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 (PrPSc). 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 PrPSc 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.

Altered properties of amyloidogenic prion protein in genetic Creutzfeldt–Jakob disease with PRNP V180I mutation in response to pentosan polysulfate

“…In particular, there are mild but evident differences in pathological changes between non‐PPS cases, as coarse granular deposition of PrP seen in only the case with heterozygosity for methionine/valine at PRNP codon 129, suggesting the changing pathophysiology due to PRNP codon 129 polymorphisms. In addition, the survival time of non‐PPS cases is shorter than those reported in the past systematic review [ 34 ], so we cannot be certain that the course of non‐PPS cases are consistent with the natural history of V180I gCJD. Regarding PPS cases, the brain weights are markedly decreased less than other V180I gCJD cases with similar incubation periods [ 35 , 36 ].…”

“…Because our samples are small and biased, we need to analyze the clinicopathological differences between our cases and the natural history of V180I gCJD. We have compared the characteristics between our cases and other 186 cases of V180I gCJD described in the past systematic review [ 34 ], and the result is shown in Table 3 . In the past systematic review, the characteristics in patients of V180I has been shown as follows: (i) the ratio of female patients is greater than that of males (females 58.1%), (ii) the average age at the onset is 78.9 ± 7.0 years, (iii) the disease duration is 23.1 ± 15.1 months, (iv) methionine homozygosity at PRNP codon 129 is observed in most patients (75.5%), while methionine/valine heterozygosity is observed in others (24.5%).…”

“…Natural history of V180I gCJD from systematic review [34] PPS cases Non-PPS cases Total cases Short duration [35] Long duration [35,36] We could identify a lower molecular weight PrP Sc corresponding to 13 kDa in immunoblotting with primary antibody clone 3F4, whereas the detailed compositions remain unknown. Satoh et al previously reported the presence of two C-terminal fragments (CTF12/13) truncated from full length PrP sc , which is specific for V180I gCJD and weight approximately 11 kDa [40].…”