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; originally reported as new variant CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), and variably protease-sensitive prionopathy (VPSPr) [2-4].
These diseases share 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 accumulation of an abnormal form of a host cell protein; the normal form is designated "PrPC," and the abnormal form "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 pathogenic component and 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 on both neuronal and nonneuronal cells in normal human brains [7,8]. PrPC can be detected attached to the plasma membrane of neurons [9] and may be concentrated at synaptic membranes [10]. 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 exist [12].
A key step during PrPC biosynthesis involves modification of both 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 copper ions, suggesting that PrPC could play a role in copper homeostasis, which in turn plays a role in endocytosis and neurotransmission [17,18]. 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]. PrPC is also 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 resulting from an as yet uncharacterized conformational alteration [14,15]. Recombinant forms of PrP show a large unstructured protein motif, which may more easily convert to a beta-pleated sheet structure [24,25].
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 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 development of prion disease. When transgenic mice with an abnormal form of PrPC that lacked the glycophospholipid cell membrane anchor were inoculated with PrPSc, they accumulated abnormal PrP in abundant amyloid plaques but remained asymptomatic and did not accumulate PrPSc or develop titers of infectivity at nearly the same rate as wild-type mice [35].
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 PrP are used, and conversion of PrPC to PrPSc is inhibited by glycosylation [39]. Other non-PrP cellular cofactors may also be associated with different prion strain properties [40].
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 [41]. 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 familial forms [42]. 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 [43]. The two dominant theories for the origin of sporadic prion disease, which are not mutually exclusive, include posttranslational modification of PrPC and somatic mutation of the prion protein (PRNP) gene.
Transport of PrPSc to and within the nervous system — Transport of PrPSc to the nervous system occurs via axonal transport [44]. Both slow and rapid, likely nonuniform, axonal transport appear to play a role [45-48]. Prions may also propagate via extracellular vesicles and/or tunneling nanotubes [49].
The finding of PrPC and PrPSc in olfactory sensory neurons has suggested that the olfactory system may serve as an entry pathway for infection, though there is no epidemiologic evidence of disease via this exposure route [50].
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 vCJD, than for sporadic and genetic forms of prion diseases [51-53]. 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 [54,55]. Other studies have shown variable immune responses to different experimental PrP conformations [56].
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 [57,58]. PrPC must be present for this effect to occur [58]. 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 [59].
Misfolded PrP is transported in a retrograde fashion to the cytosol for degradation [60]. Even small amounts of this protein in the cytosol are highly neurotoxic, and this accumulation may be an important step in prion disease pathogenesis [60,61].
The demonstration of high amyloid plaque burdens in mice inoculated with PrPSc who yet remained asymptomatic [35] suggests a specific neurotoxic role of PrPSc beyond amyloid deposition [62].
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, with one possible exception [63].
PRNP in humans is located on the short arm of chromosome 20 [64]. 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 [65,66].
Some experts advocate classifying prion diseases based upon the responsible mutation rather than the traditional clinicopathologic classifications such as gCJD or GSS since a single mutation can produce different clinical phenotypes in different individuals or families (ie, genetic pleiotropy) [64,67-69]. As an example, the D178N mutation, in which asparagine substitutes for aspartic acid in codon 178, occurs in families with FFI and gCJD [64]. Pedigrees with this mutation often demonstrate marked variability in the age of onset as well as disease phenotype [68]. A large English and Irish kindred has been described containing individuals clinically diagnosed with a variety of conditions including CJD, vCJD, and GSS [69]. 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 polymorphic; individuals without disease code for either valine or methionine [70-73]. Neither V129 nor M129 appears to be pathogenic; however, genotype-phenotype correlation studies suggest that amino acid 129 allele status modifies the effect of other pathogenic PRNP mutations. This modifying influence appears to be predominately cis-acting, meaning that the impact on phenotype is due to the presence of both variants in the same protein product. This is likely a result of the joint effect of both variants together conferring a unique conformational change in protein structure, resulting in altered patterns of PRNP cleavage by proteases [74]. Patients with the D178N mutation cis with valine at codon 129 appear to develop CJD, while those who are cis with methionine tend to have FFI.
In another kindred, PrP gene polymorphism was found to influence the age of disease onset [73], though this initial finding has since been called into question [75]. Despite these patterns, the clinical expression of individual mutations can vary even among affected members of the same family [67].
●Acquired and sporadic prion diseases – Unlike gCJD, sCJD, iCJD, and vCJD are not associated with PRNP gene mutations. However, even in these patients, the codon 129 polymorphism appears to affect susceptibility and expression of the clinical illness [76]. 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 are homozygous [76]. Five of seven patients who developed iCJD after receiving human cadaveric growth hormone were homozygous at codon 129 [77].
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 [78]. 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'.)
Role of polymorphism at codon 219 — A polymorphism at codon 219, only occurring in East and South Asian populations, is protective against sCJD [79].
The role of non-PRNP polymorphisms — In an effort to characterize the effects of other genes besides PRNP on prion disease incidence, a large genome-wide association study (GWAS) composed of 5208 individuals with sCJD was conducted. Two non-PRNP genes were associated with sCJD, including syntaxin 6 (STX6) and galactose-3-O-sulfotransferase 1 (GAL3ST1). STX6 has also been associated with progressive supranuclear palsy [80].
DETECTION OF ABNORMAL PRION PROTEIN
●Immunoblotting – Western blot analysis following proteinase K digestion is commonly used to detect disease-causing prion protein (PrPSc) in brain tissue [81]. 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 PrPSc, and it was discovered that PrPSc exists in both protease-resistant and protease-sensitive forms [82]. Unlike other immunoassays, CDI is able to measure both protease-resistant and protease-sensitive forms of PrPSc [82]. CDI appears to have a much higher sensitivity for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) compared with routine neuropathologic examination and immunohistochemistry [83]. 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), as well as 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) [84], which has been used to detect the biphasic appearance of PrPSc in inoculated hamsters [85]. PrPSc was found 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 [86]. 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, tears, and other types of tissue [87-91]. (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 [92].
Other methods are also in development [86,93-97].
The need for highly sensitive and specific testing 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 traditional decontamination procedures based on eradicating nucleic acids, such as hydrolysis or shearing [98].
On the other hand, agents that digest, denature, or modify proteins are effective 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 by immersion in 1 N NaOH (for 30 minutes, repeated three times) or in concentrated (>3 M) solutions of guanidine thiocyanate [99]. However, certain cautions prevail; it appears that inadequate autoclaving can establish heat-resistant subpopulations that fail to diminish with further cycles of autoclaving [100]. Stainless steel instruments also may retain infectivity even after treatment with 10 percent formaldehyde [101,102].
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 [103]. A radiofrequency gas-plasma treatment has been shown to effectively decontaminate surgical instruments [104]. Another group has tested a decontamination formula combining copper metal ions with hydrogen peroxide [105]. Prion decontamination has also been demonstrated with hypochlorous acid [106].
CREUTZFELDT-JAKOB DISEASE — Creutzfeldt-Jakob disease (CJD) is the most frequent human prion disease. CJD most often occurs as a sporadic disorder, although genetic forms have been described, and is clinically manifested by 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 representing 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 pathogenic PRNP mutation and has been observed in many regions, including Libya, Chile, and Hungary [107-109]. In Slovakia, this mutation underlies more than 70 percent of all prion diseases [110]. One study described a differing presentation of this syndrome with codon 129 phenotype changes [111]. 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 [112,113]. The V180I mutation in PRNP associated with gCJD was identified in 186 Japanese patients [114]. Other missense mutations as well as insertion and deletion mutations have been described [113,115-119].
Penetrance varies by mutation, with some mutations having extremely low penetrance and others approaching 100 percent penetrance [120]. Initial reports postulated genetic anticipation, especially in E200K families [121,122], but this finding has since been ascribed to data biases [123,124].
●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 Japanese patients is characterized by more slowly progressive dementia than other sporadic and genetic CJD variants and is more likely to occur later in life [114]. Because myoclonus, visual disturbance, and cerebellar and pyramidal signs occur at lower frequency, this syndrome is difficult to distinguish from other degenerative dementias.
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 [125-127]; however, many other mutations have been identified [128-133].
Neuropathology — GSS is characterized by multicentric amyloid plaques in the cerebral cortex, basal ganglia, cerebellum, and elsewhere within the brain [134]. 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 [135,136]. The biochemical properties of prion protein (PrP) differ from those observed in Creutzfeldt-Jakob disease (CJD), characterized by protease-resistant C- and N-terminally truncated fragments.
Clinical features — The clinical hallmark is progressive cerebellar degeneration and/or parkinsonism accompanied by varying degrees of dementia in patients entering midlife (mean age 43 to 48 years), although the onset of symptoms in older patients has been reported [137-141].
Cerebellar manifestations include clumsiness, incoordination, and gait ataxia. Dysesthesia, hyporeflexia, and proximal weakness in the legs are other early signs [142]. 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 [136,143,144].
Part of the variability of expression of this illness is due to differences in the underlying PRNP mutation [145]. Patients with GSS with the P102L mutation manifest more prominent cerebellar features [126], while dementia may predominate in patients with A117V, Y145STOP, and F198S mutations. Polymorphism at codon 129 may also play a modulating role in GSS patients with the P102L mutation [140,146,147]. However, the varied clinical expression of these diseases both between and within affected families with identical gene mutations suggests that other unidentified factors are likely to be influential [140,147-149].
The course of the illness typically advances for approximately five years before culminating in death [150].
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 testing prior to in vitro fertilization was successful in one woman with a family history of GSS [151].
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 [152]. 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 [153], along with nonspecific cerebellar and/or cortical atrophy on structural neuroimaging [154]. 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 [142]. 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 [155].
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 [156].
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 [157]. FFI is inherited as an autosomal disease and results from a missense mutation at codon 178 of the PRNP gene coupled with methionine at codon 129 on the mutated allele [158-161].
Sporadic fatal insomnia (sFI) mimics the clinical and pathologic findings of FFI, but without the presence of a genetic mutation [158-161].
Neuropathology — Neuronal loss and gliosis, most pronounced within the thalamus, are consistent findings in FFI [161-164]. These changes can also occur in the cerebellar cortex, deep cerebellar nuclei, and inferior 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 [163-165]. Spongiform degeneration, the characteristic feature of most of the human prion diseases, is rarely detected in FFI, particularly in those with the methionine-homozygous polymorphism [163].
Clinical and laboratory features — Symptoms of FFI generally begin in midlife; median age at onset is 56 years (range 18 to 73 years) [162,163,166]. 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 [167]. Sleep studies demonstrate a dramatic reduction in total sleep time and disruption of normal sleep architecture [163].
●Neuropsychiatric symptoms – Mental status and behavioral changes include inattention, impaired concentration and memory, confusion, and hallucinations, but overt dementia is rare and occurs late in the illness [168]. As the disease progresses, motor disturbances such as myoclonus, ataxia, parkinsonism, and spasticity may occur along with dysarthria and dysphagia [164,166,168,169]. 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 [163,169].
●Dysautonomia and endocrine disturbances – Dysautonomia may induce hyperhidrosis, hyperthermia, tachycardia, obstipation, and hypertension [162,164,170].
Endocrine disturbances include decreased corticotropin (ACTH) secretion, increased cortisol secretion, and loss of the normal diurnal variations in growth hormone, melatonin, and prolactin [162,164,170].
●Laboratory testing and neuroimaging – Computed tomography (CT) and magnetic resonance imaging (MRI) usually show no distinctive abnormalities in 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 [171-173].
The cerebrospinal fluid (CSF) is unremarkable, 14-3-3 protein is usually not detectable, total tau is typically in the normal range, and real-time quaking-induced conversion (RT-QuIC) results are usually negative [174,175].
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 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 [176]. To make a clinical diagnosis of FFI, patients must manifest:
●Sleep disturbance and/or abnormal polysomnography (see 'Clinical and laboratory features' 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 81 percent sensitivity, but were not specific to FFI as 7 of 40 patients with sporadic CJD (sCJD) also met these criteria [176]. This approach awaits independent validation but may serve to select 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. Management is generally supportive; however, patients often respond poorly to symptomatic treatments. One case report describes that agomelatine was useful in improving sleep [177]. (See "Care of patients with advanced dementia".)
There is an ongoing Italian clinical trial using doxycycline as prophylaxis for FFI mutation carriers [178].
KURU — Kuru was the first transmissible neurodegenerative disease identified and has served as the prototype of human prion diseases [179,180]. Kuru also remains important because of 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 these 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 [128,181]. 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 [182].
●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 [183]. Individuals who were exposed to kuru and survived the epidemic were usually heterozygotes at codon 129. The kuru epidemic led to a reduced prevalence of codon 129 homozygosity in the affected population [184].
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 [185]. The fact that this allele was found exclusively in individuals from a kuru-prevalent geographic region indicates that it 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 [183]. 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 other prion diseases, kuru occurs in predictable stages [128]:
•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, 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, characterizes 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 initial onset of symptoms.
●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 is not characterized by periodic sharp wave complexes found in some sCJD cases [186]. (See "Creutzfeldt-Jakob disease", section on 'Electroencephalogram'.)
VARIABLY PROTEASE-SENSITIVE PRIONOPATHY — Variably protease-sensitive prionopathy (VPSPr) is a novel sporadic prion disease first described in a 2008 case series of 11 patients identified by the National Prion Disease Pathology Surveillance Center [187]. Other case series have been published subsequently, such that almost 40 patients in the United States and Europe have been identified [4,188-190].
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 later in the disease course [187]. Across series, the mean age at presentation is 70 years and mean duration of illness is approximately two years, although cases with a duration of six to seven years have been described [4,187-190].
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 [187]. The majority of reported patients with VPSPr have the 129VV polymorphism; the MM polymorphism is least frequent [187-190]. 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 polymorphisms compared with 129VV [4]. Patients with the 129MM phenotype also had less severe or absent neuropsychiatric symptoms [189]. The prion protein (PrP) associated with the 129MV and 129MM polymorphisms is also relatively protease resistant compared with those associated with the 129VV polymorphism. 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 of 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 [187].
Neuropathologic examination reveals spongiform degeneration in the cerebral cortex, basal ganglia, and thalamus with relative sparing of the brainstem and cerebellum [4,187]. PrP immunostaining is characterized by a distinctive flocculent pattern in the cerebral cortex and small cluster-forming granules, "mini-plaques," most notably in the cerebellum. Immunoreactivity is 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 rarely demonstrates the diffusion restriction commonly seen in sCJD. CSF 14-3-3 protein tests are less sensitive compared with sCJD: When combined with total tau levels, they 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 [191]. These results are difficult to interpret given the known prolonged survival times and atypical pathology observed in VPSPr.
OTHER PRION DISEASES
●A novel familial prion disease was described in a British kindred that included 11 affected family members [192]. 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 [192]. 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 rare PRNP mutation (Q160x) that resulted in production of a truncated prion protein (PrP) [193]. 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 [193].
●Three family members (two sisters and their father) presented with progressive cognitive decline characteristic of frontotemporal dementia, along with ataxia and seizures [194]. 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 [194].
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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 with long incubation periods that 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 exclusive, component. A characteristic feature 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 PrP due to conformational variation, variations in amino acid sequence, and/or glycosylation of PrP. (See 'Conversion of PrPC to PrPSc' above.)
Abnormal PrP may be 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 human prion disease. Most often, CJD is a sporadic disorder and is clinically manifested by 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".)
Genetic CJD (gCJD), which presents with a clinical syndrome and test features similar to sporadic CJD (sCJD), has been identified in families who demonstrate mutations in PRNP. (See 'Genetic CJD' above.)
●Gerstmann-Sträussler-Scheinker syndrome – GSS is inherited in an autosomal-dominant pattern with nearly 100 percent penetrance. (See 'Gerstmann-Sträussler-Scheinker syndrome' above.)
•Patients present in midlife with progressive cerebellar degeneration accompanied by differing degrees of dementia. Death usually occurs within five years of symptom onset. (See 'Clinical features' above.)
•The diagnosis of GSS requires genetic testing. Other laboratory or routine imaging studies are generally unhelpful. (See 'Diagnosis' above.)
●Fatal familial insomnia – FFI is an autosomal disease. An acquired, sporadic form also occurs. (See 'Fatal familial insomnia' above.)
•Patients present in midlife with progressive insomnia and loss of normal circadian pattern. Mental status and behavioral changes 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 dysfunction.
The mean disease duration is approximately 13 months.
•A diagnosis of FFI requires genetic testing.
A sporadic and nonfamilial variety of this disorder may be diagnosed by neuropathologic examination demonstrating neuronal loss and gliosis primarily affecting the thalamus and inferior olivary nuclei. 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 disease progression more prolonged than in sCJD, which may suggest a neurodegenerative dementia.
•Compared with typical CJD, neuroimaging, electroencephalography (EEG) results, and cerebrospinal fluid (CSF) biomarkers are less sensitive in this disorder. Neuropathologic features and Western blot abnormalities 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 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 earlier versions of this topic review.
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