Fatal Insomnia Research Articles

Dopaminergic neurodegeneration in Gerstmann-Sträussler-Scheinker (P102L) disease: insights from imaging and pathological examination.

Gerstmann-Sträussler-Scheinker (GSS) disease is an inherited prion disease characterized by dementia, cerebellar ataxia, and painful sensory disturbances. GSS is pathologically defined by the presence of amyloid plaques comprised of prion protein predominantly localized in the cerebral cortex, cerebellar cortex, and basal ganglia, resulting from mutations in the prion protein gene. This study investigated five cases of GSS P102L [GSS caused by a leucine (L) substitution of proline (P) at position 102 of the prion protein gene] with L-dopa-resistant extrapyramidal symptoms and reduced dopamine transporter single-photon emission computed tomography (DAT-SPECT) uptake. Clinical findings revealed diverse manifestations, with all cases exhibiting parkinsonism, and four patients had a vertical gaze palsy. Notably, all patients showed reduced striatal DAT-SPECT uptake, indicating neurodegeneration of the nigrostriatal system. Autopsy findings in one case confirmed prion protein plaques and dopaminergic neuron loss in the substantia nigra of a patient with GSS P102L. Additionally, reduced DAT immunostaining was observed in the putamen compared with a control. While previous studies have identified reduced DAT-SPECT and positron emission tomography uptake in Creutzfeldt-Jakob disease and fatal familial insomnia owing to nigrostriatal neurodegeneration induced by abnormal prion protein deposition, similar phenomena in GSS P102L have not been reported. This study provides support for a correlation between abnormal prion protein deposition and nigrostriatal system degeneration in GSS P102L. Our results reveal the importance of considering GSS P102L in cases of atypical Parkinsonism and abnormal DAT-SPECT results, which would serve as a valuable indicator for subsequent prion genetic testing.

Agrypnia excitata: a human model to explore the derailment of sleep-wake cycle integrated control.

The commemoration of the 70th anniversary of rapid eye movement sleep discovery offers a unique possibility to reassess the peculiar organic condition of agrypnia excitata. Agrypnia excitata is characterized by a severe loss of sleep leading to a complete derangement of physiological sleep-wake cycle and body homeostasis. Agrypnia excitata is a definite clinico-neurophysiological condition characterized by: (1) slow-wave sleep loss with disruption of sleepwake cycle; (2) a 24-hr motor and autonomic overactivity; and (3) peculiar episodes of oneiric stupor. Agrypnia excitata may happen within different pathophysiologies, such as delirium tremens, Morvan's syndrome and fatal familial insomnia, suggesting some general reflections on the composition and function of the cerebral neuronal network generating wake and sleep behaviour and regulating body homeostasis, with a focus on rapid eye movement sleep.

Creutzfeldt-Jakob Disease and Fatal Familial Insomnia: Demographics and In-Hospital Mortality in Spain.

Background: Creutzfeldt-Jakob disease (CJD) and fatal familial insomnia (FFI) are prion diseases characterized by severe neurodegenerative conditions and a short duration of illness. Methods: This study explores the characteristics of hospitalizations for CJD and FFI in Spain from 2016 to 2022 using the Spanish National Hospital Discharge Database (SNHDD). Results: We identified a total of 1063 hospital discharges, including 1020 for CJD and 43 for FFI. Notably, the number of hospitalized patients with FFI showed a significant peak in 2017. The average length of hospital stay (LOHS) was 13 days for CJD and 6 days for FFI, with in-hospital mortality rates (IHM) of 36.37% for CJD and 32.56% for FFI. Among CJD patients, the average LOHS was 14 days, with a significantly longer duration for those who experienced IHM. Conclusions: The presence of sepsis or pneumonia and older age were associated with a higher IHM rate among CJD patients. The total estimated cost for managing CJD and FFI patients over the study period was EUR 6,346,868. This study offers new insights into the epidemiology and healthcare resource utilization of CJD and FFI patients, which may inform future research directions and public health strategies.

Genetic prion disease – fatal familial insomnia (clinical case)

Background. Fatal familial insomnia is a rare genetically determined neurodegenerative disorder from the group of prion diseases. Its main cause is the autosomal dominant D178N mutation of the PRNP gene, which leads to the synthesis of the pathological prion protein PrP.The aim. Using the example of a clinical case to describe an example of the early onset of fatal familial insomnia in a teenager, a clinical example of its management.Materials and methods. Female patient V., 16 years old, of hyposthenic constitution, undernourished, with negative family history (multiple sclerosis in her paternal grandmother) for the first time consulted a neurologist in Tver for the complaints of superficial sleep, shortened to 4–5 hours, unspecific pain all over the body, periodic numbness in the upper limbs. Six months later, retardation of speech and movements, changes in gait, and intentional tremor occurred; sleep was shortened to 2 hours. In the future, the teenager lost the ability to independently maintain the vertical body position, the ability to walk without assistance, speech was reduced to syllable answers to questions. In order to verify the diagnosis and to carry out differential diagnosis with other neurodegenerative diseases, the girl underwent auxiliary research methods: detection of antibodies to nuclear antigens, magnetic resonance imaging, computer electroencephalography, polyexomal genome sequencing.Results. Based on the anamnesis, complaints, clinical picture and results of genetic research the final diagnosis of fatal familial insomnia was made. Due to the lack of etiological and pathogenetic therapy, the patient was subsequently provided with palliative medical care. The fatal outcome occurred 19 months after the onset of the disease.Conclusions. The presented clinical case reflects the complexity of managing patients with rare genetic diseases, confirms the need for mandatory polyexomal genome sequencing in order to verify the diagnosis, which allows timely palliative care

Sleep Disorder and its Treatment: From Nature to Laboratory

Sleep is the natural cellular repair mechanism to improve and restore central neural mechanism, memory, hormonal imbalance, and finally, cell rejuvenation. Sleep disorder is characterized by insomnia, circadian rhythm disorder (CRD), sleep apnea, narcolepsy, parasomnia, and restless leg syndrome (RLS) or periodic limb movement disorder (PLMD). Both oversleeping and less sleeping are associated with sleep disorders (SD). Anxiety, schizophrenia, weight loss/gain, hypothyroidism, and oxidative stress are the most common outcomes of SD. There is also a genetic explanation behind circadian rhythmicity, circadian disorder, narcolepsy-cataplexy syndrome, fatal familial insomnia, and somnambulism. Excessive work pressure, stress, and consumption of caffeine and alcohol collectively push a person toward sleep deprivation. Anxiety, schizophrenia, weight loss/gain, hypothyroidism, and oxidative stress are the most common outcomes of SD. Adenosine, melatonin, dopamine, serotonin, gamma amino butyric acid (GABA), orexin, and histamine regulate SDs by various pathways. Among natural sources, Centella asiatica, Bacopa monnieri, Acorus calamus, Withania somnifera, Nardostachys jatamansi, Poria cocos is, Valeriana officinalis, Matricaria chamomilla, Lavandula angustifolia, Nelumbo nucifera, Melissa officinalis, Convolvulus pluricaulis, Camellia sinensis, Ziziphus jujube, Datura stramonium, Zhizhipus jujube, Passiflora incarnata, and Moringa oleifera showed remarkable effects on different forms of SDs through GABAA, serotonin, and melatonin receptors. Pramipexole, ropinirole, rotigotine, clonazepam, lorazepam, estazolam, zolpidem, lemborexant, daridorexant, and suvorexant showed its activity in the treatment of SDs as a dopamine agonist, inhibitor of GABAA receptor, dual orexin receptor antagonist, respectively. This article focused on the types of SDs, the effects of SDs on mental health, receptors involved in the sleep cycle, and the impact of natural molecules and synthetic molecules in the management of SDs.

Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease.

Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found. In this study, we evaluated the efficacy of various anti-prion drugs on newly-developed knock-in mouse models for FFI and fCJD. These models express bank vole prion protein (PrP) with the pathogenic D178N and E200K mutations. We applied various drug regimens known to be highly effective against wild-type prions in vivo as well as a brain-penetrant compound that inhibits mutant PrPSc propagation in vitro. None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrPSc accumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions, as well as anti-prion strategies that are not strain-dependent.

Clinical characteristics and diagnostics of human spongiform encephalopathies: an update

Human spongiform encephalopathies are rare transmissible neurodegenerative diseases of the brain and the nervous system that are caused by misfolding of the physiological prion protein into apathological form and its deposition in the central nervous system (CNS). Prion diseases include Creutzfeldt-Jakob disease (CJD, sporadic or familial), Gerstmann-Straussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI). Prion diseases can be differentiated into three etiological categories: spontaneous (sporadic CJD), inherited (familial CJD, FFI, and GSS) and acquired (variant CJD and iatrogenic CJD). Most cases occur sporadically. Prion diseases can lead to avariety of neurological symptoms and always have an inevitably fatal course. Cerebrospinal fluid analysis and magnetic resonance imaging (MRI) play acrucial role in the diagnostics of prion diseases and may facilitate an early and reliable clinical diagnosis. Acausal treatment or specific therapeutic agents are not yet available. In general, apalliative therapeutic concept is indicated.

Selective Vulnerability to Neurodegenerative Disease: Insights from Cell Type-Specific Translatome Studies.

Neurodegenerative diseases (NDs) manifest a wide variety of clinical symptoms depending on the affected brain regions. Gaining insights into why certain regions are resistant while others are susceptible is vital for advancing therapeutic strategies. While gene expression changes offer clues about disease responses across brain regions, the mixture of cell types therein obscures experimental results. In recent years, methods that analyze the transcriptomes of individual cells (e.g., single-cell RNA sequencing or scRNAseq) have been widely used and have provided invaluable insights into specific cell types. Concurrently, transgene-based techniques that dissect cell type-specific translatomes (CSTs) in model systems, like RiboTag and bacTRAP, offer unique advantages but have received less attention. This review juxtaposes the merits and drawbacks of both methodologies, focusing on the use of CSTs in understanding conditions like amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Alzheimer's disease (AD), and specific prion diseases like fatal familial insomnia (FFI), genetic Creutzfeldt-Jakob disease (gCJD), and acquired prion disease. We conclude by discussing the emerging trends observed across multiple diseases and emerging methods.

Scoring sleep in neurodegenerative diseases: A pilot study in the synucleinopathies

BackgroundNeurodegenerative diseases often alter sleep architecture, complicating the application of the standard sleep scoring rules. There are no recommendations to overcome this problem. Our aim was to develop a scoring method that incorporates the stages previously applied in dementia with Lewy Bodies (DLB), anti-IgLON5 disease, and fatal insomnia, and to test it in patients with alpha-synucleinopathies. MethodsVideo-polysomnographies (VPSG) of nine patients (DLB:3, Parkinson's disease (PD):3, and multiple system atrophy (MSA):3) selected for their difficulty in applying standard rules were scored independently by two authors, using additional Sleep/Wake stages. These included Abnormal Wake, Subwake, Undifferentiated NREM sleep (UNREM), Poorly structured N2 (P–S N2) and abnormal REM sleep including REM without atonia (RWA), REM without low-amplitude, mixed-frequency EEG activity (RWL) and REM without rapid eye movements (RWR). ResultsPatients (4 females) had a median age of 74 (range 63–85). Six patients (all with PD or DLB) had abnormal EEG awake and Subwake stage. UNREM sleep was present in all patients, typically at sleep onset, and was the most common sleep stage in five. P–S N2 was recorded only in the three patients with MSA. Periods of normal and abnormal NREM coexisted in three patients. RWA was the predominant REM subtype, RWR occurred mainly in patients with MSA and RWL in those with DLB. Six patients had brief REM episodes into NREM sleep which we termed “Encapsulated RBD”. ConclusionOur scoring system allows an accurate description of the complex sleep-wake changes in patients with alpha-synucleinopathies.

Genetic Variants Associated with the Age of Onset Identified by Whole-Exome Sequencing in Fatal Familial Insomnia.

Fatal familial insomnia (FFI) is a rare autosomal-dominant inherited prion disease with a wide variability in age of onset. Its causes are not known. In the present study, we aimed to analyze genetic risk factors other than the prion protein gene (PRNP), in FFI patients with varying ages of onset. Whole-exome sequencing (WES) analysis was performed for twenty-five individuals with FFI (D178N-129M). Gene ontology enrichment analysis was carried out by Reactome to generate hypotheses regarding the biological processes of the identified genes. In the present study, we used a statistical approach tailored to the specifics of the data and identified nineteen potential gene variants with a potential effect on the age of onset. Evidence for potential disease modulatory risk loci was observed in two pseudogenes (NR1H5P, GNA13P1) and three protein coding genes (EXOC1L, SRSF11 and MSANTD3). These genetic variants are absent in FFI patients with early disease onset (19-40 years). The biological function of these genes and PRNP is associated with programmed cell death, caspase-mediated cleavage of cytoskeletal proteins and apoptotic cleavage of cellular proteins. In conclusions, our study provided first evidence for the involvement of genetic risk factors additional to PRNP, which may influence the onset of clinical symptoms in FFI.

Proposal of new clinical diagnostic criteria for fatal familial insomnia

AbstractBackgroundEarly and accurate diagnosis of fatal familial insomnia (FFI) is critical for effective screening; however, this rare disease remains difficult to recognize. This work aimed to propose a new diagnostic criterion for fatal familial insomnia (FFI) with optimal sensitivity, specificity, and likelihood ratio.MethodsAn international group of experts was established and 128 genetically confirmed FFI cases and 281 non‐FFI prion disease controls are enrolled in the validation process. The new criteria were proposed based on the following steps with 2‐round expert consultation: 1) Validation of the 2018 FFI criteria. 2) Diagnostic item selection according to statistical analysis and expert consensus. 3) Validation of the new criteria.ResultsThe 2018 criteria for possible FFI had a sensitivity of 90.6%, specificity of 83.3%, the positive likelihood ratio (PLR) of 5.43, and negative likelihood ratio (NLR) of 0.11; the probable FFI criteria had a sensitivity of 83.6%, specificity of 92.9%, the PLR of 11.77, and NLR of 0.18. The new criteria included more specific and/or common clinical features, 2 exclusion items, and summarized a precise and flexible diagnostic hierarchy. The new criteria for possible FFI had a sensitivity of 92.2%, specificity of 96.1%, a PLR of 23.64, and NLR of 0.08, while the probable FFI criteria had a sensitivity of 90.6%, specificity of 98.2%, the PLR of 50.33, and NLR of 0.095.ConclusionA new clinical diagnostic criteria was proposed for FFI, which will be practical at the clinic for early recognition of FFI and differentiation from other prion diseases then help further referral and genetic test.

Specific structuro‐metabolic pattern of thalamic subnuclei in fatal familial insomnia: A PET/MRI imaging study

AbstractBackgroundDysfunction of the thalamus has been proposed as a core mechanism of fatal familial insomnia. However, detailed metabolic and structural alterations in thalamic subnuclei are not well documented. We aimed to address the multimodal structuro‐metabolic pattern at the level of the thalamic nuclei in fatal familial insomnia patients, and investigated the clinical presentation of primary thalamic alterations.MethodFive fatal familial insomnia patients and 10 healthy controls were enrolled in this study. All participants underwent neuropsychological assessments, polysomnography, electroencephalogram, and cerebrospinal fluid tests. MRI and fluorodeoxyglucose PET were acquired on a hybrid PET/MRI system. Structural and metabolic changes were compared using voxel‐based morphometry analyses and standardized uptake value ratio analyses, focusing on thalamic subnuclei region of interest analyses. Correlation analysis was conducted between gray matter volume and metabolic decrease ratios, and clinical features.ResultThe whole‐brain analysis showed that gray matter volume decline was confined to the bilateral thalamus and right middle temporal pole in fatal familial insomnia patients, whereas hypometabolism was observed in the bilateral thalamus, basal ganglia, and widespread cortices, mainly in the forebrain. In the regions of interest analysis, gray matter volume and metabolism decreases were prominent in bilateral medial dorsal nuclei, anterior nuclei, and the pulvinar, which is consistent with neuropathological and clinical findings. A positive correlation was found between gray matter volume and metabolic decrease ratios.ConclusionOur study revealed specific structuro‐metabolic pattern of fatal familial insomnia that demonstrated the essential roles of medial dorsal nuclei, anterior nuclei, and pulvinar, which may be a potential biomarker in diagnosis. Also, primary thalamic subnuclei alterations may be correlated with insomnia, neuropsychiatric, and autonomic symptoms sparing primary cortical involvement.

Thalamic‐insomnia phenotype in genetic E200K Creutzfeldt‐Jakob disease: A PET/MRI study

AbstractBackgroundInsomnia and thalamic involvement are hallmarks of fatal familial insomnia; however, it was occasionally reported that genetic E200K Creutzfeldt‐Jakob disease (CJD) patients had also manifested thalamic‐insomnia phenotype. The study aimed to explore the clinical and neuroimage characteristics of genetic E200K CJD by comprehensive neuroimage analysis.MethodsSix genetic CJD patients carried Glu to Lys change at codon 200 (E200K) mutations on prion protein gene (PRNP), thirteen sporadic CJD (sCJD), and twenty‐two age‐ and sex‐matched normal controls were enrolled in the study. All participants completed hybrid positron emission tomography/ magnetic resonance imaging (PET/MRI) examinations. The high signal was visually inspected on diffusion weighted imaging (DWI) sequence. 18F‐fluorodeoxyglucose positron emission tomography (18F‐FDG‐PET) and structural images were quantitively analyzed by statistically parameter mapping (SPM). Clinical and image characteristics are compared between genetic E200K CJD patients and sporadic CJD patients.ResultsThere was no group difference in age (49.0±7.1 versus 55.0±4.9 versus 52.7±7.3, p = 0.193) and gender (3/3 versus 4/9 versus 11/11, p = 0.513) between genetic E200K CJD, sCJD, and normal controls. Insomnia was the main complaint in the genetic E200K CJD patients’ group (4/2 versus 1/12, p = 0.007). Hyperintensity, hypometabolism but not predominant atrophy of the thalamus was found by visual inspection in genetic E200K CJD patients. A decreased trend was found on gray matter volume (uncorrected p<0.0001) and metabolism (FWE corrected) of the thalamus in genetic E200K patients.ConclusionThe clinical and image characteristics of genetic E200K CJD mimic fatal familial insomnia, manifested as a thalamic‐insomnia phenotype, indicating some specific underlying pathological changes might exist in E200K mutations. PET measurement is a sensitive approach to help identify the functional changes of the thalamus in prion disease.

Sleep in Gerstmann-Straüssler-Scheinker disease

BackgroundGerstmann-Sträussler-Scheinker (GSS) is a rare prion disease with heterogeneous clinical presentation. Although sleep-related abnormalities are prominent and well-known in other prion diseases such as fatal familial insomnia and Creutzfeldt-Jakob disease, information on sleep is limited in GSS. MethodsWe evaluated sleep in three genetically confirmed GSS cases using clinical history, sleep scales and video-polysomnography. In addition, patients underwent neurological assessment, neurological scales, neuropsychological testing, lumbar puncture, brain MRI and brain 18F-FDG-PET. ResultsTwo patients reported sleep maintenance insomnia attributed to leg stiffness and back pain while the remaining patient did not report sleep problems. Video-polysomnography showed normal sleep staging in all of them. Findings such as reduced sleep efficiency in two patients, a confusional arousal in one patient, obstructive apneas in one patient, and periodic legs movements in sleep in two patients were observed. ConclusionsIn contrast to fatal familial insomnia, the normal sleep staging in GSS may suggest dissimilar involvement of the neuronal structures that regulate sleep. We found non-specific sleep alterations in GSS such as obstructive apneas and periodic leg movements in sleep which are of unknown origin and of uncertain clinical relevance. Studies including a larger number of patients, serial sleep evaluations and incorporating neuropathological assessment will further help to understand sleep in GSS.

From parasomnia to agrypnia excitata - An illustrative case on diagnostic approach

The diagnostic approach to sleep-related movements disorders is seldom discussed. We report a case of fatal familial insomnia who initially presented with persistent limb movements in sleep, which later progressed to a state of agrypnia excitata. Here, the evaluation of abnormal movements in sleep is discussed using a step-by-step diagnostic approach. Although no cure is available for fatal familial insomnia, prompt recognition of this condition is important to facilitate proper management, including the involvement of interdisciplinary neuropalliative care.

Clinical profiles and ethnic heterogeneity of sporadic fatal insomnia.

This study was undertaken to elucidate the clinical profile of sporadic fatal insomnia (sFI), assess the similarities and differences between sFI and fatal familial insomnia (FFI), and evaluate the influence of ethnicity on the phenotype of sFI patients. The data of sFI and FFI patients were retrieved from our case series and through literature review. The clinical and diagnostic features of sFI and FFI were compared, as were the phenotypes of Asian and Caucasian sFI patients. We identified 44 sFI and 157 FFI cases. The prevalence of sleep-related, neuropsychiatric, and autonomic symptoms among the sFI patients were 65.9%, 100.0%, and 43.2%, respectively. Compared to FFI, sFI exhibited longer disease duration and a higher proportion of neuropsychiatric symptoms, whereas FFI was characterized by a higher incidence of sleep-related and autonomic symptoms in the early stages of the disease or throughout its course. In addition, a higher proportion of the sFI patients showed hyperintensity on magnetic resonance imaging (MRI) and periodic sharp wave complexes on electroencephalography compared to the FFI patients, especially those presenting with pathological changes associated with MM2-cortical type sporadic Creutzfeldt-Jakob disease. The Asian sFI patients had a higher proportion of males and positivity for cerebrospinal fluid 14-3-3 protein, and fewer sleep-related symptoms compared to Caucasian sFI patients. The age at onset and duration of sFI differed between ethnic groups, but the difference failed to reach statistical significance. Despite its similarities to FFI, sFI is characterized by longer disease duration, higher proportion of neuropsychiatric symptoms, and hyperintensity on MRI, along with differences in the clinical characteristics based on ethnicity.

Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction.

Fatal familial insomnia (FFI) is a rare neurodegenerative disease caused by a dominantly inherited single amino acid substitution (D178N) within the prion protein (PrP). No in vitro human brain tissue model for this disease has previously been available. Consequently, how this mutation exerts its damaging effect on brain cells is still unknown. Using CRISPR-Cas9 engineered induced pluripotent stem cells, we made D178N cerebral organoids and compared these with isotype control organoids. We found that, in the absence of other hallmarks of FFI, the D178N organoids exhibited astrogliosis with cellular oxidative stress. Abnormal post-translational processing of PrP was evident but no tissue deposition or propagation of mis-folded PrP isoforms were observed. Neuronal electrophysiological function was compromised and levels of neurotransmitters, particularly acetylcholine and GABA, altered. Underlying these dysfunctions were changes in cellular energy homeostasis, with substantially increased glycolytic and Krebs cycle intermediates, and greater mitochondrial activity. This increased energy demand in D178N organoids was associated with increased mitophagy and depletion of lipid droplets, in turn resulting in shifts of cellular lipid composition. Using a double mutation (178NN) we could confirm that most changes were caused by the presence of the mutation rather than interaction with PrP molecules lacking the mutation. Our data strongly suggests that shifting biosynthetic intermediates and oxidative stress, caused by an imbalance of energy supply and demand, results in astrogliosis with compromised neuronal activity in FFI organoids. They further support that many of the disease associated changes are due to a corruption of PrP function and do not require propagation of PrP mis-folding.

A Theoretical Framework on the Biology of Prion Diseases.

Prion diseases or TSE diseases are a group of neurodegenerative disorders that manifest in several forms in humans, such as Kuru disease, Creutzfeldt‒Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS) and fatal familial insomnia. In this study, we propose a multimodular hypothesis of prion diseases. According to this hypothesis, a prion disease manifests because of the interaction of two genetic modules, such as the PRNP gene module and that of the gene or genes responsible for one or more chaperones, with one or some chemical module on whose structure the products of the genes or genetic modules interact. This study presents the perspective that modular thinking can allow us to overcome conceptual obstacles in the understanding and interpretation of prion diseases. The structure of the chemical module or modules is directly responsible for the folding or misfolding of the PrPC protein. The etiology of acquired prion diseases is explained based on this hypothesis. Hence, it has been proposed that (g) CJD involves the PRNP gene mutant and one or more mutant genes for one or more chaperone genes. In contrast, sCJD has one or more mutant chaperone genes. When does iCJD occur? Healthy individuals manifest acquired prion disease through contamination when infected with one or more mutant chaperones. The mutant chaperones interact with the prion protein, and PrPC is converted to its isoform PrPSc. In a recent study, there was a case of an individual with CJD after COVID-19 infection. This case emphasizes the link between neuroinflammation and protein misfolding and provides proof that chemical module formation is a necessary condition for the manifestation of prion diseases.

Prion Mutations in Republic of Republic of Korea, China, and Japan.

Prion gene (PRNP) mutations are associated with diverse disease phenotypes, including familiar Creutzfeldt-Jakob Disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), and fatal familial insomnia (FFI). Interestingly, PRNP mutations have been reported in patients diagnosed with Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, and frontotemporal dementia. In this review, we describe prion mutations in Asian countries, including Republic of Republic of Korea, China, and Japan. Clinical phenotypes and imaging data related to these mutations have also been introduced in detail. Several prion mutations are specific to Asians and have rarely been reported in countries outside Asia. For example, PRNP V180I and M232R, which are rare in other countries, are frequently detected in Republic of Korea and Japan. PRNP T188K is common in China, and E200K is significantly more common among Libyan Jews in Israel. The A117V mutation has not been detected in any Asian population, although it is commonly reported among European GSS patients. In addition, V210I or octapeptide insertion is common among European CJD patients, but relatively rare among Asian patients. The reason for these differences may be geographical or ethical isolation. In terms of clinical phenotypes, V180I, P102L, and E200K present diverse clinical symptoms with disease duration, which could be due to other genetic and environmental influences. For example, rs189305274 in the ACO1 gene may be associated with neuroprotective effects in cases of V180I mutation, leading to longer disease survival. Additional neuroprotective variants may be possible in cases featuring the E200K mutation, such as KLKB1, KARS, NRXN2, LAMA3, or CYP4X1. E219K has been suggested to modify the disease course in cases featuring the P102L mutation, as it may result in the absence of prion protein-positive plaques in tissue stained with Congo red. However, these studies analyzed only a few patients and may be too preliminary. The findings need to be verified in studies with larger sample sizes or in other populations. It would be interesting to probe additional genetic factors that cause disease progression or act as neuroprotective factors. Further studies are needed on genetic modifiers working with prions and alterations from mutations.

Dysfunction of the cardiac parasympathetic system in fatal familial insomnia: a heart rate variability study.

Although sympathetic hyperactivity with preserved parasympathetic activity has been extensively recognized in fatal familial insomnia (FFI), the symptoms of parasympathetic nervous system failure observed in some patients are difficult to explain. Using heart rate variability (HRV), this study aimed to discover evidence of parasympathetic dysfunction in patients with FFI and the difference of parasympathetic activity between patients with FFI and Creutzfeldt-Jakob disease (CJD). This study enrolled nine patients with FFI, eight patients with CJD and 18 healthy controls (HCs) from May 2013 to August 2020. All participants underwent a nocturnal video-polysomnography with lead II electrocardiography, and the data were analyzed using linear and nonlinear indices of HRV during both wake and sleep states. Compared to the HC and CJD groups, the FFI group had a continuously higher heart rate with a lower amplitude of oscillations. The low frequency (LF)/high frequency (HF) ratio and ratio of SD1 to SD2 and correlation dimension D2 (CD2) were significantly different in the FFI group compared to the HC group. The root mean square of successive differences (RMSSD), HF and SD1 in the FFI group were significantly lower than in the HC group. RMSSD, SD1, and CD2 in the FFI group were all significantly lower than in the CJD group. Cardiovascular dysautonomia in FFI may be partly attributable to parasympathetic abnormalities, not just sympathetic activation. HRV may be helpful as a noninvasive, quantitative, and effective autonomic function test for FFI diagnosis.