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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.

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., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Purpose: 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., Methods: 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., Results: 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., Conclusions: 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., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Fatal familial insomnia (FFI) is a rare prionopathy with unusually high incidence in the Basque Country. We report detailed data on clinical, diagnostic, histopathological, and biochemical characteristics of a recent FFI case series. The Basque Brain Bank database was screened for patients diagnosed from 2010 to 2021 with standard genetic and/or neuropathological criteria. This series includes 16 patients, 25% without family history, with 12 cases from 9 unrelated (but geographically-linked, Basque country) kindreds, onset ranging from 36 to 70 years, and disease course from 7 to 11.5 months. Insomnia was the initial symptom in most cases, with consistent polysomnography in 92% of the cases. In contrast, 14-3-3 and RT-QuIC from cerebrospinal fluid were negative. Most patients were homozygous for methionine. Gliosis and neuronal loss in basal ganglia and thalamus were the main histopathological findings; Western blotting identified preferentially the protease-resistant prion protein (PrPres) type 2, although detection of the scrapie isoform of the prion protein (PrPSc) identified using brain tissue RT-QuIC was more successful. This is one of the largest current studies on FFI patients performed to provide improvements in diagnostic reliability. Among the analyzed tests, polysomnography and the genetic study show the highest diagnostic value in FFI., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Engaging patients as partners in biomedical research has gradually gained consensus over the last two decades. They provide a different perspective on health priorities and help to improve design and outcomes of clinical studies. This paper describes the relationship established between scientists and members of a large family at genetic risk of very rare lethal disease, fatal familial insomnia (FFI). This interaction led to a clinical trial based on the repurposing of doxycycline - an antibiotic with a known safety profile and optimal blood-brain barrier passage - which in numerous preclinical and clinical studies had given evidence of its potential therapeutic effect in neurodegenerative disorders, including prion diseases like FFI. The design of this trial posed several challenges, which were addressed jointly by the scientists and the FFI family. Potential participants excluded the possibility of being informed of their own FFI genotype; thus, the trial design had to include both carriers of the FFI mutation (10 subjects), and non-carriers (15 subjects), who were given placebo. Periodic clinical controls were performed on both groups by blinded examiners. The lack of surrogate outcome measures of treatment efficacy has required to compare the incidence of the disease in the treated group with a historical dataset during 10 years of observation. The trial is expected to end in 2023. Regardless of the clinical outcome, it will provide worthwhile knowledge on the disease. It also offers an important example of public engagement and collaboration to improve the quality of clinical science.

Selective neuronal vulnerability is common in neurodegenerative diseases but poorly understood. In genetic prion diseases, including fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD), different mutations in the Prnp gene manifest as clinically and neuropathologically distinct diseases. Here we report with electroencephalography studies that theta waves are mildly increased in 21 mo old knock-in mice modeling FFI and CJD and that sleep is mildy affected in FFI mice. To define affected cell types, we analyzed cell type-specific translatomes from six neuron types of 9 mo old FFI and CJD mice. Somatostatin (SST) neurons responded the strongest in both diseases, with unexpectedly high overlap in genes and pathways. Functional analyses revealed up-regulation of neurodegenerative disease pathways and ribosome and mitochondria biogenesis, and down-regulation of synaptic function and small GTPase-mediated signaling in FFI, implicating down-regulation of mTOR signaling as the root of these changes. In contrast, responses in glutamatergic cerebellar neurons were disease-specific. The high similarity in SST neurons of FFI and CJD mice suggests that a common therapy may be beneficial for multiple genetic prion diseases., (© 2022 Bauer et al.)

Methionine/valine polymorphism at position 129 of the human prion protein, huPrP, is tightly associated with the pathogenic phenotype, disease progress, and age of onset of neurodegenerative diseases such as Creutzfeldt-Jakob disease or Fatal Familial Insomnia. This raises the question of whether and how the amino acid type at position 129 influences the structural properties of huPrP, affecting its folding, stability, and amyloid formation behavior. Here, our detailed biophysical characterization of the 129M and 129V variants of recombinant full-length huPrP(23-230) by amyloid formation kinetics, CD spectroscopy, molecular dynamics simulations, and sedimentation velocity analysis reveals differences in their aggregation propensity and oligomer content, leading to deviating pathways for the conversion into amyloid at acidic pH. We determined that the 129M variant exhibits less secondary structure content before amyloid formation and higher resistance to thermal denaturation compared to the 129V variant, whereas the amyloid conformation of both variants shows similar thermal stability. Additionally, our molecular dynamics simulations and rigidity analyses at the atomistic level identify intramolecular interactions responsible for the enhanced monomer stability of the 129M variant, involving more frequent minimum distances between E196 and R156, forming a salt bridge. Removal of the N-terminal half of the 129M full-length variant diminishes its differences compared to the 129V full-length variant and highlights the relevance of the flexible N terminus in huPrP. Taken together, our findings provide insight into structural properties of huPrP and the effects of the amino acid identity at position 129 on amyloid formation behavior., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s).)

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., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP. CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt-Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt-Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt-Jakob disease-E200K, Gerstmann-Sträussler-Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels. In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration., (© The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., (© 2022 Royal Australasian College of Physicians.)

Objective: Elucidate the core clinical and genetic characteristics and identify the phenotypic variation between different regions and genotypes of fatal familial insomnia (FFI)., Methods: A worldwide large sample of FFI patients from our case series and literature review diagnosed by genetic testing were collected. The prevalence of clinical symptoms and genetic profile were obtained, and then the phenotypic comparison between Asians versus non-Asians and 129Met/Met versus 129Met/Val were conducted., Results: In total, 131 cases were identified. The age of onset was 47.51±12.53 (range 17-76) years, 106 patients died and disease duration was 13.20±9.04 (range 2-48) months. Insomnia (87.0%) and rapidly progressive dementia (RPD; 83.2%) occurred with the highest frequency. Hypertension (33.6%) was considered to be an objective indicator of autonomic dysfunction. Genotype frequency at codon 129 was Met/Met (84.7%) and Met/Val (15.3%), and allele frequency was Met (92.4%) and Val (7.6%).129 Met was a risk factor (OR: 3.728, 95% CI: 2.194 to 6.333, p=0.000) for FFI in the non-Asian population. Comparison of Asians and non-Asians revealed clinical symptoms and genetic background to show some differences (p<0.05). In the comparison of 129 polymorphisms, a longer disease duration was found in the 129 MV group, with alleviation of some clinical symptoms (p<0.05). After considering survival probability, significant differences in survival time between genotypes remained (p<0.0001)., Conclusions: Insomnia, RPD and hypertension are representative key clinical presentations of FFI. Phenotypic variations in genotypes and geographic regions were documented. Prion protein gene 129 Met was considered to be a risk factor for FFI in the non-Asian population, and 129 polymorphisms could modify survival duration., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

We report a case of genetic Creutzfeldt-Jakob disease (gCJD), which has a clinical phenotype that is highly similar to Fatal Family Insomnia (FFI) and has a triad of Wernicke-Korsakoff syndrome (WKs) at the developmental stage of the disease. The 51-year-old male complained of sleep disorder and imbalance who had visited five different hospitals before diagnosed. A neurological examination revealed a triad of symptoms characteristic for WKs such as gaze paresis, ataxia of limbs and trunk, and memory disturbances. The disturbances increased during the course of the disease, which led to the death of the patient 18 months after the appearance of the signs. Although the patient show negative in brain magnetic resonance imaging (MRI) and 14-3-3 protein of cerebrospinal fluid (CSF), he was finally diagnosed with gCJD disease by the human prion protein (PRNP) gene mutations.

Conformational conversion of the cellular isoform of prion protein, PrP C , into the abnormally folded, amyloidogenic isoform, PrP Sc , is an underlying pathogenic mechanism in prion diseases. The diseases manifest as sporadic, hereditary, and acquired disorders. Etiological mechanisms driving the conversion of PrP C into PrP Sc are unknown in sporadic prion diseases, while prion infection and specific mutations in the PrP gene are known to cause the conversion of PrP C into PrP Sc in acquired and hereditary prion diseases, respectively. We recently reported that a neurotropic strain of influenza A virus (IAV) induced the conversion of PrP C into PrP Sc as well as formation of infectious prions in mouse neuroblastoma cells after infection, suggesting the causative role of the neuronal infection of IAV in sporadic prion diseases. Here, we discuss the conversion mechanism of PrP C into PrP Sc in different types of prion diseases, by presenting our findings of the IAV infection-induced conversion of PrP C into PrP Sc and by reviewing the so far reported transgenic animal models of hereditary prion diseases and the reverse genetic studies, which have revealed the structure-function relationship for PrP C to convert into PrP Sc after prion infection.

Introduction: Fatal familial insomnia (FFI) is a rare clinical case. The study was mainly to report the clinical symptoms and imaging and genetic characteristics of a FFI case with depression, with relevant literature summarized., Patient Concerns: A male, aged 57 years old, with mental disorders and progressive memory decline one year before admission., Diagnosis: Clinical manifestations: he had obvious abnormal mental behavior, rapidly progressing dementia symptoms, stubborn insomnia, abnormal movements and laryngeal stridor after falling asleep at night. Imaging and genetic test results: the cranial magnetic resonance imaging showed frontal temporal lobe atrophy; the polysomnography results showed no effective sleep; the 14-3-3 test result of cerebrospinal fluid was negative; the prion protein (PRNP) test showed that the D178N gene locus had mutations. And the patient was finally diagnosed as FFI., Interventions: There were no obvious effects in the treatment using medicines such as Risperidone, Olanzapine, Alprazolam, Clonazepam, and Deanxit., Outcomes: Mobility dysfunction of the patient was further aggravated. He was no longer able to move around on his own, and there were serious mental disorders., Conclusion: PRNP examination is of guiding significance for the diagnosis of the FFI of depression. Hence, it is very necessary to perform PRNP examination in clinical diagnosis of FFI of depression., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

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 (PrP Sc ), defining two major PrP Sc 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 PrP Sc 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 PrP Sc 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 PrP Sc 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., (© 2021. The Author(s).)

Fatal familial insomnia (FFI) is a dominantly inherited prion disease linked to the D178N mutation in the gene encoding the prion protein (PrP). Symptoms, including insomnia, memory loss and motor abnormalities, appear around 50 years of age, leading to death within two years. No treatment is available. A ten-year clinical trial of doxycycline (doxy) is under way in healthy individuals at risk of FFI to test whether presymptomatic doxy prevents or delays the onset of disease. To assess the drug's effect in a tractable disease model, we used Tg(FFI-26) mice, which accumulate aggregated and protease-resistant PrP in their brains and develop a fatal neurological illness highly reminiscent of FFI. Mice were treated daily with 10 mg/kg doxy starting from a presymptomatic stage for twenty weeks. Doxy rescued memory deficits and restored circadian motor rhythmicity in Tg(FFI-26) mice. However, it did not prevent the onset and progression of motor dysfunction, clinical signs and progression to terminal disease. Doxy did not change the amount of aggregated and protease-resistant PrP, but reduced microglial activation in the hippocampus. Presymptomatic doxy treatment rescues cognitive impairment and the motor correlates of sleep dysfunction in Tg(FFI-26) mice but does not prevent fatal disease., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

A previously well 54- year-old woman presented with a short history of diplopia, cognitive decline, hallucinations and hypersomnolence. The patient had progressive deterioration in short-term memory, ocular convergence spasm, tremor, myoclonus, gait apraxia, central fever, dream enactment and seizures. Results of investigations were normal including MRI brain, electroencephalogram, cerebrospinal fluid (CSF, including CSF prion protein markers) and brain biopsy. The patient died from pneumonia and pulmonary embolus. Brain postmortem analysis revealed neuropathological changes in keeping with Fatal familial insomnia (FFI); the diagnosis was confirmed on genetic testing. FFI is caused by an autosomal dominant and highly penetrant pathogenic Prion Protein gene PRNP Although usually familial, fatal insomnia (FI) also occurs in a rare sporadic form. FI is a rare human prion disease with prominent sleep disturbance, autonomic, motor, cognitive and behavioural involvement. Patient management is with best supportive care and early suspected diagnosis allows for timely palliation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Fatal familial insomnia (FFI) is a rare inherited prion disease characterized by sleep, autonomic, and motor disturbances. Neuro-ophthalmological abnormalities have been reported at the onset of disease, although not further characterized. We analyzed video recordings of eye movements of 6 patients with FFI from 3 unrelated kindreds, seen within 6 months from the onset of illness. Excessive saccadic intrusions were the most prominent findings. In patients with severe insomnia, striking saccadic intrusions are an early diagnostic clue for FFI. The fact that the thalamus is the first structure affected in FFI also suggests its role in the control of steady fixation. ANN NEUROL 2021;89:823-827., (© 2021 American Neurological Association.)

Fatal familial insomnia (FFI), genetic Creutzfeldt-Jakob disease (gCJD), and Gerstmann-Sträussler-Scheinker (GSS) syndrome are neurodegenerative disorders linked to prion protein (PrP) mutations. The pathogenic mechanisms are not known, but increasing evidence points to mutant PrP misfolding and retention in the secretory pathway. We previously found that the D178N/M129 mutation associated with FFI accumulates in the Golgi of neuronal cells, impairing post-Golgi trafficking. In this study we further characterized the trafficking defect induced by the FFI mutation and tested the 178N/V129 variant linked to gCJD and a nine-octapeptide repeat insertion associated with GSS. We used transfected HeLa cells, embryonic fibroblasts and primary neurons from transgenic mice, and fibroblasts from carriers of the FFI mutation. In all these cell types, the mutant PrPs showed abnormal intracellular localizations, accumulating in the endoplasmic reticulum (ER) and Golgi. To test the efficiency of the membrane trafficking system, we monitored the intracellular transport of the temperature-sensitive vesicular stomatite virus glycoprotein (VSV-G), a well-established cargo reporter, and of endogenous procollagen I (PC-I). We observed marked alterations in secretory trafficking, with VSV-G accumulating mainly in the Golgi complex and PC-I in the ER and Golgi. A redacted version of mutant PrP with reduced propensity to misfold did not impair VSV-G trafficking, nor did artificial ER or Golgi retention of wild-type PrP; this indicates that both misfolding and intracellular retention were required to induce the transport defect. Pharmacological activation of Src family kinase (SFK) improved intracellular transport, suggesting that mutant PrP impairs secretory trafficking through corruption of SFK-mediated signaling., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The conversion of the normal prion protein (PrP) into a scrapie prion (PrP Sc ) is incompletely understood. Theoretically, the smallest PrP aggregate is a dimer. Human PrP contains two cysteines at positions 179 (C179) and 214 (C214) enabling disulfide bonding. Here, we report that our recombinant human PrP (r-hPrP) preparations contain 0.2-0.8% dimer, which is linked by either one or two disulfide bonds, connected by C179-C179, C214-C214, or C179-C214. Furthermore, dimerization is regulated by multiple motifs. While residues 36-42 inhibit, residues 90-125, and 195-212 promote dimerization. Mutating individual residue between 36 and 42 enhances dimerization whereas mutating the positively charged residues within 95-115, or the negatively charged residues within 195-212 prevent dimerization. Although deletion of the entire octapeptide-repeat (5OR) region prevents dimerization, mutating the histidines within the 5OR enhances dimerization. In addition, we found that two out of three brain lysates from patients with inherited prion disease had more PrP dimers than controls. Thus, PrP dimerization may contribute to prion diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background : Fatal familial insomnia (FFI) is a rare autosomal-dominant inherited prion disease characterized clinically by severe sleep disorder, motor signs, dysautonomia and abnormal behaviour. FFI is caused by a missense mutation at codon 178 of the prion protein gene (PRNP). Our study is aimed to explore typical clinical and genetic features of two Chinese pedigrees with FFI and review the related literatures. Methods : Two FFI cases with family histories were recruited in our study. The main clinical features, genetic features and possible pathophysiologic mechanisms of these two FFI cases were analysed. Results : The foremost symptoms seemed to be sleep disturbances and psychosis. Progressive sympathetic symptoms, movement disturbances and memory loss were frequently observed as well. Electroencephalography (EEG) showed a minor slowing without periodic triphasic waves. Polysomnography (PSG) showed reduction in total sleep time and disturbance of sleep-related respiratory. Brain magnetic resonance imaging (MRI) did not reveal obvious abnormality. Genetic analysis disclosed the prion protein gene mutation at codon 178 (D178N), with methionine (Met) homozygosity at the polymorphic position 129 (Met129Met). Conclusions : The major clinical features of Chinese FFI are sleep dysfunction, psychiatric symptoms and sympathetic symptoms. Our patients have similar clinical characteristics as that of the typical FFI cases.

A 57-year-old woman presented with a 3-month history of cognitive impairment, daytime somnolence, and violent sleep behavior. Her first- and second-degree relatives had similar symptoms prior to their premature deaths. Her MRI scan of the brain showed no significant abnormality. Electroencephalogram showed loss of slow-wave activity. Functional brain imaging performed with F-FDG PET was fused with her MRI scans. This demonstrated profound hypometabolism in bilateral thalami and the posterior cingulate cortex, which is pathognomonic for familial fatal insomnia. Hypometabolism in the temporal lobes suggests a long-standing course of the disease. Genetic testing confirmed a mutation of the prion-protein gene (PRNP).

Background and Purpose: Fatal familial insomnia (FFI) is an autosomal dominant disease due to the D178N mutation of PRNP gene coupling with homozygous methionine (Met) at codon 129. It is generally considered that D178N mutation cases with 129 M/M homozygotes present as FFI, and 129 V/V as genetic CJD. However, the frequency of 129 Met alleles in Chinese population is much higher than that in Caucasians. This study aims to investigate the clinical features and genetic characteristics of Chinese D178N mutants in this genetic context., Methods: We reviewed the clinical and genetic features of seven D178N patients. The clinical data, genetic data, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), polysomnography (PSG), CSF 14-3-3 protein examinations of the seven patients were analyzed., Results: The genotypes at codon 129 were all M/M. Four of the seven cases reported positive family history. Four patients were more likely the CJD phenotype and three were FFI phenotype according to the core clinical features. No major differences were found on the EEG, CSF 14-3-3 protein, and PSG presentations between this study and western studies. Novel neuroimaging findings were two patients had typical neuroimaging abnormalities of CJD and frontotemporal dementia, respectively., Conclusions: Unlike the western populations, the diverse phenotypical presentations of D178N mutants were not simply determined by the 129 genotypes in Chinese. The underlying modifying factors for phenotypical variations warrant further investigations. For those with atypical clinical and imaging features, genetic testing was important for final diagnosis., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Fatal familial insomnia (FFI) is a rare prion disease commonly inherited in an autosomal dominant pattern from a mutation in the PRioN Protein (PRNP) gene. Hashimoto's encephalopathy (HE) is characterised by encephalopathy associated with antithyroid peroxidase (TPO) or antithyroglobulin (Tg) antibodies. These two conditions characteristically have differing clinical presentations with dramatically different clinical course and outcomes. Here, we present a case of FFI mimicking HE. A woman in her 50s presented with worsening confusion, hallucinations, tremor and leg jerks. Several maternal relatives had been diagnosed with FFI, but the patient had had negative genetic testing for PRNP. MRI of brain, cervical and thoracic spine were unremarkable except for evidence of prior cervical transverse myelitis. Cerebrospinal fluid analysis was normal. Anti-TPO and anti-Tg antibodies were elevated. She was started on steroids for possible HE and showed improvement in symptoms. Following discharge, the results of her PRNP gene test returned positive for variant p.Asp178Asn., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Prion diseases are a group of fatal neurodegenerative disorders that affect humans and animals. Besides of the pathological agent, prion, there are some elements that can influence or determine susceptibility to prion infection and the clinical phenotype of the diseases, e.g., the polymorphism in PRNP gene. Another polymorphism in ZBTB38-RASA2 has been observed to be associated with the susceptibility of sporadic Creutzfeldt-Jacob disease (sCJD) in UK. MicroRNAs are endogenous small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. In this study, two polymorphic loci in miR-146a (rs2910164 and rs57095329) and one locus in ZBTB38-RASA2 (rs295301) of 561 Chinese patients of sCJD and 31 cases of fatal familial insomnia (FFI) were screened by PCR and sequencing. Our data did not figure out any association of those three SNPs with the susceptibility of sCJD. However, a significant association of the SNP of rs57095329 in miR-146a showed the association with the susceptibility of FFI. Additionally, the SNP of rs57095329 showed statistical significances with the appearances of mutism and the positive of cerebrospinal fluid (CSF) protein 14-3-3 in sCJD patients, while the SNP of ZBTB38-RASA2 was significantly related with the appearance of myoclonus in sCJD patients. It indicates that the SNPs of ZBTB38-RASA2 and miR-146a are not associated with the susceptibility of the Chinese sCJD patients, but may influence the appearances of clinical manifestations somehow.

Fatal familial insomnia (FFI) and sporadic fatal insomnia (sFI), or thalamic form of sporadic Creutzfeldt-Jakob disease MM2 (sCJDMM2T), are prion diseases originally named and characterized in 1992 and 1999, respectively. FFI is genetically determined and linked to a D178N mutation coupled with the M129 genotype in the prion protein gene (PRNP) at chromosome 20. sFI is a phenocopy of FFI and likely its sporadic form. Both diseases are primarily characterized by progressive sleep impairment, disturbances of autonomic nervous system, and motor signs associated with severe loss of nerve cells in medial thalamic nuclei. Both diseases harbor an abnormal disease-associated prion protein isoform, resistant to proteases with relative mass of 19 kDa identified as resPrP TSE type 2. To date at least 70 kindreds affected by FFI with 198 members and 18 unrelated carriers along with 25 typical cases of sFI have been published. The D178N-129M mutation is thought to cause FFI by destabilizing the mutated prion protein and facilitating its conversion to PrP TSE . The thalamus is the brain region first affected. A similar mechanism triggered spontaneously may underlie sFI., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Prion diseases are fatal neurodegenerative disorders with sporadic, genetic or acquired etiologies. The molecular alterations leading to the onset and the spreading of these diseases are still unknown. In a previous work we identified a five-gene signature able to distinguish intracranially BSE-infected macaques from healthy ones, with SERPINA3 showing the most prominent dysregulation. We analyzed 128 suitable frontal cortex samples, from prion-affected patients (variant Creutzfeldt-Jakob disease (vCJD) n = 20, iatrogenic CJD (iCJD) n = 11, sporadic CJD (sCJD) n = 23, familial CJD (gCJD) n = 17, fatal familial insomnia (FFI) n = 9, Gerstmann-Sträussler-Scheinker syndrome (GSS)) n = 4), patients with Alzheimer disease (AD, n = 14) and age-matched controls (n = 30). Real Time-quantitative PCR was performed for SERPINA3 transcript, and ACTB, RPL19, GAPDH and B2M were used as reference genes. We report SERPINA3 to be strongly up-regulated in the brain of all human prion diseases, with only a mild up-regulation in AD. We show that this striking up-regulation, both at the mRNA and at the protein level, is present in all types of human prion diseases analyzed, although to a different extent for each specific disorder. Our data suggest that SERPINA3 may be involved in the pathogenesis and the progression of prion diseases, representing a valid tool for distinguishing different forms of these disorders in humans.

Purpose of Review: Fatal familiar insomnia (FFI) is an autosomal dominant inherited prion disease caused by D178N mutation in the prion protein gene (PRNP D178N) accompanied by the presence of a methionine at the codon 129 polymorphic site on the mutated allele. FFI is characterized by severe sleep disorder, dysautonomia, motor signs and abnormal behaviour together with primary atrophy of selected thalamic nuclei and inferior olives, and expansion to other brain regions with disease progression. This article reviews recent research on the clinical and molecular aspects of the disease., Recent Findings: New clinical and biomarker tools have been implemented in order to assist in the diagnosis of the disease. In addition, the generation of mouse models, the availability of 'omics' data in brain tissue and the use of new seeding techniques shed light on the molecular events in FFI pathogenesis. Biochemical studies in human samples also reveal that neuropathological alterations in vulnerable brain regions underlie severe impairment in key cellular processes such as mitochondrial and protein synthesis machinery. Although the development of a therapy is still a major challenge, recent findings represent a step toward understanding of the clinical and molecular aspects of FFI.

In most human sporadic prion diseases the phenotype is consistently associated with specific pairings of the genotype at codon 129 of the prion protein gene and conformational properties of the scrapie PrP (PrP Sc ) grossly identified types 1 and 2. This association suggests that the 129 genotype favours the selection of a distinct strain that in turn determines the phenotype. However, this mechanism cannot play a role in the phenotype determination of sporadic fatal insomnia (sFI) and a subtype of sporadic Creutzfeldt-Jakob disease (sCJD) identified as sCJDMM2, which share 129 MM genotype and PrP Sc type 2 but are associated with quite distinct phenotypes. Our detailed comparative study of the PrP Sc conformers has revealed major differences between the two diseases, which preferentially involve the PrP Sc component that is sensitive to digestion with proteases (senPrP Sc ) and to a lesser extent the resistant component (resPrP Sc ). We conclude that these variations are consistent with two distinct strains in sFI and sCJDMM2, and that the rarer sFI is the result of a variant strain selection pathway that might be favoured by a different brain site of initial PrP Sc formation in the two diseases.

The expression of subunits of mitochondrial respiratory complexes and components of the protein synthesis machinery from the nucleolus to the ribosome was analyzed in the mediodorsal thalamus in seven cases of fatal familial insomnia (FFI) compared with age-matched controls. NDUFB8 (complex I subunit), SDHB (complex II subunit), UQCRC2 (complex III subunit), COX2 (complex IV subunit), and ATP50 (complex V subunit) expression levels, as revealed by western blotting, were reduced in FFI. Voltage-dependent anion channel (VDAC) and ATP5H were also reduced due to the marked depopulation of neurons. In contrast, a marked increase in superoxide dismutase 2 (SOD2) was found in reactive astrocytes thus suggesting that astrocytes are key factors in oxidative stress responses. The histone-binding chaperones nucleolin and nucleoplasmin 3, and histone H3 di-methylated K9 were markedly reduced together with a decrease in the expression of protein transcription elongation factor eEF1A. These findings show severe impairment in the expression of crucial components of mitochondrial function and protein synthesis in parallel with neuron loss in mediodorsal thalamus at terminal stages of FFI. Therapeutic measures must be taken long before the appearance of clinical symptoms to prevent the devastating effects of FFI., (© 2016 International Society of Neuropathology.)

Although prion diseases are generally thought to present as rapidly progressive dementias with survival of only a few months, the phenotypic spectrum for genetic prion diseases (gPrDs) is much broader. The majority have a rapid decline with short survival, but many patients with gPrDs present as slowly progressive ataxic or parkinsonian disorders with progression over a few to several years. A few very rare mutations even present as neuropsychiatric disorders, sometimes with systemic symptoms such as gastrointestinal disorders and neuropathy, progressing over years to decades. gPrDs are caused by mutations in the prion protein gene (PRNP), and have been historically classified based on their clinicopathological features as genetic Jakob-Creutzfeldt disease (gJCD), Gerstmann-Sträussler-Scheinker (GSS), or Fatal Familial Insomnia (FFI). Mutations in PRNP can be missense, nonsense, and octapeptide repeat insertions or a deletion, and present with diverse clinical features, sensitivities of ancillary testing, and neuropathological findings. We present the UCSF gPrD cohort, including 129 symptomatic patients referred to and/or seen at UCSF between 2001 and 2016, and compare the clinical features of the gPrDs from 22 mutations identified in our cohort with data from the literature, as well as perform a literature review on most other mutations not represented in our cohort. E200K is the most common mutation worldwide, is associated with gJCD, and was the most common in the UCSF cohort. Among the GSS-associated mutations, P102L is the most commonly reported and was also the most common at UCSF. We also had several octapeptide repeat insertions (OPRI), a rare nonsense mutation (Q160X), and three novel mutations (K194E, E200G, and A224V) in our UCSF cohort. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

This commentary highlights the study by Frau-Mendez and coworkers in this issue of Brain Pathology (xxx) in which the authors show evidence for involvement of mitochondria in the pathophysiology of fatal familial insomnia (FFI). Using genetic, biochemical and morphological means, they provide a comprehensive picture of the degree of mitochondrial damage in FFI and show that this leads to increased oxidative stress. This adds FFI to the growing list of dementias with mitochondrial involvement. Future studies will have to address the causality dilemma of which came first, mitochondrial damage and subsequent neurodegeneration or vice versa. Either way, these data provide the basis to devise novel therapeutic strategies for FFI., (© 2016 International Society of Neuropathology.)

The alteration of protein tau in the cerebrospinal fluid (CSF) of Creutzfeldt-Jakob disease (CJD) has been widely evaluated, possessing a significant diagnostic value for CJD. With the biotin-labeled tau-exon-specific mAbs, direct ELISA methods were established and the levels of tau isoforms containing exon-2 and exon-10 segments in CSF of the patients with various human prion diseases and in brain tissues of scrapie-infected animals were evaluated. The results showed that the levels of tau, especially containing four repeats in microtubule binding domain, were increased in the CSF samples of the patients with sporadic CJD (sCJD). Using the unlabeled (cold) mixed exon-specific mAbs, a competitive tau ELISA was conducted based on a commercial tau kit. It revealed that the majority of the increased tau in the CSF of sCJD cases was derived from the tau isoforms with exon-2 and exon-10 segments. Increases of CSF tau isoforms with exon-2 and exon-10 segments were also observed in the patients of E200K and T188K genetic CJD (gCJD), but not in the cases of fatal familiar insomnia (FFI). The increasing levels of tau isoforms with exon-2 and exon-10 segments in the group of sCJD correlated well with the positive 14-3-3 in CSF. Additionally, the similar alterative profiles of tau isoforms with exon-2 and exon-10 segments were also observed in the brain tissues of scrapie-infected rodents and a sCJD patient. Our data here propose the tau isoforms with exon-2 and exon-10 segments increase in CSF of sCJD and some types of gCJD, which may help to understand the physiological metabolism and pathological significance of various tau isoforms in the pathogenesis of prion diseases.

Fatal familial insomnia is a rare disease caused by a D178N mutation in combination with methionine (Met) at codon 129 in the mutated allele of PRNP (D178N-129M haplotype). FFI is manifested by sleep disturbances with insomnia, autonomic disorders and spontaneous and evoked myoclonus, among other symptoms. This study describes new neuropathological and biochemical observations in a series of eight patients with FFI. The mediodorsal and anterior nuclei of the thalamus have severe neuronal loss and marked astrocytic gliosis in every case, whereas the entorhinal cortex is variably affected. Spongiform degeneration only occurs in the entorhinal cortex. Synaptic and fine granular proteinase K digestion (PrPres) immunoreactivity is found in the entorhinal cortex but not in the thalamus. Interleukin 6, interleukin 10 receptor alpha subunit, colony stimulating factor 3 receptor and toll-like receptor 7 mRNA expression increases in the thalamus in FFI. PrPc levels are significantly decreased in the thalamus, entorhinal cortex and cerebellum in FFI. This is accompanied by a particular PrPc and PrPres band profile. Altered PrP solubility consistent with significantly reduced PrP levels in the cytoplasmic fraction and increased PrP levels in the insoluble fraction are identified in FFI cases. Amyloid-like deposits are only seen in the entorhinal cortex. The RT-QuIC assay reveals that all the FFI samples of the entorhinal cortex are positive, whereas the thalamus is positive only in three cases and the cerebellum in two cases. The present findings unveil particular neuropathological and neuroinflammatory profiles in FFI and novel characteristics of natural prion protein in FFI, altered PrPres and Scrapie PrP (abnormal and pathogenic PrP) patterns and region-dependent putative capacity of PrP seeding., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Genetic prion diseases are degenerative brain disorders caused by mutations in the gene encoding the prion protein (PrP). Different PrP mutations cause different diseases, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome and fatal familial insomnia (FFI). The reason for this variability is not known. It has been suggested that prion strains with unique self-replicating and neurotoxic properties emerge spontaneously in individuals carrying PrP mutations, dictating the phenotypic expression of disease. We generated transgenic mice expressing the FFI mutation, and found that they developed a fatal neurological illness highly reminiscent of FFI, and different from those of similarly generated mice modeling genetic CJD and GSS. Thus transgenic mice recapitulate the phenotypic differences seen in humans. The mutant PrPs expressed in these mice are misfolded but unable to self-replicate. They accumulate in different compartments of the neuronal secretory pathway, impairing the membrane delivery of ion channels essential for neuronal function. Our results indicate that conversion of mutant PrP into an infectious isoform is not required for pathogenesis, and suggest that the phenotypic variability may be due to different effects of mutant PrP on intracellular transport.

To explore clinical, histopathological and genetic features of a case with fatal familial insomnia (FFI) and review the related literatures. A middle-aged woman who complained of "insomnia for 9 months and psychosis for 3 months" was suspicious of FFI. The clinical features of the patient were analyzed, and the dead patient was examined by autopsy and the brain tissues were obtained for histopathological studies, and the blood samples from the patient and some of her familial members were collected for the sequencing of prion protein gene (PRNP). The main clinical features included intractable insomnia, psychiatric symptoms and abnormal night sleep behavior, unsteady gait, difficulty swallowing, sudden death, and positive family history. The pathological studies showed neuronal loss and gliosis of multiple brain tissues in the proband, predominated with thalamus; and analysis of PRNP revealed gene D178N mutation, and linkage with 129 methionine (Met) allele in the proband and a relative. FFI patients may manifest as sudden death, and may have prominent psychiatric symptoms; the corresponding gene mutation could occur in the asymptomatic carriers; the data of autopsy and brain tissue pathology is helpful for further understanding of this disease.

Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.

The development of in vitro amplification systems allows detecting femtomolar amounts of prion protein scrapie (PrP(Sc)) in human cerebrospinal fluid (CSF). We performed a CSF study to determine the effects of prion disease type, codon 129 genotype, PrP(Sc) type, and other disease-related factors on the real-time quaking-induced conversion (RT-QuIC) response. We analyzed times to 10,000 relative fluorescence units, areas under the curve and the signal maximum of RT-QuIC response as seeding parameters of interest. Interestingly, type of prion disease (sporadic vs. genetic) and the PRNP mutation (E200K vs. V210I and FFI), codon 129 genotype, and PrP(Sc) type affected RT-QuIC response. In genetic forms, type of mutation showed the strongest effect on the observed outcome variables. In sporadic CJD, MM1 patients displayed a higher RT-QuIC signal maximum compared to MV1 and VV1. Age and gender were not associated with RT-QuIC signal, but patients with a short disease course showed a higher seeding efficiency of the RT-QuIC response. This study demonstrated that PrP(Sc) characteristics in the CSF of human prion disease patients are associated with disease subtypes and rate of decline as defined by disease duration.

Familial fatal insomnia (FFI) is fatal disorder characterized by damage to select thalamic nuclei, together with progressive insomnia and dysautonomia. In subjects carrying the D178N prion protein (PRNP) mutation, distinct phenotypes can be observed, depending on the methionine (Met) /valine (Val) codon 129 polymorphism. We report here a Chinese case of FFI with a D178N/Met129 genotype of the PRNP gene, who exhibited rapidly progressive dementia combined with behavioral disturbances and paroxysmal limb myoclonus. Our patient did not show refractory insomnia early in the disease course, nor demonstrate typical MRI and EEG alterations. There was remarkable family history of similar symptoms.

The text describes a preventive clinical trial with drug treatment in a very rare neurodegenerative disease (Fatal familial Insomnia, FFI) designed with the help of individuals at genetic risk of developing the disease, asymptomatic carriers, who have agreed to be exposed over a 10-year period to doxycycline, an antibiotic with anti-prion activity. At least 10 carriers of the FFI mutation over 42 y old will be treated with doxycycline (100 mg/die) and the incidence of the disease will be compared to that of an historical dataset. For ethical reasons a randomized, double-blind, placebo-controlled trial was not feasible, however the study design and the statistical analysis ensure the scientific value of the results. This approach might represent an important breakthrough in terms of potential therapy and knowledge of rare diseases that could give some hopes to these neglected patients.

The D178N mutation in the PRNP gene is associated with fatal familial insomnia and Creutzfeldt-Jakob disease (CJD). Typically, the D178N mutation associated with the 129M genotype is related to fatal familial insomnia while the same mutation associated with the 129V genotype is linked to familial CJD. We describe a D178N-129M haplotype in a patient with early, severe dementia and late-onset minor insomnia, mainly presenting as the CJD phenotype. Cerebrospinal fluid 14-3-3 protein was positive. Diffusion weighted imaging demonstrated widespread cortical ribbon-like high signal intensity, which was also seen in the basal ganglia bilaterally. Arterial spin labeling (ASL) MRI showed severe hypoperfusion in the cerebral cortex, basal ganglia and thalami but this was least marked in the thalami. Neuroimaging abnormalities were more prominent in the cerebral cortex than the thalamus, which was in line with the clinical picture of severe dementia rather than insomnia. ASL-MRI seems to be a useful tool for the detection and follow-up of perfusion changes in patients and asymptomatic carriers harboring the PRNP mutation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)