the congenital presence of mutated PrP. Differences in PrP genotype (PRNP) and in conversion circumstances lead to PrP^Sc with distinct characteristics that elicit different disease phenotypes. Here, we describe a case of fCJD with a substitution of histidine (H) for arginine (R) at codon 148 (R148H) and heterozygosity of the methionine/valine (M/V) polymorphic codon 129, with the 129M allele coupled with the mutation. The disease phenotype and all major characteristics of PrP^Sc of fCJD^R148H were virtually indistinguishable from those of sCJDMV2, which has features different from those of any other sCJD. Therefore, despite the differences in etiology, PRNP, and conversion process, the two forms of PrP^Sc had similar characteristics. Furthermore, comparison of fCJD^R148H with a recently reported case carrying R148H and homozygosity at codon 129 suggests that codon 129 coupled with the mutation as well as that located on the normal allele can modify major phenotypic and PrP^Sc features of fCJD^R148H.

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