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Diseases of the central nervous system caused by prions

Diseases of the central nervous system caused by prions
Authors:
Brian S Appleby, MD
Mark L Cohen, MD
Section Editors:
Steven T DeKosky, MD, FAAN, FACP, FANA
Benjamin A Raby, MD, MPH
Deputy Editor:
Janet L Wilterdink, MD
Literature review current through: Dec 2022. | This topic last updated: Nov 09, 2021.

INTRODUCTION — Prion diseases are neurodegenerative diseases that have long incubation periods and progress inexorably once clinical symptoms appear. No effective treatment has been identified for human prion diseases, which are universally fatal [1].

Several human prion diseases are currently recognized: kuru, Creutzfeldt-Jakob disease (CJD), variant CJD (vCJD; also known as new variant CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), and variably protease-sensitive prionopathy (VPSPr) [2-4].

These diseases share certain common neuropathologic features including accumulation of protease-resistant prion protein, neuronal loss, proliferation of glial cells, absence of a classic inflammatory response, and presence of small vacuoles within the neuropil, which produces a spongiform appearance. Prion diseases are associated with the accumulation of an abnormal form of a host cell protein; the normal form is designated "PrPC," and the abnormal form is designated "PrPSc" (for scrapie) [5].

The clinical manifestations and diagnosis of genetic CJD (gCJD), GSS, FFI, kuru, and VPSPr will be reviewed here. Sporadic CJD (sCJD), iatrogenic CJD (iCJD), and vCJD are discussed separately.

●(See "Creutzfeldt-Jakob disease".)

●(See "Variant Creutzfeldt-Jakob disease".)

PATHOGENESIS OF PRION DISEASES

Biology of prions — The term "prion" was coined in 1982, denoting a small infectious pathogen containing protein but lacking nucleic acid [6]. The prion protein (PrP) is the critical component of these agents and is likely its exclusive constituent. Scrapie, a nonhuman prion disease, serves as a model for human prion diseases.

Prion protein — The normal (cellular) prion protein, PrPC, is a membrane-bound glycophosphatidylinositol-anchored protein found in normal human brains on both neuronal and nonneuronal cells [7,8]. PrPC can be detected attached to the plasma membrane of neurons [9] and may be concentrated at synaptic membranes [10]. In addition, PrPC has transmembrane domains, indicating that it spans the cellular cytoplasmic membrane. Surface PrPC is degraded after endocytosis in acidic vesicles, although some protein may recycle to the cell surface [11]. Secreted forms of PrPC also occur [12].

A key step during the biosynthesis of PrPC involves modification of both the amino and carboxy terminals, including the addition of a phosphatidylinositol glycolipid, which serves to anchor the protein to the cell surface [8,13]. PrPC exists primarily in an alpha-helical conformation [14,15].

PrPC is believed to be involved in a variety of physiologic functions, but these remain to be fully elucidated [16]. A number of studies have shown that PrPC is capable of reversibly binding to copper ions, suggesting that PrPC could play a role in copper homeostasis [17,18]. Copper plays a role in endocytosis and neurotransmission. PrPC also acts as a mediator of copper superoxide dismutase involved in the cellular response to oxidative stress [19,20] and may play a role in regulating apoptosis [21]. In addition, PrPC is expressed in immune cells, red blood cells, and platelets [22]; one study found that PrP was upregulated during T cell activation and that antibody crosslinking of surface PrPC led to increased phosphorylation of signaling proteins, suggesting a role for PrPC in immune function [23].

Conversion of PrPC to PrPSc — The abnormal prion protein, PrPSc (so-designated after scrapie), is a conformational isomer of PrPC. PrPSc exists primarily as a beta-pleated sheet and appears to result from a yet uncharacterized conformational alteration [14,15]. Recombinant forms of PrP show a large unstructured protein motif, which may more easily convert to a beta structure [24,25].

The PrPSc molecules form amyloid fibrils made of a continuous array of beta sheets that are oriented perpendicular to the fibril axis. The resistance of PrPSc to digestion with proteases and its tendency to polymerize into scrapie-associated fibrils or prion rods differentiate PrPSc from PrPC [26,27]. The hydrophobicity of this protein, which may in turn affect aggregation, and its beta-sheet conformation may play a role in neurotoxicity [28,29]. A peptide, iPrP13, that can break beta-sheet conformations was shown to reduce the protease resistance of PrPSc and delay the onset of symptoms in transmission experiments in mice [30].

In contrast to PrPC, PrPSc accumulates within cells and does not normally appear on the cell surface. PrPSc is found predominantly in cytoplasmic vacuoles and secondary lysosomes [31]. Conversion of PrPC to PrPSc may occur in caveolae-like membranous domains [32].

Animal studies have demonstrated that host PrPC is required for the development of prion disease, as accumulation of abnormal isoforms of PrP is dependent upon conversion of normal PrPC into PrPSc [33,34]. In particular, the PrP membrane anchor appears necessary for the pathogenesis of prion disease. One study used transgenic mice with an abnormal form of PrPC lacking the glycophospholipid cell membrane anchor [35]. When inoculated with PrPSc, these mice accumulated abnormal PrP in abundant amyloid plaques but were asymptomatic and did not accumulate PrPSc or develop titers of infectivity at nearly the same rate as wild-type mice.

It has been hypothesized that another as yet unidentified host factor, designated "protein X," may facilitate conversion of normal PrP to PrPSc by binding to the carboxy terminus of PrPC and interacting with a site near the N terminus of the protein to effect a conformational change [36].

In vitro studies have shown the importance of glycosylation in the formation of PrPSc. Changes in electrophoretic mobility secondary to conformational changes, glycosylation levels, and/or amino acid sequence are linked to different phenotypic presentations of Creutzfeldt-Jakob disease (CJD) [37,38]. Experimentally, infectivity across the species barrier is enhanced when unglycosylated forms of the PrP are used, and conversion of PrPC to PrPSc is inhibited by glycosylation [39].

How the first molecule of PrPSc appears in the host remains a mystery, but the initial appearance, which may be de novo, probably triggers the replication of PrPSc [40]. It is hypothesized that the initiating PrPSc molecule is derived from an exogenous source in acquired prion diseases (ie, iatrogenic CJD [iCJD], variant CJD [vCJD], and kuru), while mutations are invariably detected within the gene encoding PrP in genetic forms [41]. These mutations could destabilize PrPC, which might lead to spontaneous conversion to PrPSc. Studies of yeast prion Sup53 have shown that small, specific elements of the primary amino acid sequence are responsible for initial nucleation as well as for specific prion conformations [42].

Transport of PrPSc to and within the nervous system — Transport of PrPSc to the nervous system occurs via axonal transport [43]. Both slow axoplasmic transport and rapid anterograde axonal transport appear to play a role [44-46]. Prions may also propagate via extracellular vesicles and/or tunneling nanotubes [47].

The finding of PrPC and PrPSc in olfactory sensory neurons has suggested that the olfactory system may serve as an entry pathway for infection in some cases [48].

The lymphoreticular system appears to play a critical role in the initiation and/or propagation of some prion diseases, more likely for exogenously acquired prion diseases, such as iCJD, kuru, and perhaps vCJD, than for sporadic and genetic forms of prion diseases [49-51]. Prior to transport to the nervous system, follicular dendritic cells within germinal centers of lymphoid tissue appear to act as a reservoir for the protein. Some animal studies suggest that complement plays a role in early pathogenesis [52,53]. Other studies have shown variable immune responses to different experimental conformations of the PrP [54].

Neurotoxicity of PrPSc — PrPSc appears to be neurotoxic as accumulation of this protein or fragments of it in neurons leads to apoptosis and cell death [55,56]. PrPC must be present for this effect to occur [56]. However, abnormal PrP released by astrocytes still destroys PrP-negative neurons in mice, suggesting that the neuronal injury is not caused by a loss of function of normal neuronal PrP or any interaction between normal and abnormal forms [57].

Misfolded PrP is transported in a retrograde fashion to the cytosol for degradation [58]. Even small amounts of this protein in the cytosol are highly neurotoxic, and this accumulation may be an important step in prion disease pathogenesis [58,59].

The demonstration of significant amyloid plaque in mice inoculated with PrPSc who yet remained asymptomatic [35] suggests a specific neurotoxic role of PrPSc beyond amyloid deposition [60].

Genetics of human prion diseases

Mutations causing prion disease — Genetic prion diseases (genetic CJD [gCJD], Gerstmann-Sträussler-Scheinker syndrome [GSS], fatal familial insomnia [FFI]) are inherited in an autosomal-dominant manner.

The gene encoding prion protein (PRNP) in humans is located on the short arm of chromosome 20 [61]. A strong link has been established between mutations in the PRNP gene and genetic forms of prion disease. More than 50 different mutations have been identified, including point and premature stop codon mutations as well as the insertion of repeats and deletions of an octapeptide region [62,63].

Some experts advocate classifying prion diseases based upon the responsible mutation rather than the traditional classifications such as gCJD or GSS since a single mutation can produce different clinical phenotypes in different individuals or families (ie, genetic pleiotropy) [61,64-66]. As an example, the D178N mutation, in which asparagine substitutes for aspartic acid in codon 178, occurs in families with FFI and gCJD [61]. Pedigrees with this mutation often demonstrate marked variability in the age of onset as well as the disease phenotype [65]. A large English and Irish kindred has been described containing individuals clinically diagnosed with a variety of conditions including CJD, vCJD, and GSS [66]. However, when the PRNP gene was examined, all affected individuals had a valine-for-alanine substitution at codon 117 regardless of the clinical diagnosis.

PRNP point mutations may influence the glycoform ratios and conformation of PrPSc; while these can differ among patients with the same inherited mutation, they are distinct from PrPSc seen in sporadic CJD (sCJD), iCJD, and vCJD [38]. This suggests that strain variation is a composite of both abnormal conformation and glycosylation.

Role of polymorphism at codon 129

●Inherited prion diseases – Codon 129 of the PRNP gene is a polymorphic codon; normal individuals have either valine or methionine at that site [67-70]. Neither V129 nor M129 appears to be pathogenic itself. However, genotype-phenotype correlation studies suggest that amino acid 129 allele status modifies the effect of other pathogenic PRNP mutations. The modifying influence appears to be predominately a cis-acting effect, meaning that the impact on phenotype is due to the presence of both variants in the same protein product. The effect is likely a result of the joint effect of both variants together on conferring a unique conformational change in protein structure, resulting in altered patterns of PRNP cleavage by proteases [71]. Patients with the D178N mutation who are homozygous for valine at codon 129 appear to develop CJD, while those who are homozygous for methionine tend to have FFI.

In another kindred, PrP gene polymorphism was found to influence the age of disease onset [70], though this initial finding has since been called into question [72]. Despite these patterns, the clinical expression of individual mutations can vary even between affected members of the same family [64].

●Acquired and sporadic prion diseases – Unlike gCJD, sCJD, iCJD, and vCJD are not associated with PRNP gene mutations. However, even in these forms of CJD the codon 129 polymorphism appears to affect susceptibility and expression of the clinical illness [73]. While 51 percent of the general population is heterozygous at codon 129, all cases of vCJD and 85 to 95 percent of individuals with sCJD have been found to be homozygous at this codon [73]. In a separate report, five of seven patients who developed iCJD after receiving human cadaveric growth hormone were homozygous at codon 129 [74].

The most commonly accepted molecular classification scheme for sCJD is based upon codon 129 polymorphism and characterization of the properties of PrPSc, which was used to evaluate 300 patients with sCJD [75]. As examples, a pattern of type 1 PrPSc plus at least one methionine at codon 129 was demonstrated in 70 percent, while type 2 PrPSc plus codon 129 homozygous or heterozygous for valine was present in 25 percent and associated with ataxia. (See "Creutzfeldt-Jakob disease", section on 'Subtypes of sCJD'.)

Polymorphism at codon 129 also influences the expression of vCJD. (See "Variant Creutzfeldt-Jakob disease", section on 'Genetic risk factors'.)

DETECTION OF ABNORMAL PRION PROTEIN

●Immunoblotting – Western blot analysis following proteinase K digestion is commonly used to detect disease-causing prion protein (PrPSc) in human brain tissue at autopsy or in biopsy samples [76]. These methods use limited proteolysis to hydrolyze the normal precursor cellular prion protein (PrPC) in order to measure the protease-resistant core of the pathologic PrPSc.

Subsequently, the conformation-dependent immunoassay (CDI) method was developed, which did not require proteolysis to digest PrPC, and it was discovered that PrPSc exists in both protease-resistant and protease-sensitive forms [77]. Unlike other immunoassays, CDI is able to measure both protease-resistant and protease-sensitive forms of PrPSc [77]. CDI appears to have a much higher sensitivity for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) compared with routine neuropathologic examination and immunohistochemistry [78]. While this method appears promising, further study is needed to determine its specificity as well as its role in other human prion diseases, particularly variant CJD (vCJD), and its possible antemortem diagnostic utility in brain biopsy and extraneural tissue specimens.

●Protein misfolding cyclic amplification – Another promising method is one that amplifies prion protein (PrP) in a variety of tissues by a process called protein misfolding cyclic amplification (PMCA) [79], which can detect biphasic appearance of PrPSc in inoculated hamsters [80]. PrPSc was detected in approximately one-half of asymptomatic animals three to six weeks postinoculation. The signal subsequently disappeared, but then reappeared four months postinoculation when the hamsters became symptomatic.

●Real-time quaking-induced conversion – A similar assay, called real-time quaking-induced conversion (RT-QuIC), uses shaking instead of sonication to amplify minute levels of PrP by inducing pathologic seeding activity [81]. RT-QuIC is the preferred protein amplification assay for clinical testing given its ease of standardization, faster turnaround time, and absence of infectious byproducts. RT-QuIC can detect abnormal prion seeding activity in cerebrospinal fluid (CSF), olfactory epithelium, skin, ocular tissue, and other types of tissue [82-85]. (See "Creutzfeldt-Jakob disease", section on 'Real-time quaking-induced conversion'.)

●Other tests – Antibodies that uniquely react with PrPSc may provide a diagnostic method for prion disease. Investigators have described a repeat Tyr-Tyr-Arg epitope that is hidden in PrPC but becomes accessible in PrPSc following the misfolding process [86].

Other methods are also in development [81,87-91].

The need for a highly sensitive and specific test to detect PrPSc will increase when effective treatment for human prion disease becomes available.

DECONTAMINATION PROCEDURES — One of the characteristic features of prions is their resistance to decontamination procedures based on eradicating nucleic acids, such as hydrolysis or shearing [92].

On the other hand, agents that digest, denature, or modify proteins are useful against prions [5]. The prion protein (PrP) purified from the brains of scrapie-infected animals (PrPSc) can be inactivated by prolonged autoclaving (at 121ºC and 15 pounds per square inch [psi] for 4.5 hours), or immersion in 1 N NaOH (for 30 minutes, repeat three times), or immersion in concentrated (>3 M) solutions of guanidine thiocyanate [93]. However, certain cautions prevail; it appears that inadequate autoclaving can establish heat-resistant subpopulations that fail to diminish with further cycles of autoclaving [94]. Stainless steel instruments also may retain infectivity even after treatment with 10 percent formaldehyde [95,96].

Newer decontamination techniques are being investigated. There has been some success in sterilization using a combination of sodium dodecyl sulfate (SDS), proteinase K, and pronase [97]. A radiofrequency gas-plasma treatment has been shown to effectively decontaminate surgical instruments [98]. Another group has tested a decontamination formula combining copper metal ions with hydrogen peroxide [99]. Prion decontamination has also been demonstrated with hypochlorous acid [100].

CREUTZFELDT-JAKOB DISEASE — Creutzfeldt-Jakob disease (CJD) is the most frequent of the human prion diseases. CJD most often occurs as a sporadic disorder, although genetic forms have been described, and it is clinically manifested by a rapidly progressive cognitive deterioration, often with behavioral abnormalities, and myoclonus.

Sporadic CJD — Sporadic CJD (sCJD) is discussed separately. (See "Creutzfeldt-Jakob disease".)

Variant CJD — Variant CJD (vCJD) is a distinct disorder that represents transmission of bovine spongiform encephalopathy; most patients acquire the disorder through ingestion of infected meat products. Clinical, diagnostic, and pathologic features are distinct from sCJD. vCJD is discussed separately. (See "Variant Creutzfeldt-Jakob disease".)

Genetic CJD

●Genetics – A missense mutation involving the substitution of lysine for glutamine in codon 200 is the most common PRNP gene mutation and has been observed in many regions, including Libya, Chile, and Hungary [101-103]. In Slovakia, this mutation underlies more than 70 percent of all prion diseases [104]. One study described a differing presentation of this syndrome with codon 129 phenotype changes [105]. When the mutant codon 200 was linked to a valine at codon 129, prion protein (PrP) deposits were observed in the cerebellum and were composed of type 2 PrP by Western blot analyses; neither of these features has been described with methionine at codon 129.

The D178N mutation occurs in genetic CJD (gCJD) as well as fatal familial insomnia (FFI), depending on the codon 129 polymorphism present on the mutated allele. A substitution of isoleucine for valine in codon 210 has also been noted in gCJD and was the most common PRNP mutation type observed among 104 cases of gCJD in Italy [106,107]. The V180I mutation in PRNP associated with gCJD was identified in 186 Japanese patients [108]. Other missense mutations as well as insertion and deletion mutations have been described as well [107,109-113].

Penetrance varies by mutation, with some mutations having extremely low penetrance and others approaching 100 percent penetrance [114]. Initial reports postulated genetic anticipation, especially in E200K families [115,116], but this finding has since been ascribed to data biases [117,118].

●Clinical and diagnostic features – In general, the clinical features of gCJD – disease duration, clinical symptoms, and diagnostic test results (electroencephalography [EEG], cerebrospinal fluid [CSF] results, and brain magnetic resonance imaging [MRI]) – closely resemble sCJD but can vary by mutation and even within families that carry the same mutation. (See "Creutzfeldt-Jakob disease", section on 'Clinical features' and "Creutzfeldt-Jakob disease", section on 'Brain MRI' and "Creutzfeldt-Jakob disease", section on 'Electroencephalogram'.)

CJD associated with the V180I mutation in PRNP that was observed in Japanese patients was characterized by more slowly progressive dementia than other sporadic and genetic CJD variants and was more likely to occur later in life [108]. Because myoclonus, visual disturbance, and cerebellar and pyramidal signs occur at lower frequency, this syndrome is difficult to distinguish from other forms of degenerative dementia.

GERSTMANN-STRÄUSSLER-SCHEINKER SYNDROME

Epidemiology and genetic features — Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare genetic human prion disease with an incidence of 1 to 10 cases per 100 million population per year.

GSS is inherited in an autosomal-dominant pattern with high penetrance caused by several different point mutations as well as octapeptide repeat insertion mutations. At least 24 separate kindreds have been identified throughout the world. The P102L is the most common mutation [119-121]; however, many other mutations have been identified [122-127].

Neuropathology — GSS is characterized by the presence of multicentric amyloid plaques in the cerebral cortex, basal ganglia, cerebellum, and elsewhere within the brain [128]. Spongiform degeneration is common but not universally present. Neurofibrillary tangles and neuropil threads, identical to those seen in Alzheimer disease, have been seen in brains from several kindreds [129,130]. The biochemical properties of prion protein (PrP) differ from those observed in Creutzfeldt-Jakob disease (CJD) and are characterized by protease-resistant C- and N-terminally truncated fragments.

Clinical features — The hallmark of the clinical disease is progressive cerebellar degeneration and/or parkinsonism accompanied by differing degrees of dementia in patients entering midlife (mean age 43 to 48 years), although the onset of symptoms in older patients has been reported [131-135].

Cerebellar manifestations include clumsiness, incoordination, and gait ataxia. Dysesthesia, hyporeflexia, and proximal weakness in the legs are other early signs [136]. Myoclonus is typically absent or occurs later in the illness in GSS. Whether and to what degree dementia develops varies among affected families and individuals within the same family [130,137,138].

Part of the variability of expression of this illness is due to differences in the underlying PRNP mutation and the associated polymorphisms in codon 129 [139]. Patients with GSS with the P102L mutation appear to have more prominent cerebellar features [120], while dementia may be a more prominent feature in patients with A117V, Y145STOP, and F198S mutations. Polymorphism at codon 129 may also play a modulating role in the manifestations of GSS in patients with the P102L mutation [134,140,141]. However, the varied clinical expression of these diseases both between and within affected families with the same gene mutations suggests that other unidentified factors are likely to be influential [134,141-143].

The course of the illness typically advances for approximately five years before culminating in death [144].

Diagnosis — Demonstration of PRNP gene mutations is a sensitive and specific way to diagnose GSS, as all patients with definite GSS have been found to have PRNP mutations. Preimplantation genetic diagnosis prior to in vitro fertilization was successful in one woman with a family history of GSS [145].

Brain biopsy should be considered only when a treatable condition is within the clinical differential diagnosis.

Laboratory and imaging studies are less helpful in the diagnosis of GSS than for sporadic CJD (sCJD). The majority of GSS cases have normal cerebrospinal fluid (CSF) 14-3-3 and tau results. While some cases demonstrate positive CSF real-time quaking-induced conversion (RT-QuIC) results, RT-QuIC is a less sensitive test in GSS compared with sCJD [146]. The electroencephalogram (EEG) may show slowing but does not typically show the periodic sharp wave complexes characteristic of sCJD. (See "Creutzfeldt-Jakob disease", section on 'Electroencephalogram' and "Creutzfeldt-Jakob disease", section on 'Cerebrospinal fluid protein markers'.)

Brain magnetic resonance imaging (MRI) findings are not specific or sensitive but may show areas of decreased T2 signal in the striatum and midbrain in some patients [147], along with nonspecific cerebellar and/or cortical atrophy on structural neuroimaging [148]. Rarely, patients with GSS demonstrate hyperintensity on fluid-attenuated inversion recovery (FLAIR) and/or diffusion-weighted imaging (DWI) sequences in the basal ganglia and/or cortical ribbon, findings that are common in sCJD. (See "Creutzfeldt-Jakob disease", section on 'Brain MRI'.)

Advanced neuroimaging modalities are not routinely performed. Single-photon emission computed tomography (SPECT) may demonstrate diffusely decreased blood flow; in one study, findings on SPECT that were very sensitive for GSS early in the disease course included decreased blood flow in the occipital lobe and spinal cord [136]. Despite the presence of amyloid plaques on neuropathology, positron emission tomography (PET) using amyloid tracers does not appear to demonstrate uptake in patients with GSS [149].

Management — There is no specific treatment for GSS that has been shown to improve outcomes. Management is generally supportive. (See "Care of patients with advanced dementia".)

An observational study using intraventricular pentosan polysulfate included two patients with GSS who may have demonstrated prolonged survival, but with uncertain clinical significance as prolonged survival has been observed in untreated patients as well [150].

FATAL FAMILIAL INSOMNIA

Epidemiology and genetics — Fatal familial insomnia (FFI) was first identified in Italian families, but kindreds have now been reported throughout the world [151]. FFI is inherited as an autosomal disease and results from a missense mutation at codon 178 of the PRNP gene located on chromosome 20p13 coupled with methionine at codon 129 on the mutated allele [152-155].

Sporadic cases are also described, termed "sporadic fatal insomnia" (sFI), which mimic the clinical and pathologic findings of FFI, but without the presence of a genetic mutation [152-155].

Neuropathology — Neuronal loss and gliosis, most pronounced within the thalamus, are consistent findings in FFI [155-158]. These changes can also occur in the cerebellar cortex, cerebellar nuclei, and olivary nuclei. The cerebral cortex may be spared, resulting in false-negative brain biopsies.

Immunoreactivity may be restricted to the entorhinal cortex and is usually much more subtle than that seen in other prion diseases [157-159]. Spongiform degeneration, the characteristic feature of most of the human prion diseases, is rarely detected in FFI, particularly in those with the methionine-homozygous genotype [157].

Clinical and laboratory features — Symptoms of FFI generally begin in midlife; median age at onset is 56 years (range 18 to 73 years) [156,157,160]. Disease onset is earlier and duration is shorter in those who are homozygous for methionine at codon 129.

●Sleep disturbance – Patients characteristically develop progressive insomnia with loss of the normal circadian sleep-activity pattern, which may manifest as a dream-like confusional state during waking hours [161]. Sleep studies demonstrate a dramatic reduction in total sleep time and disruption of the normal sleep architecture [157].

●Neuropsychiatric symptoms – Mental status and behavioral changes include inattention, impaired concentration and memory, confusion, and hallucinations, but overt dementia is rare or occurs late in the illness course [162]. As the disease progresses, motor disturbances such as myoclonus, ataxia, parkinsonism, and spasticity can occur along with dysarthria and dysphagia [158,160,162,163]. Methionine-homozygous patients are more likely to have hallucinations and myoclonus as prominent disease features, while codon 129-heterozygous patients are more likely to develop early and more severe problems with ataxia, bulbar signs, and nystagmus [157,163].

●Dysautonomia and endocrine disturbances – Dysautonomia may induce hyperhidrosis, hyperthermia, tachycardia, obstipation, and hypertension [156,158,164].

Endocrine disturbances include decreases in corticotropin (ACTH) secretion, increases in cortisol secretion, and loss of the normal diurnal variations in levels of growth hormone, melatonin, and prolactin [156,158,164].

●Laboratory testing and neuroimaging – Computed tomography (CT) and magnetic resonance imaging (MRI) usually show no distinctive abnormalities in patients with FFI. 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) has been reported to show decreased glucose utilization in the thalamus, which may be detectable even before the development of clinical symptoms [165-167].

The cerebrospinal fluid (CSF) is unremarkable, 14-3-3 protein is usually not detectable in the CSF, total tau is typically in the normal range, and real-time quaking-induced conversion (RT-QuIC) results are usually negative [168,169].

Electroencephalograms (EEGs) do not show periodic sharp wave complexes.

Diagnosis — PRNP genetic testing for the FFI mutation is the diagnostic procedure of choice. All cases of FFI are associated with the D178N-129M PRNP haplotype. sFI does not have a pathogenic PRNP mutation but is characterized by methionine homozygosity of the polymorphic codon 129 accompanied by the typical FFI neuropathology.

As fatal insomnia spares the cortex until very late in the disease process, brain biopsies are unhelpful.

One clinical center has developed a diagnostic algorithm for FFI based upon clinical findings [170]. To make a clinical diagnosis of FFI, patients must have:

●Sleep disturbance and/or abnormal polysomnography as described above

●Two of the following Creutzfeldt-Jakob disease (CJD)-like symptoms:

•Psychiatric (visual hallucinations, personality changes, depression, anxiety, aggression, disinhibition)

•Ataxia

•Visual

•Myoclonus

•Cognitive, memory deficits

●One of the following FFI-specific symptoms:

•Weight loss of >10 kg in the last six months

•Dysautonomia

•Husky voice

In their cohort, these criteria had an 81 percent sensitivity, but were not specific to FFI as 7 of 40 patients with sporadic CJD (sCJD) also met these criteria [170]. This diagnostic approach awaits independent validation but may serve as a means of selecting patients for genetic testing.

Treatment and prognosis — FFI is a rapidly fatal disease with a mean duration of 13 months. There is no specific treatment for FFI. Management is generally supportive; however, patients often respond poorly to symptomatic treatments. One case report describes that agomelatine was useful in improving sleep [171]. (See "Care of patients with advanced dementia".)

There is an ongoing Italian clinical trial using doxycycline as prophylaxis for FFI mutation carriers [172].

KURU — Kuru was the first transmissible neurodegenerative disease to be identified and studied; it has served as the prototype of human prion diseases [173,174]. Kuru also remains important because of some overlapping clinical and pathologic features with iatrogenic Creutzfeldt-Jakob disease (iCJD), variant CJD (vCJD), and Gerstmann-Sträussler-Scheinker syndrome (GSS) that provide clues to the pathogenesis of other human prion diseases.

●Epidemiology – Endemic in Papua New Guinea among the Fore linguistic group, kuru is believed to have been transmitted from person to person by ritual cannibalism [122,175]. The cessation of these practices in the 1950s had been thought to end incident cases of kuru; however, increased active surveillance in Papua New Guinea led to the identification of 11 new cases of kuru between July 1996 and June 2004, with a likely incubation period of more than 50 years in some cases [176].

●Genetics – Only limited molecular genetic studies of patients with kuru have been undertaken, and no mutations in the PRNP gene have been reported. Homozygosity at the polymorphic codon 129 of the PRNP gene has been detected at a higher than expected frequency in kuru similar to iCJD, sporadic CJD (sCJD), and vCJD [177]. Individuals who were exposed to kuru and survived the epidemic were usually heterozygotes at a known resistance factor site at codon 129. The kuru epidemic led to a reduced prevalence of codon 129 homozygosity in the affected population [178].

A genetic study undertaken in Papua New Guinea identified a novel PRNP variant, G127V, which appeared to confer protection from kuru among geographically and genetically at-risk families [179]. The fact that this allele was found exclusively in individuals from a kuru-prevalent geographic region indicates that this is an acquired genetic response through selection.

●Neuropathology – Although the pathologic hallmark of kuru is abnormal prion protein (PrPSc)-reactive plaques occurring in the cerebellum, this finding is only present in approximately 60 percent of patients dying from kuru [177]. Kuru plaques are unicentric and round with radiating spicules and are periodic acid-Schiff (PAS) positive. Neuronal loss and hypertrophy of astrocytes are also observed.

●Clinical features – Unlike some of the other prion diseases, kuru occurs in predictable stages [122]:

•The early or ambulatory phase is characterized by tremors, ataxia, and postural instability. The tremors resemble shivering, which accounts for the name of the disease (kuru = shivering).

•The sedentary stage follows as the disease progresses with loss of ambulation resulting from increased tremors and ataxia. Involuntary movements, including myoclonus, choreoathetosis, and fasciculations, also appear.

•Dementia, which usually begins as slowing of the mental processes, progresses in the late stages of the disease. Patients may exhibit indifference or seem unconcerned with their disease.

•Frontal release signs, cerebellar-type dysarthria, and inability to get out of bed mark the terminal stage, with death typically due to pneumonia occurring within 9 to 24 months from the onset of the disease.

●Diagnosis – Few laboratory studies have been performed on patients with kuru, and neuroimaging has not been reported. The cerebrospinal fluid (CSF) is unremarkable. The electroencephalogram (EEG) is abnormal, but it is not characterized by the periodic sharp wave complexes found in some of the sCJD cases [180]. (See "Creutzfeldt-Jakob disease", section on 'Electroencephalogram'.)

VARIABLY PROTEASE-SENSITIVE PRIONOPATHY — Variably protease-sensitive prionopathy (VPSPr) is a novel sporadic prion disease that was first described in a 2008 case series of 11 patients identified by the National Prion Disease Pathology Surveillance Center [181]. Other case series have been published subsequently, such that almost 40 patients in the United States and Europe have been identified [4,182-184].

Clinical, genetic, and neuropathologic features — Patients with VPSPr present with prominent neuropsychiatric manifestations, aphasia, and dementia, with progressive motor decline (ataxia and/or parkinsonism) appearing somewhat later in the disease course [181]. Across series, the mean age at presentation is 70 years and the mean duration of illness is approximately two years, although cases with a duration of six to seven years are described [4,181-184].

A family history of dementia was present in 7 of the original 11 patients, suggesting a possible genetic origin; however, sequencing of the PRNP gene demonstrated no mutations [181]. The majority of reported patients with VPSPr have the 129VV genotype; the MM genotype is least frequent [181-184]. Clinical features were similar across genotypes; distinguishing features included a longer mean disease duration (45 months) and older age of onset (72 years) among those with the 129MV and 129MM genotypes compared with 129VV [4]. Patients with the 129MM phenotype also had less severe or absent neuropsychiatric symptoms [183]. The prion protein (PrP) associated with the 129MV and 129MM genotypes is also relatively protease resistant compared with those associated with the 129VV genotype. In contrast to sporadic Creutzfeldt-Jakob disease (sCJD), the presence of valine appears to result in a shorter disease duration as well as a younger age of onset, albeit with extensive overlap in both these features.

Cerebrospinal fluid (CSF) 14-3-3 was negative in the five patients in whom it was tested, magnetic resonance imaging (MRI) demonstrated diffuse atrophy without restricted diffusion, and electroencephalograms (EEGs) were normal or showed only diffuse slowing [181].

Neuropathologic examination reveals spongiform degeneration in the cerebral cortex, basal ganglia, and thalamus with relative sparing of the brainstem and cerebellum [4,181]. PrP immunostaining is characterized by a distinctive pattern of small cluster-forming granules, "mini-plaques," most notably in the cerebellum and hippocampus. Immunoreactivity was virtually abolished by protein digestion.

Diagnostic challenges — VPSPr can be difficult to diagnose; many patients are initially thought to have a non-Alzheimer dementia such as Lewy body disease, frontotemporal dementia, or normal pressure hydrocephalus. Routine test results only rarely raise suspicion for prion disease. EEG findings are normal or demonstrate mild slowing, while periodic sharp wave complexes have a sensitivity of only 9 percent in VPSPr [4]. Brain MRI only rarely demonstrates the diffusion restriction commonly seen in sCJD. CSF 14-3-3 protein tests are less sensitive compared with sCJD, and when combined with total tau levels, reach a sensitivity of only 21 percent across all VPSPr cases. Few VPSPr cases have been tested by CSF real-time quaking-induced conversion (RT-QuIC); while often positive, this test may not demonstrate the high sensitivity observed in sCJD.

As with all cases of suspected prion disease, brain biopsy is not recommended unless a different disease is suspected that requires brain tissue to diagnose or guide treatment.

Treatment and prognosis — As with all prion diseases, the disease is universally fatal and there are no effective treatments. The duration of disease is variable; cases of prolonged survival are reported.

Supportive care of patients with advanced dementia is described separately. (See "Care of patients with advanced dementia".)

Doxycycline was given to a case of VPSPr, resulting in prolonged survival time with fewer than expected histopathologic changes at autopsy [185]. These results are difficult to interpret given the known prolonged survival times and atypical pathology observed in VPSPr in general.

OTHER PRION DISEASES

●A novel familial prion disease was described in a British kindred that included 11 affected family members [186]. Patients presented in early adulthood with watery diarrhea and a sensory autonomic neuropathy manifesting with urinary retention, impotence, and postural hypotension. Seizures and cognitive decline developed subsequently. The mean age of death was 57 years.

Pathologic examination revealed prion amyloid protein deposits in the bowel and peripheral nerves; the brain showed amyloid plaques, cerebral amyloid angiopathy, and tauopathy [186]. Genetic sequencing showed a novel mutation at PRNP Y163X in association with valine at amino acid residue 129. Digestion and immunoblotting of brain samples revealed an unusual pattern of proteinase K-resistant fragments and the lack of a glycosylphosphatidylinositol membrane anchor.

●A mother and daughter were described with a prion disease with a rare PRNP mutation (Q160x) that resulted in production of a truncated prion protein (PrP) [187]. The clinical presentation resembled early-onset Alzheimer disease (ages 42 and 59 at symptom onset) with progressive short-term memory impairment over three years, followed by impairments in other cognitive domains and mild parkinsonism. Both patients died eight years after the first clinical symptoms.

Neuropathologic examination revealed extensive tau-positive neurofibrillary tangles and neuritic plaques; the latter were immunonegative for beta-amyloid but stained positive for PrP [187].

●Three family members (two sisters and their father) presented with progressive cognitive decline characteristic of frontotemporal dementia, along with ataxia and seizures [188]. A novel 12-octapeptide repeat insertion in PRNP was discovered in the proband.

Neuropathologic examination of the sisters revealed PrP-positive plaques and tau-positive tangles [188].

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Dementia (including Alzheimer disease) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Pathogenesis of prion disease – Prion diseases are neurodegenerative diseases that have long incubation periods, when acquired, and progress inexorably once clinical symptoms appear. (See 'Pathogenesis of prion diseases' above.)

Prions are small, infectious pathogens. The prion protein (PrP) is the critical, and likely its exclusive, component. A characteristic feature of prions is their resistance to a number of normal decontaminating procedures. (See 'Prion protein' above.)

Prion diseases appear to result from accumulation of abnormal isoforms of the PrP. These changes are due to conformational variation, variations in amino acid sequence, and/or glycosylation levels of PrP. (See 'Conversion of PrPC to PrPSc' above.)

The abnormal PrP is transported to the brain via axonal transport; accumulation of this protein or its fragments leads to apoptosis and cell death. (See 'Transport of PrPSc to and within the nervous system' above.)

PRNP, the gene encoding PrP, is located on the short arm of chromosome 20. Mutations in this gene are linked to prion diseases with a familial predisposition including genetic Creutzfeldt-Jakob disease (gCJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). A single mutation can produce different clinical phenotypes in different individuals and families. (See 'Genetics of human prion diseases' above.)

●Creutzfeldt-Jakob disease – CJD is the most frequent of the human prion diseases. CJD most often occurs as a sporadic disorder and is clinically manifested by a rapidly progressive mental deterioration, often with behavioral abnormalities, and myoclonus. (See "Creutzfeldt-Jakob disease".)

Variant CJD (vCJD) is a distinct disorder that represents transmission of bovine spongiform encephalopathy; most patients acquire the disorder through ingestion of infected meat products. Clinical, diagnostic, and pathologic features are distinct from CJD. (See "Variant Creutzfeldt-Jakob disease".)

gCJD, which presents with a clinical syndrome and test features very similar to that of sporadic CJD (sCJD), has been identified in families who demonstrate one or more mutations in PRNP. (See 'Genetic CJD' above.)

●Gerstmann-Sträussler-Scheinker syndrome – GSS is inherited in an autosomal-dominant pattern with virtual complete penetrance. (See 'Gerstmann-Sträussler-Scheinker syndrome' above.)

•Patients present in midlife with a progressive cerebellar degeneration accompanied by differing degrees of dementia. Death usually occurs within five years after the onset of symptoms. (See 'Clinical features' above.)

•The diagnosis of GSS can be made with genetic testing. Other laboratory or routine imaging studies are generally unhelpful. (See 'Diagnosis' above.)

●Fatal familial insomnia – FFI is inherited as an autosomal disease. An acquired, sporadic form also occurs. (See 'Fatal familial insomnia' above.)

•Patients present in midlife with progressive insomnia and loss of the normal circadian pattern. Mental status and behavioral changes also develop but fall short of dementia until later in the disease. With disease progression, motor disturbances such as myoclonus, ataxia, and spasticity can occur, along with dysautonomia and endocrine disturbances.

The mean disease duration is approximately 13 months.

•A diagnosis of FFI is made with genetic testing.

A sporadic and nonfamilial variety of this disorder exists and may be diagnosed with neuropathological examination demonstrating neuronal loss and gliosis primarily affecting the thalamus. PrP immunohistochemistry staining is often scant, which may result in false-negative results.

●Variably protease-sensitive prionopathy (VPSPr) – VPSPr is an atypical, sporadic prion disease. (See 'Variably protease-sensitive prionopathy' above.)

•Symptoms include early cognitive and psychiatric changes presenting in older individuals with a disease progression that is somewhat more prolonged than that of sCJD and may suggest a neurodegenerative dementia.

•While diagnostic test results can mirror that of CJD in regard to neuroimaging, electroencephalography (EEG) results, and cerebrospinal fluid (CSF) biomarkers, these are less sensitive in this disorder. Neuropathologic changes and Western blots also differ from what is typically observed in sCJD.

●Kuru – Kuru, which was endemic in Papua New Guinea among the Fore linguistic group, appears to be transmitted from person to person by ritual cannibalism. (See 'Kuru' above.)

•Symptoms begin with tremors, ataxia, and postural instability, followed by loss of ambulation and involuntary movements. Dementia progresses in the late stages of the disease, with death typically occurring within 9 to 24 months from the onset.

•Diagnostic testing has not been well characterized in this disorder. Characteristic pathologic findings have been described.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Henry G Brown, MD, PhD, and John M Lee, MD, PhD, who contributed to an earlier version of this topic review.

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Topic 5074 Version 15.0

References

1 : Systematic review of therapeutic interventions in human prion disease.

2 : Transmissible spongiform encephalopathies.

3 : Shattuck lecture--neurodegenerative diseases and prions.

4 : Variably protease-sensitive prionopathy.

5 : Variably protease-sensitive prionopathy.

6 : Novel proteinaceous infectious particles cause scrapie.

7 : Cellular biology of prion diseases.

8 : Scrapie prion protein contains a phosphatidylinositol glycolipid.

9 : Prion proteins carrying pathogenic mutations are resistant to phospholipase cleavage of their glycolipid anchors.

10 : Evidence of presynaptic location and function of the prion protein.

11 : A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cells.

12 : Evidence for a secretory form of the cellular prion protein.

13 : Processing of a cellular prion protein: identification of N- and C-terminal cleavage sites.

14 : Molecular modelling indicates that the pathological conformations of prion proteins might be beta-helical.

15 : Thermodynamics of model prions and its implications for the problem of prion protein folding.

16 : Physiology of the prion protein.

17 : Human prion diseases.

18 : Extracellular copper ions regulate cellular prion protein (PrPC) expression and metabolism in neuronal cells.

19 : Normal prion protein has an activity like that of superoxide dismutase.

20 : Octapeptide repeat region and N-terminal half of hydrophobic region of prion protein (PrP) mediate PrP-dependent activation of superoxide dismutase.

21 : Cross-linking cellular prion protein triggers neuronal apoptosis in vivo.

22 : Cellular prion protein is released on exosomes from activated platelets.

23 : The role of the cellular prion protein in the immune system.

24 : Membrane environment alters the conformational structure of the recombinant human prion protein.

25 : Is the prion domain of soluble Ure2p unstructured?

26 : Scrapie prions aggregate to form amyloid-like birefringent rods.

27 : Antisera to scrapie-associated fibril protein and prion protein decorate scrapie-associated fibrils.

28 : The hydrophobic core sequence modulates the neurotoxic and secondary structure properties of the prion peptide 106-126.

29 : Correlation of structural elements and infectivity of the HET-s prion.

30 : Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides.

31 : Evidence for synthesis of scrapie prion proteins in the endocytic pathway.

32 : Subcellular colocalization of the cellular and scrapie prion proteins in caveolae-like membranous domains.

33 : Mice devoid of PrP are resistant to scrapie.

34 : Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.

35 : Anchorless prion protein results in infectious amyloid disease without clinical scrapie.

36 : Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation.

37 : Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Sträussler-Scheinker disease.

38 : Distinct glycoform ratios of protease resistant prion protein associated with PRNP point mutations.

39 : Prion protein glycosylation.

40 : Variant Creutzfeldt-Jakob disease.

41 : Pathologic conformations of prion proteins.

42 : Prion recognition elements govern nucleation, strain specificity and species barriers.

43 : Pathogenesis of mouse scrapie: evidence for neural spread of infection to the CNS.

44 : Targeting of scrapie lesions and spread of agent via the retino-tectal projection.

45 : Rapid anterograde axonal transport of the cellular prion glycoprotein in the peripheral and central nervous systems.

46 : A novel cellular prion protein isoform present in rapid anterograde axonal transport.

47 : Cellular mechanisms responsible for cell-to-cell spreading of prions.

48 : Detection of pathologic prion protein in the olfactory epithelium in sporadic Creutzfeldt-Jakob disease.

49 : A crucial role for B cells in neuroinvasive scrapie.

50 : Peripheral circulation of the prion infectious agent in transgenic mice expressing the ovine prion protein gene in neurons only.

51 : The nasal cavity is a route for prion infection in hamsters.

52 : Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie.

53 : Complement facilitates early prion pathogenesis.

54 : Protein conformation significantly influences immune responses to prion protein.

55 : Neurotoxicity of a prion protein fragment.

56 : Role of microglia and host prion protein in neurotoxicity of a prion protein fragment.

57 : Scrapie-specific neuronal lesions are independent of neuronal PrP expression.

58 : Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol.

59 : Prion protein trafficking and the development of neurodegeneration.

60 : Anchors away--of plaques and pathology in prion disease.

61 : Assignment of the human and mouse prion protein genes to homologous chromosomes.

62 : Molecular and clinical classification of human prion disease.

63 : Molecular and clinical classification of human prion disease.

64 : Discordant clinicopathologic phenotypes in a Japanese kindred of fatal familial insomnia.

65 : Prion mutation D178N with highly variable disease onset and phenotype.

66 : Inherited prion disease with an alanine to valine mutation at codon 117 in the prion protein gene.

67 : The D178N (cis-129M) "fatal familial insomnia" mutation associated with diverse clinicopathologic phenotypes in an Australian kindred.

68 : Fatal familial insomnia and familial Creutzfeldt-Jakob disease: a tale of two diseases with the same genetic mutation.

69 : Phenotypic variability in familial prion diseases due to the D178N mutation.

70 : Inherited prion disease with six octapeptide repeat insertional mutation--molecular analysis of phenotypic heterogeneity.

71 : Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different prion proteins determined by a DNA polymorphism.

72 : Age at onset in genetic prion disease and the design of preventive clinical trials.

73 : Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease.

74 : Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease.

75 : Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects.

76 : Rapid detection of Creutzfeldt-Jakob disease and scrapie prion proteins.

77 : Eight prion strains have PrP(Sc) molecules with different conformations.

78 : Diagnosis of human prion disease.

79 : Detection of prions in blood.

80 : Presymptomatic detection of prions in blood.

81 : Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion.

82 : Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease.

83 : A test for Creutzfeldt-Jakob disease using nasal brushings.

84 : Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease.

85 : Prion Seeds Distribute throughout the Eyes of Sporadic Creutzfeldt-Jakob Disease Patients.

86 : A prion protein epitope selective for the pathologically misfolded conformation.

87 : Capillary electrophoresis-based noncompetitive immunoassay for the prion protein using fluorescein-labeled protein A as a fluorescent probe.

88 : Immunoquantitative PCR for prion protein detection in sporadic Creutzfeldt-Jakob disease.

89 : Conformational biosensor for diagnosis of prion diseases.

90 : Detection of prion particles in samples of BSE and scrapie by fluorescence correlation spectroscopy without proteinase K digestion.

91 : Recent developments in prion disease research: diagnostic tools and in vitro cell culture models.

92 : Purified scrapie prions resist inactivation by procedures that hydrolyze, modify, or shear nucleic acids.

93 : Decontamination of Creutzfeldt-Jakob disease and other transmissible agents.

94 : Observations on thermostable subpopulations of the unconventional agents that cause transmissible degenerative encephalopathies.

95 : Infectivity of scrapie prions bound to a stainless steel surface.

96 : Transmission of scrapie by steel-surface-bound prions.

97 : An enzyme-detergent method for effective prion decontamination of surgical steel.

98 : Elimination of transmissible spongiform encephalopathy infectivity and decontamination of surgical instruments by using radio-frequency gas-plasma treatment.

99 : A novel copper-hydrogen peroxide formulation for prion decontamination.

100 : Inactivation of Prions and Amyloid Seeds with Hypochlorous Acid.

101 : Familial Creutzfeldt-Jakob disease. Codon 200 prion disease in Libyan Jews.

102 : Familial Creutzfeldt-Jakob disease in Chile is associated with the codon 200 mutation of the PRNP amyloid precursor gene on chromosome 20.

103 : Increased incidence of genetic human prion disease in Hungary.

104 : Creutzfeldt-Jakob disease with E200K mutation in Slovakia: characterization and development.

105 : A novel phenotype in familial Creutzfeldt-Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein.

106 : Prion diseases and the BSE crisis.

107 : High incidence of genetic human transmissible spongiform encephalopathies in Italy.

108 : Clinical features of genetic Creutzfeldt-Jakob disease with V180I mutation in the prion protein gene.

109 : Familial Creutzfeldt-Jakob disease with an R208H-129V haplotype and Kuru plaques.

110 : Creutzfeldt-Jakob disease in a Chinese patient with a novel seven extra-repeat insertion in PRNP.

111 : Familial prion disease in a Hungarian family with a novel 144-base pair insertion in the prion protein gene.

112 : First demonstrated de novo insertion in the prion protein gene in a young patient with dementia.

113 : Inherited Creutzfeldt-Jakob disease in a Dutch patient with a novel five octapeptide repeat insertion and unusual cerebellar morphology.

114 : Quantifying prion disease penetrance using large population control cohorts.

115 : Preliminary evidence for anticipation in genetic E200K Creutzfeldt-Jakob disease.

116 : Age at Death of Creutzfeldt-Jakob disease in subsequent family generation carrying the E200K mutation of the prion protein gene.

117 : Ascertainment bias causes false signal of anticipation in genetic prion disease.

118 : Pseudo-anticipation in Creutzfeldt-Jakob disease is due to a rhomboid-shaped artifact.

119 : Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome.

120 : Prion protein mutation at codon 102 in an Italian family with Gerstmann-Sträussler-Scheinker syndrome.

121 : The original Gerstmann-Sträussler-Scheinker family of Austria: divergent clinicopathological phenotypes but constant PrP genotype.

122 : The original Gerstmann-Sträussler-Scheinker family of Austria: divergent clinicopathological phenotypes but constant PrP genotype.

123 : Inherited prion diseases.

124 : A new PRNP mutation (G131V) associated with Gerstmann-Sträussler-Scheinker disease.

125 : Prion proteins with different conformations accumulate in Gerstmann-Sträussler-Scheinker disease caused by A117V and F198S mutations.

126 : Novel prion protein gene mutation presenting with subacute PSP-like syndrome.

127 : Gerstmann-Straussler-Scheinker disease due to a novel prion protein gene mutation.

128 : Relationship of microglia and scrapie amyloid-immunoreactive plaques in kuru, Creutzfeldt-Jakob disease and Gerstmann-Sträussler syndrome.

129 : Gerstmann-Sträussler-Scheinker syndrome,fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies.

130 : A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann-Sträussler-Scheinker disease phenotype: comparison with similar cases from the literature.

131 : Clinical and molecular genetic study of a large German kindred with Gerstmann-Sträussler-Scheinker syndrome.

132 : Gerstmann-Sträussler-Scheinker disease and the Indiana kindred.

133 : Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies.

134 : Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series.

135 : Unusual clinical and molecular-pathological profile of gerstmann-Sträussler-Scheinker disease associated with a novel PRNP mutation (V176G).

136 : Early clinical signs and imaging findings in Gerstmann-Sträussler-Scheinker syndrome (Pro102Leu).

137 : Neuropsychological function in patients with Gerstmann-Sträussler-Scheinker disease from the Indiana kindred (F198S).

138 : The dementia of Gerstmann-Sträussler-Scheinker syndrome: clinical variability demonstrated by two case reports.

139 : Clinical Variability in P102L Gerstmann-Sträussler-Scheinker Syndrome.

140 : Gerstmann-Sträussler-Scheinker disease with mutation at codon 102 and methionine at codon 129 of PRNP in previously unreported patients.

141 : Polymorphism at codon 129 or codon 219 of PRNP and clinical heterogeneity in a previously unreported family with Gerstmann-Sträussler-Scheinker disease (PrP-P102L mutation).

142 : A Japanese family with a variant of Gerstmann-Sträussler-Scheinker disease.

143 : Phenotypic heterogeneity in inherited prion disease (P102L) is associated with differential propagation of protease-resistant wild-type and mutant prion protein.

144 : Gerstmann-Sträussler-Scheinker disease.

145 : Preimplantation genetic diagnosis (PGD) for genetic prion disorder due to F198S mutation in the PRNP gene.

146 : High diagnostic value of second generation CSF RT-QuIC across the wide spectrum of CJD prions.

147 : Gerstmann-Sträussler-Scheinker syndrome: MR findings.

148 : Dominantly inherited prion protein cerebral amyloidoses - a modern view of Gerstmann-Sträussler-Scheinker.

149 : [(11)C]PiB PET in Gerstmann-Sträussler-Scheinker disease.

150 : Intraventricular pentosan polysulphate in human prion diseases: an observational study in the UK.

151 : Fatal familial insomnia and sporadic fatal insomnia.

152 : Sporadic fatal insomnia masquerading as a paraneoplastic cerebellar syndrome.

153 : Prion protein conformation in a patient with sporadic fatal insomnia.

154 : A subtype of sporadic prion disease mimicking fatal familial insomnia.

155 : Two distinct prions in fatal familial insomnia and its sporadic form.

156 : Fatal familial insomnia: clinical and pathologic study of five new cases.

157 : Fatal familial insomnia: Clinical features and early identification.

158 : Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene.

159 : Intracerebral distribution of infectious amyloid protein in spongiform encephalopathy.

160 : Complex movement disorders in fatal familial insomnia: a clinical and genetic discussion.

161 : Motor overactivity and loss of motor circadian rhythm in fatal familial insomnia: an actigraphic study.

162 : "Fatal familial insomnia": neuropsychological study of a disease with thalamic degeneration.

163 : Gait disorders in fatal familial insomnia.

164 : Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei.

165 : [18F]FDG PET in fatal familial insomnia: the functional effects of thalamic lesions.

166 : Cerebral metabolism in fatal familial insomnia: relation to duration, neuropathology, and distribution of protease-resistant prion protein.

167 : Pre-symptomatic diagnosis in fatal familial insomnia: serial neurophysiological and 18FDG-PET studies.

168 : Phenotypic variability in fatal familial insomnia (D178N-129M) genotype.

169 : Clinical Laboratory Tests Used To Aid in Diagnosis of Human Prion Disease.

170 : A proposal of new diagnostic pathway for fatal familial insomnia.

171 : Agomelatine improves sleep in a patient with fatal familial insomnia.

172 : Preventive study in subjects at risk of fatal familial insomnia: Innovative approach to rare diseases.

173 : Degenerative disease of the central nervous system in New Guinea; the endemic occurrence of kuru in the native population.

174 : Kuru with incubation periods exceeding two decades.

175 : Kuru, the First Human Prion Disease.

176 : Kuru in the 21st century--an acquired human prion disease with very long incubation periods.

177 : Pathology and immunocytochemistry of a kuru brain.

178 : Balancing selection at the prion protein gene consistent with prehistoric kurulike epidemics.

179 : A novel protective prion protein variant that colocalizes with kuru exposure.

180 : The EEG of kuru.

181 : A novel human disease with abnormal prion protein sensitive to protease.

182 : The first case of protease-sensitive prionopathy (PSPr) in The Netherlands: a patient with an unusual GSS-like clinical phenotype.

183 : Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein.

184 : Variably protease-sensitive prionopathy in the UK: a retrospective review 1991-2008.

185 : A case of variably protease-sensitive prionopathy treated with doxycyclin.

186 : A novel prion disease associated with diarrhea and autonomic neuropathy.

187 : Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype.

188 : Clinical characterization of a kindred with a novel 12-octapeptide repeat insertion in the prion protein gene.