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Summary 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. [ABSTRACT FROM AUTHOR]

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

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 a pathological 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 a variety of neurological symptoms and always have an inevitably fatal course. Cerebrospinal fluid analysis and magnetic resonance imaging (MRI) play a crucial role in the diagnostics of prion diseases and may facilitate an early and reliable clinical diagnosis. A causal treatment or specific therapeutic agents are not yet available. In general, a palliative therapeutic concept is indicated. [ABSTRACT FROM AUTHOR]

Prion diseases and the prion protein are only partially understood so far in many aspects. This explains the continued research on this topic, calling for an overview on the current state of knowledge. The main objective of the present review article is to provide a comprehensive up-to-date presentation of all major features of human prion diseases bridging the gap between basic research and clinical aspects. Starting with the prion protein, current insights concerning its physiological functions and the process of pathological conversion will be highlighted. Diagnostic, molecular, and clinical aspects of all human prion diseases will be discussed, including information concerning rare diseases like prion-associated amyloidoses and Huntington disease-like 1, as well as the question about a potential human threat due to the transmission of prions from prion diseases of other species such as chronic wasting disease. Finally, recent attempts to develop future therapeutic strategies will be addressed.

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. [ABSTRACT FROM AUTHOR]

Study Objectives: Fatal insomnia (FI) is a rare prion disease severely affecting sleep architecture. Breathing during sleep has not been systematically assessed. Our aim was to characterize the sleep architecture, respiratory patterns, and neuropathologic findings in FI.Methods: Eleven consecutive FI patients (ten familial, one sporadic) were examined with video-polysomnography (vPSG) between 2002 and 2017. Wake/sleep stages and respiration were evaluated using a modified scoring system. Postmortem neuropathology was assessed in seven patients.Results: Median age at onset was 48 years and survival after vPSG was 1 year. All patients had different combinations of breathing disturbances including increased respiratory rate variability (RRV; n = 7), stridor (n = 9), central sleep apnea (CSA) (n = 5), hiccup (n = 6), catathrenia (n = 7), and other expiratory sounds (n = 10). RRV in NREM sleep correlated with ambiguous and solitary nuclei degeneration (r = 0.9, p = 0.008) and reduced survival (r = -0.7, p = 0.037). Two new stages, Subwake1 and Subwake2, present in all patients, were characterized. NREM sleep (conventional or undifferentiated) was identifiable in ten patients but reduced in duration in eight. REM sleep occurred in short segments in nine patients, and their reduced duration correlated with medullary raphe nuclei degeneration (r = -0.9, p = 0.005). Seven patients had REM without atonia. Three vPSG patterns were identified: agitated, with aperiodic, manipulative, and finalistic movements (n = 4); quiet-apneic, with CSA (n = 4); and quiet-non-apneic (n = 3).Conclusions: FI patients show frequent breathing alterations, associated with respiratory nuclei damage, and, in addition to NREM sleep distortion, have severe impairment of REM sleep, related with raphe nuclei degeneration. Brainstem impairment is crucial in FI. [ABSTRACT FROM AUTHOR]

Human prion diseases are rapidly progressive and fatal neurodegenerative conditions caused by a disease-causing isoformof the native prion protein. The prion protein gene (PRNP) encodes for the cellular prion protein, which is the biological substrate for prion disease transmission and neurotoxicity. Human prion diseases have three etiologies: sporadic, genetic, and acquired. PRNP polymorphisms and pathogenic variants play a large role in the frequency, age at onset, and clinicopathologic phenotype of prion diseases. Genetic prion diseases will be covered in detail and information necessary for clinical care, predictive genetic testing, and genetic counseling will be reviewed. Because the prion protein is necessary for transmission and neurotoxicity, many experimental treatments targeting its production are being investigated and hold potential promise as a disease modifying treatment for all forms of prion disease, including asymptomaticmutation carriers. This article will review genetic aspects of human prion disease and their influence on epidemiology, clinicopathologic phenotype, diagnostics, clinical management, and potential treatment approaches. [ABSTRACT FROM AUTHOR]

Background: The understanding of fatal familial insomnia (FFI), a rare neurodegenerative autosomal dominant prion disease, has improved in recent years as more cases were reported. This work aimed to propose new diagnostic criteria for FFI with optimal sensitivity, specificity, and likelihood ratio. Methods: An 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 two-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. Results: The 2018 criteria for possible FFI had a sensitivity of 90.6%, a specificity of 83.3%, with a positive likelihood ratio (PLR) of 5.43, and a negative likelihood ratio (NLR) of 0.11; and the probable FFI criteria had a sensitivity of 83.6%, specificity of 92.9%, with a PLR of 11.77, and a NLR of 0.18. The new criteria included more specific and/or common clinical features, two exclusion items, and summarized a precise and flexible diagnostic hierarchy. The new criteria for possible FFI had therefore reached a better sensitivity and specificity (92.2% and 96.1%, respectively), a PLR of 23.64 and a NLR of 0.08, whereas the probable FFI criteria showed a sensitivity of 90.6%, a specificity of 98.2%, with a PLR of 50.33 and a NLR of 0.095. Conclusions: We propose new clinical diagnostic criteria for FFI, for a better refining of the clinical hallmarks of the disease that ultimately would help an early recognition of FFI and a better differentiation from other prion diseases. [ABSTRACT FROM AUTHOR]

Introduction. Fatal familial insomnia (FFI) is one of the transmissible spongiform encephathalopathies characterized by neuronal loss, sleep impairment, subsequent non-specific disturbances of autonomic nervous system (e.g. tachycardia) and endocrine dysfunctions. It is fatal autosomal dominant prion disease, which is extremaly rare- FFI affects only about one person per milion annually. The aim of this study is to review the literature and systematize knowledge about fatal familial insomnia.Brief description of the state of knowledge. The causative agent of this disease is a misfolded version of the physiological prion protein called PrP(Sc) in the brain. Major vulnerable regions in FFI are mediodorsal and anterior ventral nuclei of the thalamus. Average survival time after the onset of symptoms is 18 months. Hence molecular mechanisms involved in pathogenesis are poorly understood, the disease is incureable yet. However, there are a number of therapeutic options currently under investigation, e.g. immunotherapy or doxycycline usage.Conclusions. Subsequent researches are essential to improve understending of fatal familial insomnia. The prime issue is to develop functioning therapeutic or preventive treatment. While some of presented terapeutic approches appers promising, all of them require profoud research.

Human prion diseases are rapidly progressive and fatal neurodegenerative conditions caused by a disease-causing isoform of the native prion protein. The prion protein gene (PRNP) encodes for the cellular prion protein, which is the biological substrate for prion disease transmission and neurotoxicity. Human prion diseases have three etiologies: sporadic, genetic, and acquired. PRNP polymorphisms and pathogenic variants play a large role in the frequency, age at onset, and clinicopathologic phenotype of prion diseases. Genetic prion diseases will be covered in detail and information necessary for clinical care, predictive genetic testing, and genetic counseling will be reviewed. Because the prion protein is necessary for transmission and neurotoxicity, many experimental treatments targeting its production are being investigated and hold potential promise as a disease modifying treatment for all forms of prion disease, including asymptomatic mutation carriers. This article will review genetic aspects of human prion disease and their influence on epidemiology, clinicopathologic phenotype, diagnostics, clinical management, and potential treatment approaches.

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.

Background and purpose: Fatal familial insomnia is a rare hereditary prion disease associated with the D178N‐129M PRNP mutation. Early diagnosis is difficult, because the clinical syndrome may overlap with affective disorders. In addition, most known cerebrospinal fluid biomarkers for prion diseases and magnetic resonance imaging do not show a good diagnostic accuracy for fatal familial insomnia. In this context, data on plasma biomarkers are scarce. Methods: We analyzed levels of neurofilament light chain, glial fibrillary acidic protein, chitinase‐3‐like protein 1, calcium‐binding protein B, and total tau protein in six serial plasma samples from a patient with fatal familial insomnia. Subsequently, plasma neurofilament light chain was analyzed in n = 25 patients and n = 19 controls. The diagnostic accuracy and associations with disease stage and duration were explored. Results: Among all biomarker candidates in the case study, only neurofilament light chain levels showed a constant evolution and increased over time. They discriminated fatal familial insomnia from controls with an area under the curve of 0.992 (95% confidence interval [CI] = 0.974–1) in the case–control study. Higher concentrations were associated with methionine homozygosity at codon 129 PRNP (p = 0.006), shorter total disease duration (rho = −0.467, p = 0.019, 95% CI = −0.790 to −0.015), and shorter time from sampling to death (rho = −0.467, p = 0.019, 95% CI = −0.773 to −0.019). Conclusions: Plasma neurofilament light chain may be a valuable minimally invasive diagnostic biomarker for fatal familial insomnia after clinical onset. Most important, stage‐related increase and association with disease duration indicate potential as a prognostic marker and as a surrogate marker in clinical trials. [ABSTRACT FROM AUTHOR]

Fatal familial insomia (FFI) is a dominant autosomal genetic prion disease characterised by progressive sleep impairment, autonomic nervous system disorders and motor symptoms associated with significant loss of nerve cells in the medial thalamic nuclei. Making a diagnosis of FFI requires the presence of a certain or probable recognised first-degree relative of the patient, together with neuropsychiatric disorders present. In turn, the detection of the PrP mutation allows the diagnosis to be definitively established. In addition, three other tests - polysomnography, brain imaging and cerebrospinal fluid examination - can be helpful. Fatal familial insomnia is not a fully understood disease. Diagnosis is based on the presence of symptoms of the disease. An important step in diagnosis will be the development of non-invasive diagnostic tests that are reliable in the early and presymptomatic stages of the disease. Polysomnography, imaging studies (PET, SPECT) and cerebrospinal fluid examination should be improved and widely accepted.

Fatal familial insomnia (FFI) is a rare prion disease with autosomal dominant inheritance. Currently, there is only one published case study of FFI in Australia. FFI is universally fatal, with the disease duration ranging from 8 to 72 months. Clinically, it manifests with disordered sleep–wake cycle, dysautonomia, motor disturbances and neuropsychiatric disorders. We describe a case of FFI detailing the investigative process, including the importance of sleep assessment and polysomnography in obtaining a diagnosis. [ABSTRACT FROM AUTHOR]

Fatal familial insomnia (FFI) is a rare genetic human prion disease with an autosomal dominant pattern of inheritance caused by a D178N mutation in the PRNP gene. FFI is characterized by a variable clinical presentation and subacute manifestation. The latter prompts to consider autoimmune encephalitis as a differential diagnosis in the diagnostically challenging patients. Here, we present a clinical case of FFI that was initially misdiagnosed with autoimmune encephalitis. A 26-year-old woman presented with rapid development of diverse neurological features, autonomic and endocrine disturbances, which initially were considered as manifestations of an autoimmune disease due to the lack of clear indications of positive family history. She was started on corticosteroids with temporary stabilization and even with a mild improvement for several months. Progressive deterioration of her symptoms with development of the psychiatric and cognitive impairment, as well as subsequently received additional information regarding positive family history, prompted us to perform a PRNP gene test that revealed a D178N mutation and confirmed an FFI diagnosis.

Attempts to model inherited human prion disorders such as familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) disease, and fatal familial insomnia (FFI) using genetically modified mice have produced disappointing results. We recently demonstrated that transgenic (Tg) mice expressing wild-type bank vole prion protein (BVPrP) containing isoleucine at polymorphic codon 109 develop a spontaneous neurodegenerative disorder that exhibits many of the hallmarks of prion disease. To determine if mutations causing inherited human prion disease alter this phenotype, we generated Tg mice expressing BVPrP containing the D178N mutation, which causes FFI; the E200K mutation, which causes familial CJD; or an anchorless PrP mutation similar to mutations that cause GSS. Modest expression levels of mutant BVPrP resulted in highly penetrant spontaneous disease in Tg mice, with mean ages of disease onset ranging from ~120 to ~560 days. The brains of spontaneously ill mice exhibited prominent features of prion disease-specific neuropathology that were unique to each mutation and distinct from Tg mice expressing wild-type BVPrP. An ~8-kDa proteinase K-resistant PrP fragment was found in the brains of spontaneously ill Tg mice expressing either wild-type or mutant BVPrP. The spontaneously formed mutant BVPrP prions were transmissible to Tg mice expressing wild-type or mutant BVPrP as well as to Tg mice expressing mouse PrP. Thus, Tg mice expressing mutant BVPrP exhibit many of the hallmarks of heritable prion disorders in humans including spontaneous disease, protease-resistant PrP, and prion infectivity.

Les maladies à prions ou encéphalopathies spongiformes transmissibles (EST) sont des maladies humaines et animales transmissibles naturellement ou expérimentalement avec une longue durée d'incubation et une évolution fatale sans rémission. La nature exacte de l'agent transmissible reste discutée mais l'absence de structure évoquant un micro-organisme conventionnel a conduit Stanley B. Prusiner à émettre l'hypothèse qu'il pourrait s'agir d'une protéine infectieuse (proteinaceous infectious particle ou prion). Le prion serait la forme anormale d'une protéine normale, la PrP cellulaire (PrPc) qui va changer de conformation spatiale et être convertie en protéine prion scrapie (PrPsc) ayant des propriétés de résistance partielle aux protéases, d'agrégation et d'insolubilité dans les détergents. Les EST ne s'accompagnent d'aucune réaction inflammatoire ou immunitaire et se caractérisent par les lésions cérébrales associant spongiose, raréfaction neuronale, gliose astrocytaire et accumulation de la PrPsc pouvant prendre l'aspect de plaques amyloïdes. Si le lien entre l'accumulation de PrPsc et la survenue des lésions est discuté, la présence de PrPsc est constante au cours des EST et sa mise en évidence est nécessaire au diagnostic de certitude. Même si elles restent des maladies rares (2 cas par million), l'identification du kuru, à la fin des années 1950, des cas iatrogènes au courant des années 1970 et de la variante de la maladie de Creutzfeldt-Jakob (MCJ) au milieu des années 1990 expliquent l'intérêt pour ces maladies, mais aussi les craintes qu'elles peuvent faire peser sur la santé publique. Elles demeurent un modèle passionnant de recherche car elles appartiennent à la fois au groupe des maladies neurodégénératives avec accumulation de protéines (MCJ sporadique), au groupe des maladies transmissibles (MCJ iatrogènes, variante de la MCJ) mais aussi au groupe des affections génétiques de transmission mendélienne dominante (MCJ génétiques, syndrome de Gerstmann-Straussler-Scheinker, insomnie fatale familiale). Prion diseases or transmissible spongiform encephalopathies (TSEs) are human and animal diseases naturally or experimentally transmissible with a long incubation period and a fatal course without remission. The nature of the transmissible agent remains debated but the absence of a structure evoking a conventional microorganism led Stanley B. Prusiner to hypothesize that it could be an infectious protein (proteinaceous infectious particle or prion). The prion would be the abnormal form of a normal protein, cellular PrP (PrPc) which will change its spatial conformation and be converted into scrapie prion protein (PrPsc) with properties of partial resistance to proteases, aggregation and insolubility in detergents. No inflammatory or immune response are detected in TSEs which are characterized by brain damage combining spongiosis, neuronal loss, astrocytic gliosis, and deposits of PrPsc that may appear as amyloid plaques. Although the link between the accumulation of PrPsc and the appearance of lesions remains debated, the presence of PrPsc is constant during TSE and necessary for a definitive diagnosis. Even if they remain rare diseases (2 cases per million), the identification of kuru, at the end of the 1950s, of iatrogenic cases in the course of the 1970s and of the variant of Creutzfeldt-Jakob disease (CJD) in the mid-1990s explain the interest in these diseases but also the fears they can raise for public health. They remain an exciting research model because they belong both to the group of neurodegenerative diseases with protein accumulation (sporadic CJD), to the group of communicable diseases (iatrogenic CJD, variant of CJD) but also to the group of genetic diseases with a transmission Mendelian dominant (genetic CJD, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia). [ABSTRACT FROM AUTHOR]

Fatal Familial Insomnia (FFI) is an uncommon but fatal genetic condition that is characterized by severe progressive insomnia, dysautonomia, neuropsychiatric changes, and gait instability. Diagnostic workup includes genetic testing, EEG, MRI imaging of the brain, polysomnography, and CSF analysis. MRI brain imaging may be notable for areas of restricted diffusion in the thalamus. Therapeutic approaches are centered on symptom management, predominantly for insomnia. It is important for clinicians to consider FFI in patients presenting with progressive insomnia, cognitive deficits, and gait instability, and to direct patients and families toward genetic counseling and palliative care services. [ABSTRACT FROM AUTHOR]

Background: Dysfunction 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. Materials and Methods: Five 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. Results: The 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. Conclusions: Our 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.

Background: Movement disorders are frequent features of prionopathies. However, their prevalence and onset remain poorly described. Methods: We performed a systematic review of case reports and case series of pathologically- and genetically confirmed prionopathies. Timing of symptom and movement disorder onset were documented. Continuous variables were compared between two groups using the Wilcoxon rank sum test and between multiple groups using Kruskal–Wallis test. Categorical variables were compared using Fisher’s exact test. Results: A total of 324 cases were included in this analysis. Movement disorders were a common feature at the onset of symptoms in most prionopathies. Gait ataxia was present in more than half of cases in all types of prionopathies. The prevalence of limb ataxia (20%) and myoclonus (24%) was lower in Gerstmann–Sträussler–Scheinker disease compared to other prionopathies (p ≤ 0.004). Myoclonus was common but often a later feature in sporadic Creutzfeldt–Jakob disease (2 months before death). Chorea was uncommon but disproportionately prevalent in variant Creutzfeldt–Jakob disease (30% of cases; p < 0.001). In genetic Creutzfeldt–Jakob disease, E200K PRNP carriers exhibited gait and limb ataxia more often when compared to other mutation carriers. Discussion: Movement disorders are differentially present in the course of the various prionopathies. The movement phenomenology and appearance are associated with the type of prion disease and the PRNP genotype and likely reflect the underlying pattern of neurodegeneration. Reliance on myoclonus as a diagnostic feature of sporadic Creutzfeldt–Jakob disease may delay its recognition given its relatively late appearance in the disease course.

Human genetic prion diseases (gPrDs) are directly associated with mutations and insertions in the PRNP (Prion Protein) gene. We collected and analyzed the data of 218 Chinese gPrD patients identified between Jan 2006 and June 2020. Nineteen different subtypes were identified and gPrDs accounted for 10.9% of all diagnosed PrDs within the same period. Some subtypes of gPrDs showed a degree of geographic association. The age at onset of Chinese gPrDs peaked in the 50–59 year group. Gerstmann–Sträussler–Scheinker syndrome (GSS) and fatal familial insomnia (FFI) cases usually displayed clinical symptoms earlier than genetic Creutzfeldt–Jakob disease (gCJD) patients with point mutations. A family history was more frequently recalled in P105L GSS and D178N FFI patients than T188K and E200K patients. None of the E196A gCJD patients reported a family history. The gCJD cases with point mutations always developed clinical manifestations typical of sporadic CJD (sCJD). EEG examination was not sensitive for gPrDs. sCJD-associated abnormalities on MRI were found in high proportions of GSS and gCJD patients. CSF 14-3-3 positivity was frequently detected in gCJD patients. Increased CSF tau was found in more than half of FFI and T188K gCJD cases, and an even higher proportion of E196A and E200K gCJD patients. 63.6% of P105L GSS cases showed a positive reaction in cerebrospinal fluid RT-QuIC. GSS and FFI cases had longer durations than most subtypes of gCJD. This is one of the largest studies of gPrDs in East Asians, and the illness profile of Chinese gPrDs is clearly distinct. Extremely high proportions of T188K and E196A occur among Chinese gPrDs; these mutations are rarely reported in Caucasians and Japanese. [ABSTRACT FROM AUTHOR]

The current classification of sporadic Creutzfeldt–Jakob disease (sCJD) includes six major clinicopathological subtypes defined by the physicochemical properties of the protease-resistant core of the pathologic prion protein (PrPSc), defining two major PrPSc types (i.e., 1 and 2), and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein gene (PRNP). How these sCJD subtypes relate to the well-documented phenotypic heterogeneity of genetic CJD (gCJD) is not fully understood. We analyzed molecular and phenotypic features in 208 individuals affected by gCJD, carrying 17 different mutations, and compared them with those of a large series of sCJD cases. We identified six major groups of gCJD based on the combination PrPSc type and codon 129 genotype on PRNP mutated allele, each showing distinctive histopathological characteristics, irrespectively of the PRNP associated mutation. Five gCJD groups, named M1, M2C, M2T, V1, and V2, largely reproduced those previously described in sCJD subtypes. The sixth group shared phenotypic traits with the V2 group and was only detected in patients carrying the E200K-129M haplotype in association with a PrPSc type of intermediate size ("i") between type 1 and type 2. Additional mutation-specific effects involved the pattern of PrP deposition (e.g., a "thickened" synaptic pattern in E200K carriers, cerebellar "stripe-like linear granular deposits" in those with insertion mutations, and intraneuronal globular dots in E200K-V2 or -M"i"). A few isolated cases linked to rare PRNP haplotypes (e.g., T183A-129M), showed atypical phenotypic features, which prevented their classification into the six major groups. The phenotypic variability of gCJD is mostly consistent with that previously found in sCJD. As in sCJD, the codon 129 genotype and physicochemical properties of PrPSc significantly correlated with the phenotypic variability of gCJD. The most common mutations linked to CJD appear to have a variable and overall less significant effect on the disease phenotype, but they significantly influence disease susceptibility often in a strain-specific manner. The criteria currently used for sCJD subtypes can be expanded and adapted to gCJD to provide an updated classification of the disease with a molecular basis. [ABSTRACT FROM AUTHOR]

Purpose: To summarize the clinical characteristics of patients with sporadic Creutzfeldt-Jakob disease (sCJD), analyze its sleep disorder characteristics using polysomnography (PSG), and compare sleep disturbances with those of fatal familial insomnia (FFI). Patients and methods: We retrospectively reviewed the sleep disturbances; cerebrospinal fluid (CSF) protein 14-3-3 (CSF-14-3-3 protein); prion protein gene, PRNP; magnetic resonance imaging; and electroencephalogram (EEG) of nine sCJD patients Results: Of the nine sCJD patients, six were positive for CSF-14-3-3 protein. In the eight patients who completed diffusion-weighted imaging, seven showed cortical "ribbons sign" and two showed high signal in the basal ganglia. All nine patients had an EEG, which showed an increase in background slow waves; moreover, four showed typical periodic sharp wave complexes. The codon diversity at position 129, 219 of nine patients were MM, EE. Almost all nine patients had sleep disturbances such as insomnia, hypersomnia, and periodic limb movement disorder (PLMD). Five patients completed PSG, which demonstrated severe sleep structure disorder, prolonged total waking time, significantly reduced sleep efficiency, and absent rapid eye movement in some severe patients. Conclusion: Sleep disturbances are common in sCJD patients, manifested as insomnia, lethargy, and PLMD. The sCJD patients often demonstrate severe sleep structure disorder through PSG, which is similar to patients with FFI. [ABSTRACT FROM AUTHOR]

Agrypnia excitata represents a triad of three subgroups of disorders having similar clinical characteristics, namely, delirium tremens caused by alcohol withdrawal, fatal familial insomnia (an autosomal dominant prion disease) and Morvan syndrome (autoimmune encephalitis). All three disorders are characterised by motor, autonomic and hormonal hyperactivity. Clinically, the involvement of the peripheral, central and autonomic nervous systems combined with insomnia symptomatology should be considered indicative of agrypnia excitata because early diagnosis and treatment is essential for preventing disease-related mortality. Herein, we present the case of a patient who was admitted with complaints of sudden-onset diplopia, loss of balance, hallucinations and insomnia and diagnosed with delirium tremens. A literature review, including data obtained most recently on agrypnia excitata, delirium tremens, fatal familial insomnia and Morvan syndrome, was conducted with this context. [ABSTRACT FROM AUTHOR]

Background: Fatal Familial Insomnia (FFI) is a genetic prion disease caused by the D178N mutation in the prion protein gene (PRNP) in coupling phase with methionine at PRNP 129. In 2017, we have shown that the olfactory mucosa (OM) collected from FFI patients contained traces of PrPSc detectable by Protein Misfolding Cyclic Amplification (PMCA). Methods: In this work, we have challenged PMCA-generated products obtained from OM and brain homogenate of FFI patients in BvPrP-Tg407 transgenic mice expressing the bank vole prion protein to test their ability to induce prion pathology. Results: All inoculated mice developed mild spongiform changes, astroglial activation, and PrPSc deposition mainly affecting the thalamus. However, their neuropathological alterations were different from those found in the brain of BvPrP-Tg407 mice injected with raw FFI brain homogenate. Conclusions: Although with some experimental constraints, we show that PrPSc present in OM of FFI patients is potentially infectious. Funding: This work was supported in part by the Italian Ministry of Health (GR-2013-02355724 and Ricerca Corrente), MJFF, ALZ, Alzheimer’s Research UK and the Weston Brain Institute (BAND2015), and Euronanomed III (SPEEDY) to FM; by the Spanish Ministerio de Economía y Competitividad (grant AGL2016-78054-R [AEI/FEDER, UE]) to JMT and JCE; AM-M was supported by a fellowship from the INIA (FPI-SGIT-2015-02).

Abstract Introduction Surrogate cerebrospinal fluid (CSF) biomarkers of neurodegeneration still have a central role in the first‐line screening of patients with suspected Creutzfeldt‐Jakob disease (CJD). Recently, CSF α‐synuclein, a marker of synaptic damage, showed a close to optimal performance in distinguishing between CJD and other neurodegenerative dementias. Methods We evaluated the diagnostic value of CSF α‐synuclein in patients with prion disease, non‐prion rapidly progressive dementias, and non‐neurodegenerative controls. Additionally, we studied its distribution across the different prion disease subtypes and evaluated its association with survival. Results CSF α‐synuclein levels were significantly higher in patients with prion disease than in the other groups but showed a lower diagnostic value than CSF total tau or 14‐3‐3. Moreover, CSF α‐synuclein was significantly associated with survival in the whole prion cohort and the most frequent clinicopathological subtypes. Discussion In the clinical setting, CSF α‐synuclein does not exceed the diagnostic performance of currently used surrogate markers, but it might constitute a robust prognostic indicator.

This paper is intended to discuss some of the scientific and ethical issues that are created by increased research efforts towards earlier diagnosis, as well as to treatment of, human prion diseases (and related dementias), including the resulting consequences for individuals, their families, and society. Most patients with prion disease currently are diagnosed when they are about 2/3 of the way through their disease course (Geschwind et al., 2010a; Paterson et al., 2012b), when the disease has progressed so far that even treatments that stop the disease process would probably have little benefit. Although there are currently no treatments available for prion diseases, we and others have realized that we must diagnose patients earlier and with greater accuracy so that future treatments have hope of success. As approximately 15% of prion diseases have a autosomal dominant genetic etiology, this further adds to the complexity of ethical issues, particularly regarding when to conduct genetic testing, release of genetic results, and when or if to implement experimental therapies. Human prion diseases are both infectious and transmissible; great care is required to balance the needs of the family and individual with both public health needs and strained hospital budgets. It is essential to proactively examine and address the ethical issues involved, as well as to define and in turn provide best standards of care.

[Display omitted] • First report on Met/Met patient of FFI with postural instability and backward leaning from disease onset. • The phenotypic spectrum of homozygous FFI may be broader and more variable than previously described. • Positive anti-SOX1 in serum of FFI points the complicated association between prionopathies and immune-related factors. [ABSTRACT FROM AUTHOR]

Introduction: Surrogate cerebrospinal fluid (CSF) biomarkers of neurodegeneration still have a central role in the first‐line screening of patients with suspected Creutzfeldt‐Jakob disease (CJD). Recently, CSF α‐synuclein, a marker of synaptic damage, showed a close to optimal performance in distinguishing between CJD and other neurodegenerative dementias. Methods: We evaluated the diagnostic value of CSF α‐synuclein in patients with prion disease, non‐prion rapidly progressive dementias, and non‐neurodegenerative controls. Additionally, we studied its distribution across the different prion disease subtypes and evaluated its association with survival. Results: CSF α‐synuclein levels were significantly higher in patients with prion disease than in the other groups but showed a lower diagnostic value than CSF total tau or 14‐3‐3. Moreover, CSF α‐synuclein was significantly associated with survival in the whole prion cohort and the most frequent clinicopathological subtypes. Discussion: In the clinical setting, CSF α‐synuclein does not exceed the diagnostic performance of currently used surrogate markers, but it might constitute a robust prognostic indicator. [ABSTRACT FROM AUTHOR]

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 a pathological 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 a variety of neurological symptoms and always have an inevitably fatal course. Cerebrospinal fluid analysis and magnetic resonance imaging (MRI) play a crucial role in the diagnostics of prion diseases and may facilitate an early and reliable clinical diagnosis. A causal treatment or specific therapeutic agents are not yet available. In general, a palliative therapeutic concept is indicated., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Eva Bagyinszky,1 Vo Van Giau,1 Young Chul Youn,2 Seong Soo A An,1 SangYun Kim3 1Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, Gyeonggi-do, South Korea; 2Department of Neurology, Chung-Ang University College of Medicine, Seoul, South Korea; 3Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, South Korea Abstract: Abnormal prion proteins are responsible for several fatal neurodegenerative diseases in humans and in animals, including Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia. Genetics is important in prion diseases, but in the most cases, cause of diseases remained unknown. Several mutations were found to be causative for prion disorders, and the effect of mutations may be heterogeneous. In addition, different prion mutations were suggested to play a possible role in additional phenotypes, such as Alzheimer’s type pathology, spongiform encephalopathy, or frontotemporal dementia. Pathogenic nature of several prion mutations remained unclear, such as M129V and E219K. These two polymorphic sites were suggested as either risk factors for different disorders, such as Alzheimer’s disease (AD), variant CJD, or protease-sensitive prionopathy, and they can also be disease-modifying factors. Pathological overlap may also be possible with AD or progressive dementia, and several patients with prion mutations were initially diagnosed with AD. This review also introduces briefly the diagnosis of prion diseases and the issues with their diagnosis. Since prion diseases have quite heterogeneous phenotypes, a complex analysis, a combination of genetic screening, cerebrospinal fluid biomarker analysis and imaging technologies could improve the early disease diagnosis. Keywords: genetics, mutation, prion, PRNP gene, Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker disease, fatal familial insomnia, Alzheimer’s disease, diagnosis

Disease and medicine are found throughout Gabriel García Márquez's work. This article examines the insomnia plague described in the novel One Hundred Years of Solitude and performs a differential diagnosis exercise with conditions that affect both sleep and memory. The main finding is that the insomnia plague narrated by García Márquez, with its clinical manifestations, the sequence of symptoms, and its resolution, cannot be associated with any specific diagnosis. However, similarities to and differences from several clinical conditions are discussed, as well as the relation between the neurophysiologic phenomena of sleep and memory. [ABSTRACT FROM AUTHOR]

Fatal familial insomnia (FFI) belongs to the genetic human transmissible spongiform encephalopathies (TSE), such as genetic Creutzfeldt-Jakob disease (CJD) or Gerstmann-Straeussler-Scheinker syndrome (GSS). Here, we analyzed the properties of the pathological prion protein in six FFI cases by Western blot analysis, a protein aggregate stability assay, and aggregate deposition characteristics visualized with the paraffin-embedded tissue blot. While in all cases the unglycosylated fragment in Western blot analysis shared the same size with sporadic CJD prion type 2, the reticular/synaptic deposition pattern of the prion aggregates resembled the ones found in sporadic CJD type 1 (CJD types according to the Parchi classification from 1999). Regarding the conformational stability against denaturation with GdnHCl, FFI prion aggregates resembled CJD type 1 more than type 2. Our results suggest that the size of the proteinase-K-resistant fragments is not a valid criterion on its own. Additional criteria supplying information about conformational differences or similarities need to be taken into account. FFI may resemble a prion type with its own conformation sharing properties partly with type 1 and type 2 prions.

Abstract Background Fatal familial insomnia (FFI) is a rare autosomal dominant disease caused by the PRNP D178N/129 M mutation. Routine brain CT and MRI usually reveal non-specific features. We report a patient with FFI presenting with diffuse abnormal signals on MRI, later confirmed as combined with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Case presentation The patient was a 58-year-old female, whose main clinical manifestations were insomnia, movement disorders, autonomic hyperactivity and mental deterioration. The patient also suffered a typical episode of transient global amnesia. MRI indicated a diffuse white matter abnormality and microbleeding on the susceptibility-weighted imaging. On biopsy, the brain tissue sections showed spongiform changes with gliosis, neuronal degeneration, and prion protein deposition in a portion of the neurons. In addition, arteriosclerosis was prominent. Transmission electron microscopy showed osmiophilic particle deposition in the matrix of medial smooth muscle cells. Gene sequencing confirmed a diagnosis of FFI with CADASIL. Conclusions This case is a compelling example that even with evidence of leukoencephalopathy, prion disease should be an important differential diagnosis of rapidly progressive dementia and related diseases. In cases of genetic diseases with atypical manifestations, the coexistence of two or even more diseases should be considered as a possible explanation.

Fatal familial insomnia,an autosomal dominant prion disease,is rare.We reported the clinical symptoms,examination results,diagnosis,treatment,and prognosis of a patient who was diagnosed with fatal familial insomnia.Furthermore,we described the unique clinical manifestations that involuntary movements and laryngeal stridor were significantly correlated with postural changes,aiming to provide reference for the clinical diagnosis,treatment,and research of the disease in the future.