<p>Novel prion mutation (p.Tyr225Cys) in a Korean patient with atypical Creutzfeldt–Jakob disease</p>

Abstract

Background: A novel prion variant, PRNP p.Tyr225Cys (c.674A>G; p.Y225C), was identified in an atypical Creutzfeldt–Jakob disease (CJD) patient. The patient had a 5-year history of progressive cognitive impairment with speech and gait disturbances. From the basic neurological examination at his first hospital visit, rigidity and myoclonic jerks in all limbs were observed without focal weakness. Electroencephalogram showed the diffuse slow continuous delta activity in the bilateral cerebral hemisphere. Magnetic resonance imaging revealed abnormalities in the brain, such as cortical signal changes and edema in the frontotemporoparietal lobes and the basal ganglia. Cerebrospinal fluid 14–3-3 protein analysis showed a weakly positive signal. Family history remained unclear, but the patient’s mother and sister were diagnosed with cognitive impairment but both refused genetic testing. Methods: Targeted next generation sequencing (NGS) was performed on 50 genes, involved in different neurodegeneratives diseases, such as Alzheimer's, Parkinson's, frontotemporal dementia or prion diseases. In silico analyses and structure predictions were performed on the potential patohgenic mutations. Results: NGS and standard sequencing revealed the novel PRNP p.Tyr225Cys mutation in the patient. Structure predictions revealed that this may make the helix more flexible. In addition, the extra cysteine residue in TM-III of prion protein may result in disturbances of natural disulfide bond. Conclusion: Hence, the pathogenicity of PRNP p.Tyr225Cys was not fully confirmed at present, and its penetrance was suggested to be low. However, its possible pathogenic nature in prion diseases cannot be ignored, since Tyr/Cys exchange could disturb the helix dynamics and contribute to conformational alteration and disease progression.

Potential Fluid Biomarkers for the Diagnosis of Mild Cognitive Impairment

“…The ideal markers should be able to distinguish the different subtypes of MCI (amnestic-and non-amnestic), which may also improve the prediction of risk for the AD and other kinds of dementia onset [149]. A biological marker, or biomarkers, is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention” [30,101,150,151,152]. Analysis of biomarkers from blood, urine, and cerebrospinal fluid, combined with imaging data, could help to predict the prognosis of diseases.…”

APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease

“…In conclusion, among the distinct mutations in the Asian patients and isolated cases in the Asian population, definite pathogenicity accounted for less than 16%, leaving a large group of autosomal dominant pedigrees genetically unexplained. In addition, our findings suggest that continuing the investigation of families harboring known mutations and the elucidation of the missing genetic etiology in unexplained EOAD patients has a vast potential to improve our understanding about the complexity of AD [1,10,15,90,91]. We also suggest that the use of high-throughput sequencing technologies for patients with EOAD and data integration from other -omics analyses (epigenomics, proteomics, transcriptomics, and metabolomics) might help in better understanding the underlying molecular mechanisms of AD.…”

Alterations of Striatal Subregions in a Prion Protein Gene V180I Mutation Carrier Presented as Frontotemporal Dementia With Parkinsonism

“…Patients with the FTD phenotype often lack the typical ancillary findings of prion disease. Of the published prion patients with the FTD/FTDP phenotype, it is roughly estimated that no patients have periodic sharp-wave complexes on EEG, three quarters had no hyperintensity on MRI, and two-thirds were negative for CSF 14-3-3 protein (Nitrini et al, 2001;Hall et al, 2005;Woulfe et al, 2005;Clerici et al, 2008;Giovagnoli et al, 2008;Alzualde et al, 2010;Bernardi et al, 2010Bernardi et al, , 2014Jansen et al, 2010Jansen et al, , 2011Kumar et al, 2011;Beck et al, 2013;Cupidi et al, 2013;McKnight et al, 2013;San Millán et al, 2013;Riudavets et al, 2014;Mano et al, 2016;Oldoni et al, 2016;Kenny et al, 2017;Ghetti et al, 2018;Sun et al, 2018;Takayanagi et al, 2018;Bagyinszky et al, 2019b;Di Fede et al, 2019;Priemer et al, 2019;Townley et al, 2020).…”