Clinical features of genetic Creutzfeldt-Jakob disease with V180I mutation in the prion protein gene

Abstract

ObjectivesGenetic Creutzfeldt-Jakob disease (CJD) due to V180I mutation in the prion protein gene (PRNP) is of great interest because of the differences from sporadic CJD and other genetic prion diseases in terms of clinical features, as well as pathological and biochemical findings. However, few systematic observations about the clinical features in patients with this unique mutation have been published. Therefore, the goal of this study was to relate this mutation to other forms of CJD from a clinical perspective.DesignWe analysed clinical symptoms, prion protein genetics, biomarkers in cerebrospinal fluid (CSF) and MRI of patients.Participants186 Japanese patients with the V180I mutation in PRNP.ResultsOur results indicate that the V180I mutation caused CJD at an older age, with a slower progression and a lower possibility of developing myoclonus, cerebellar, pyramidal signs and visual disturbance compared with classical sporadic CJD with methionine homozygosity at codon 129 of PRNP. Cognitive impairment was the major symptom. Diffuse hyperintensity of the cerebral cortex in diffusion-weighted MRI might be helpful for diagnosis. Owing to the low positivity of PrPSc in the CSF, genetic analysis was often required for a differential diagnosis from slowly progressive dementia.ConclusionsWe conclude that the V180I mutation in PRNP produces a late-developing and slow-developing, less severe form of CJD, whose lesions are uniquely distributed compared with sporadic and other genetic forms of CJD.

The influence of PRNP polymorphisms on human prion disease susceptibility: an update

“…The pathogenic mutations were found on the 219E allele in all cases except one GSS-P102L case. In contrast, although a gCJD-V180I patient had been listed as a 219E/K heterozygote in the previous study [69], careful reviewing of the surveillance data in the present study has revealed that 219E/K heterozygotes were totally absent in the 216 cases with gCJD-V180I. Thus, 219E/K heterozygosity confers resistance against gCJD-V180I but not against gCJD-E200K or GSS-P102L (Fig.…”

“…In Japan, 129M/V heterozygotes have been overrepresented in gCJD cases with a mutation at codon 180 (valine to isoleucine, V180I) and in GSS cases with a mutation at codon 105 (proline to leucine, P105L) ( Table 2; Fig. 2b) [57,69,84]. The V180I mutation is the most frequent PRNP pathogenic mutation in Japan and accounts for 41 % of total cases with genetic prion diseases [57].…”

Clinicopathological findings of a long-term survivor of V180I genetic Creutzfeldt-Jakob disease

“…The rarity, rapidity, and clinical heterogeneity of prion disease affects study enrolment and the ability to measure treatment outcomes [34]. Since V180I gCJD is a gradually progressing prion disease [6], we believe that this phenotype may become a potential target of clinical therapeutic trials for prion disease as well as MM2-cortical-type of sCJD [35].Therefore, in the setting of clinical trials, a good understanding of the clinicopathological characteristics of a long-term survivor of V180I gCJD is required.…”

“…Conversely, V180I gCJD is extremely rare in European countries, the United States, and China [2][3][4]. Its clinical characteristics are unique: elderly-onset, gradual progression, sporadic fashion, and cortical oedematous hyper-intensity on diffusionweighted MRI (DW-MRI) [5,6]. Moreover, we previously reported unique single-photon emission computed tomography patterns such as preserve cerebral blood flow in the occipital cortices, brainstem, and cerebellum within the initial 2-3 years after disease onset [7].…”

“…Moreover, we previously reported unique single-photon emission computed tomography patterns such as preserve cerebral blood flow in the occipital cortices, brainstem, and cerebellum within the initial 2-3 years after disease onset [7]. The average disease duration of V180I gCJD patients is 23 or 27 months in methionine homozygote or M/V heterozygote at codon 129 in the PRNP gene, respectively [6]. Long-term survivors whose disease duration is ≧ 5-10 years have also been reported [8,9]; however, the influencing survival and the clinicopathological characteristics of long-term survivors of V180I gCJD remains unknown.…”