Background Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive prion disorder whose heterogeneous manifestations may overlap with potentially treatable neurological conditions. We report an atypical sCJD phenotype dominated by progressive dysarthria and an opsoclonus-myoclonus-ataxia-plus (OMAS-plus) phenotype, highlighting the diagnostic pitfalls relative to treatable mimics.Case presentation A 63-year-old man presented with progressive dysarthria and bulbar symptoms suggesting myasthenia gravis, but did not improve on pyridostigmine and progressed to right-predominant hemiataxia, acral polymyoclonus, dystonia, pyramidal signs, facial palsy, and cognitive-behavioural decline. Video-oculography showed opsoclonus, upbeat nystagmus, and abnormal saccades, raising suspicion of an immune-mediated or paraneoplastic OMAS-plus; extensive autoimmune, paraneoplastic, infectious, metabolic, and neuromuscular work-up was unrevealing, and empirical corticosteroids produced no improvement. EEG lacked periodic sharp-wave complexes and CSF 14-3-3 was negative; PRNP sequencing showed a codon 129 methionine-homozygous genotype without pathogenic mutation. Brain MRI showed cortical and basal ganglia DWI/FLAIR hyperintensities, CSF RT-QuIC was positive, and neuropathological examination, together with a type 1 PrP<^>Sc Western blot profile, confirmed sCJD of the MM1 subtype.Discussion An OMAS-plus presentation may occur in sCJD and may initially direct diagnostic reasoning towards potentially treatable disorders. Rapid progression, absent support for alternative diagnoses, characteristic MRI abnormalities, and RT-QuIC positivity should prompt consideration of prion disease even when conventional supportive markers are non-diagnostic.
Surveillance of wildlife diseases poses multiple challenges, including the availability of samples for testing and, in some situations, issues with suboptimal tissue condition. Chronic wasting disease (CWD) is a prion disease threatening the health of wild and captive cervids that is diagnosed with enzyme-linked immunosorbent assay (ELISA) and/or immunohistochemistry (IHC) of retropharyngeal lymph nodes or obex tissue. IHC uses the three-dimensional structure from fresh preserved tissues to facilitate the detection of accumulated prion proteins PrPCWD within the tissue architecture. ELISA does not require tissue structure and uses tissue lysates to detect PrPCWD, but its ability to detect PrPCWD in degraded diagnostic samples is unknown. We thus examined how lymph node decomposition at 4°C and 27°C for up to 12 months affects the ability of ELISA to detect CWD prions in known CWD-positive lymph nodes from wild white-tailed deer (Odocoileus virginianus) in Illinois, USA. We found that prions remained detectable in 100% of the lymph nodes decayed for 12 months at both temperatures, though the detection percentage in each experimental group varied over time. Our findings are the first to demonstrate that USDA-APHIS approved ELISA assays can be used on extensively degraded lymph nodes for CWD surveillance, enabling testing of tissue in suboptimal conditions using.
Managing chronic wasting disease (CWD) - a fatal, transmissible prion disease of cervids - has many challenges, such as determining the number of cervids to test to accurately estimate true prevalence with apparent prevalence. Options range from basic equations to complex techniques like agent-based modelling, but the former does not account for parameter uncertainty, and more detailed models may be less accessible for managers. Our study used Monte Carlo simulation to create a reference table showing the number of hunter-harvested deer to test to approximate herd true prevalence with a ± 2% margin of error and 95% confidence. A three-step process was simulated in which deer from the total population were harvested (testable subpopulation), and then a subset of those harvested deer were tested for CWD (tested group) with diagnostic testing error, with group assignment determined by random sampling. We evaluated true prevalences ranging from 0.5-20% and testable subpopulation sizes up to 5,000 deer from a total population of 20,000. An example from the reference table shows that detecting a 1% true prevalence in a testable subpopulation of 300 deer requires testing ≥280 deer, and that the only way to accurately detect a true prevalence of 0.5% is to test 600 out of 5,000 deer. Evaluating IDNR's CWD surveillance efforts found that 16.14% of counties had adequate sample sizes in a given year and could detect true prevalences as low as 1%, showing that these guidelines are achievable.
Prion diseases are fatal neurodegenerative disorders characterized by abnormally folded prion proteins inducing misfolding of normal prion proteins, leading to neurotoxic fibrils and plaques. Epigenetic mechanisms, particularly DNA methylation, are increasingly implicated in prion-like diseases (e.g. Alzheimer’s disease), but their role in prion pathogenesis remains unclear. To investigate, we used nanopore sequencing and RNAseq to measure genome-wide methylation and gene expression in the brains of Syrian hamsters (Mesocricetus auratus) experimentally infected with a hamster-adapted murine synthetic prion strain (n = 9) and age-matched mock-infected controls (n = 9) at 80, 120, and 160 days post-infection (dpi). We identified 1,586, 1,692, and 2,429 differentially methylated regions (DMRs) at 80, 120, and 160 dpi, respectively. Early- and mid-stage prion disease (80 and 120 dpi) skewed towards hypermethylation, whereas late-stage prion disease (160 dpi) skewed towards hypomethylation. Gene ontology (GO) of DMR-associated genes at 160 dpi included neuron regulation and signalling, neurodevelopment, and cellular stress pathways. We identified 178 differentially expressed genes (DEGs) at 80 dpi, 90 at 120 dpi, and 616 at 160 dpi. The majority of DEGs were downregulated at 80 dpi, and at 120 and 160 dpi, most were upregulated. Overlap in DEGs across timepoints was limited, and GO terms were related to upregulation of disease/injury response and cell death pathways in later timepoints. Overall, we found a stage-specific transcriptional shift from immune suppression to widespread immune and inflammation activation. These findings provide time-resolved data on methylation and transcriptional changes associated with impaired neuronal structure, function, and communication during disease.
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare, rapidly progressive, and fatal neurodegenerative disorder caused by the accumulation of abnormal prion proteins in the central nervous system. The Heidenhain variant (HvCJD), a rare subtype of sCJD, is characterized by prominent visual symptoms at onset. Diagnosing sCJD remains challenging due to non-specific clinical presentations and the limited sensitivity and specificity of conventional tests such as magnetic resonance imaging (MRI), electroencephalography (EEG), and cerebrospinal fluid (CSF) 14-3-3 protein analysis. Recently, real-time quaking-induced conversion (RT-QuIC) has emerged as a valuable tool for improving diagnostic accuracy. We present the case of a 65-year-old man who initially experienced blurred vision and diplopia, followed by rapidly progressive dementia and dysuria. Brain MRI revealed cortical diffusion-weighted imaging (DWI) hyperintensities in the right temporo-occipital region. While his CSF 14-3-3 protein test was negative, RT-QuIC assay returned positive, leading to a final diagnosis of probable CJD. The patient died 8 weeks after diagnosis. This case highlights that HvCJD is a rare but important clinical variant in which conventional CSF 14-3-3 testing may be negative, particularly early in the disease course. In contrast, RT-QuIC demonstrates high sensitivity and specificity and can significantly aid in the early and accurate diagnosis of CJD.
