Systematic Review of Clinical and Pathophysiological Features of Genetic Creutzfeldt-Jakob Disease Caused by a Val-to-Ile Mutation at Codon 180 in the Prion Protein Gene

Abstract

Genetic Creutzfeldt-Jakob disease (gCJD) is a subtype of genetic prion diseases (gPrDs) caused by the accumulation of mutated pathological prion proteins (PrP^Sc). gCJD has a phenotypic similarity with sporadic CJD (sCJD). In Japan, gCJD with a Val to Ile substitution at codon 180 (V180I-gCJD) is the most frequent gPrD, while the mutation is extremely rare in countries other than Japan and Korea. In this article, we aim to review previously elucidated clinical and biochemical features of V180I-gCJD, expecting to advance the understanding of this unique subtype in gCJD. Compared to classical sCJD, specific clinical features of V180I-gCJD include older age at onset, a relatively slow progression of dementia, and a lower positivity for developing myoclonus, cerebellar, pyramidal signs, and visual disturbance. Diffuse edematous ribboning hyperintensity of the cerebral cortex, without occipital lobes in diffusion-weighted magnetic resonance imaging, is also specific. Laboratory data reveal the low positivity of PrP^Sc in the cerebrospinal fluid and periodic sharp wave complexes on an electroencephalogram. Most patients with V180I-gCJD have been reported to have no family history, probably due to the older age at onset, and clinical and biochemical features indicate the specific phenotype associated with the prion protein gene mutation.

Keywords: V180I; Val-to-Ile substitution at codon 180; genetic Creutzfeldt–Jakob disease; genetic prion disease; normal prion proteins; pathological prion proteins; prion protein gene.

Figure 1

PRISMA flow-chart diagram showing the paper selection process.

Figure 2

Western blot analysis of PrP^res in patients with V180I-gCJD. (A–D): Brain homogenates from seven patients with V180I-gCJD, two patients with sCJD-MM1, and two patients with sCJD-MM2C were treated with proteinase K and SDS-PAGE. The figure shows the results of analyses with 3F4 (A), the type-2 specific antibody Tohoku 2 (B), and the carboxyl terminal-specific antibody #71 (C). In subsequent analyses with the #71 antibody, the samples were treated with both proteinase K and PNGase F (D). (E) Quantitative analysis of the ratio of CTF12/13 to the major unglycosylated form of PrP^res with V180I, relative to that observed in other forms of gCJD (P102L, D178N, E200K, M232R). (F) Relative amount of PrP^res in various brain regions (Frontal: frontal neocortex, Temporal: temporal neocortex, Occipital: occipital neocortex, Cerebellum: cerebellar cortex). The same amount of brain homogenate was loaded on the SDS-PAGE after treatment with proteinase K. Among the three neocortical samples, the frontal cortex exhibited the greatest amount of PrP^res, while the occipital cortex exhibited least. Very small amounts of PrP^res were observed in the hippocampus, thalamus, and cerebellum. This Figure was cited from reference [24]. (A–D): lanes 1–2, sCJD-MM1; lanes 3–4, sCJD-MM2C; lanes 5–11, V180I-gCJD; lane 12, sCJD-MM1. PrP^res, protease-resistant abnormal prion proteins; V180I, valine to isoleucine substitution at codon 180; PNGase F, N-glycosidase F; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; gCJD, genetic Creutzfeldt–Jakob disease; sCJD, sporadic Creutzfeldt–Jakob disease; CTF, carboxyl terminal fragments.

Figure 3

Diagram of the pathogenic PrP fragments. Two glycosylated sites are represented as green ellipses. Major PrP^Sc fragments (types 1 and 2) are shown, along with the two components of the PrP^Sc-V180I fragments. The polymorphisms in the prion gene are represented as inverted triangles; additionally, red (129-V) and yellow (219-K) inverted triangles show exacerbating and protective effects, respectively, on PrP^Sc-V180I toxicity [51]. This Figure was modified and cited from references [24,26]. PrP, prion proteins; PrP^C, normal prion proteins; PrP^Sc, abnormal prion proteins; PrP^res, protease-resistant abnormal prion proteins; V180I, valine to isoleucine substitution at codon 180; 129-V, valine polymorphism at codon 129; 219-K, lysine polymorphism at codon 219.