The clinical features in Chinese patients with <i>PRNP</i>
 D178N mutation

Chen, S.; He, Shuang; Shi, Xiaohong; Shen, Xiaojing; Liang, Keke; Zhao, Jingyi; Yan, B.‐C.; Zhang, J.‐W.

doi:10.1111/ane.12924

Cited by 14 publications

(9 citation statements)

References 21 publications

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“…By providing evidence for the existence of two distinct prions associated with the pathological variability of patients with FFI, our study helps to explain unresolved issues in FFI. It has been reported that there are patients with FFI who exhibit multiple and mixed clinical symptoms of both FFI and Creutzfeldt–Jakob disease ( Zarranz et al , 2005 ; Synofzik et al , 2009 ; Chen et al , 2018 ) and that patients with FFI also show significant neuropathological phenotypic variability ( Manetto et al , 1992 ; McLean et al , 1997 ; Yamashita et al , 2001 ; Sasaki et al , 2005 ). The genotype at codon 129 in the non-mutated allele is known to affect the clinical and pathological features in FFI.…”

Section: Discussionmentioning

confidence: 99%

Two distinct prions in fatal familial insomnia and its sporadic form

Takeuchi

Mohri

Kai

et al. 2019

Brain Communications

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Fatal familial insomnia is a genetic prion disease, which is associated with the aspartic acid to asparagine substitution at codon 178 of the prion protein gene. Although the hallmark pathological feature is thalamic and olivary degeneration, there is a patient with an atypical fatal familial insomnia without the hallmark feature. The cause of the pathological variability is unclear. We analysed a Japanese fatal familial insomnia kindred and compared one atypical clinicopathological fatal familial insomnia phenotype case and typical fatal familial insomnia phenotype cases with transmission studies using multiple lines of knock-in mice and with protein misfolding cyclic amplification. We also analysed the transmissibility and the amplification properties of sporadic fatal insomnia. Transmission studies revealed that the typical fatal familial insomnia with thalamic and olivary degeneration showed successful transmission only using knock-in mice expressing human–mouse chimeric prion protein gene. The atypical fatal familial insomnia with spongiform changes showed successful transmission only using knock-in mice expressing bank vole prion protein gene. Two sporadic fatal insomnia cases with thalamic and olivary degeneration showed the same transmissibility as the typical fatal familial insomnia phenotype. Interestingly, one sporadic fatal insomnia case with thalamic/olivary degeneration and spongiform changes showed transmissibility of both the typical and atypical fatal familial insomnia phenotypes. Protein misfolding cyclic amplification could amplify both typical fatal familial insomnia cases and sporadic fatal insomnia cases but not the atypical fatal familial insomnia phenotype or other sporadic Creutzfeldt–Jakob disease subtypes. In addition to clinical findings and neuropathological features, the transmission properties and the amplification properties were different between the typical and atypical fatal familial insomnia phenotypes. It is suggested that two distinct prions were associated with the diversity in the fatal familial insomnia phenotype, and these two prions could also be detected in sporadic fatal insomnia.

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Section: Discussionmentioning

confidence: 99%

Two distinct prions in fatal familial insomnia and its sporadic form

Takeuchi

Mohri

Kai

et al. 2019

Brain Communications

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“…insomnia and valine with familial CJD, 2 although this association may not be universal. 33,34 In our cohort, 28 patients could be unambiguously identified as D178N_cis129M and 5 patients as D178N_cis129V. No differences in mean antibody reactivity were seen between those 2 groups (table 4).…”

Section: Description Of the Cohortmentioning

confidence: 64%

Autoantibodies against the prion protein in individuals with PRNP mutations

Frontzek

Carta

Losa³

et al. 2020

Neurology

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ObjectiveTo determine whether naturally occurring autoantibodies against the prion protein are present in individuals with genetic prion disease mutations and controls, and if so, whether they are protective against prion disease.MethodsIn this case–control study, we collected 124 blood samples from individuals with a variety of pathogenic PRNP mutations and 78 control individuals with a positive family history of genetic prion disease but lacking disease-associated PRNP mutations. Antibody reactivity was measured using an indirect ELISA for the detection of human immunoglobulin G1–4 antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between (1) PRNP mutation carriers vs controls and (2) asymptomatic vs symptomatic PRNP mutation carriers. Robustness of results was examined in matched cohorts.ResultsWe found that antibody reactivity was present in a subset of both PRNP mutation carriers and controls. Autoantibody levels were not influenced by PRNP mutation status or clinical manifestation of prion disease. Post hoc analyses showed anti-PrPC autoantibody titers to be independent of personal history of autoimmune disease and other immunologic disorders, as well as PRNP codon 129 polymorphism.ConclusionsPathogenic PRNP variants do not notably stimulate antibody-mediated anti-PrPC immunity. Anti-PrPC immunoglobulin G autoantibodies are not associated with the onset of prion disease. The presence of anti-PrPC autoantibodies in the general population without any disease-specific association suggests that relatively high titers of naturally occurring antibodies are well-tolerated.Clinicaltrials.gov identifierNCT02837705.

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“…None of the polymorphisms significantly altered autoantibody response to PrP C in a post hoc analysis ( table 4). In D178N carriers, the clinical phenotype was suggested to be dependent on the PRNP cis c.129 polymorphism: methionine was associated with FFI and valine with fCJD 2 , although this association may not be universal 33, 34 . In our cohort, n = 28 patients could be unambiguously identified as D178N_ cis 129M and n = 5 patients as D178N_ cis 129V.…”

Section: Resultsmentioning

confidence: 99%

Autoantibodies against the prion protein in individuals with PRNP mutations

Frontzek

Carta

Losa

et al. 2019

Preprint

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Objective. To determine whether naturally occurring autoantibodies against the prion protein are present in individuals with genetic prion disease mutations and controls, and if so, whether they are protective against prion disease. Methods. In this case-control study, we collected 124 blood samples from individuals with a variety of pathogenic PRNP mutations and 78 control individuals with a positive family history of genetic prion disease but lacking disease-associated PRNP mutations. Antibody reactivity was measured using an indirect ELISA for the detection of human IgG1-4 antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between a) PRNP mutation carriers versus controls and b) asymptomatic versus symptomatic PRNP mutation carriers. Robustness of results was examined in matched cohorts. Results. We found that antibody reactivity was present in a subset of both PRNP mutation carriers and controls. Autoantibody levels were not influenced by PRNP mutation status nor clinical manifestation of prion disease. Post hoc analyses showed anti-PrPC autoantibody titers to be independent of personal history of autoimmune disease and other immunological disorders, as well as PRNP codon 129 polymorphism. Conclusions. Pathogenic PRNP variants do not notably stimulate antibody-mediated anti-PrPC immunity. Anti-PrPC IgG autoantibodies are not associated with the onset of prion disease. The presence of anti-PrPC autoantibodies in the general population without any disease-specific association suggests that relatively high titers of naturally occurring antibodies are well tolerated. Clinicaltrials.gov identifier NCT02837705.

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The clinical features in Chinese patients with PRNP D178N mutation

Cited by 14 publications

References 21 publications

Two distinct prions in fatal familial insomnia and its sporadic form

Two distinct prions in fatal familial insomnia and its sporadic form

Autoantibodies against the prion protein in individuals with PRNP mutations

Autoantibodies against the prion protein in individuals with PRNP mutations

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