Prion Disease
John Collinge
Introduction
The human prion diseases, also known as the subacute spongiform encephalopathies, have been traditionally classified into Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler syndrome (GSS) (also known as Gerstmann-Sträussler-Scheinker disease), and kuru. Although rare, affecting about 1-2 per million worldwide per annum, remarkable attention has been recently focused on these diseases. This is because of the unique biology of the transmissible agent or prion, and also because bovine spongiform encephalopathy (BSE), an epidemic bovine prion disease, appears to have transmitted to humans as variant CJD (vCJD), opening the possibility of a significant threat to public health through dietary exposure to infected tissues.
The transmissibility of the human diseases was demonstrated with the transmission, by intracerebral inoculation with brain homogenates into chimpanzees, of first kuru and then CJD in 1966 and 1968, respectively.(1,2) Transmission of GSS followed in 1981. The prototypic prion disease is scrapie, a naturally occurring disease of sheep and goats, which has been recognized in Europe for over 200 years and which is present in the sheep flocks of many countries. Scrapie was demonstrated to be transmissible by inoculation in 1936(3) and the recognition that kuru, and then CJD, resembled scrapie in its histopathological appearances led to the suggestion that these diseases may also be transmissible.(4) Kuru reached epidemic proportions amongst the Fore linguistic group in the Eastern Highlands of Papua New Guinea and was transmitted by ritual cannibalism. Since the cessation of cannibalism in the 1950s the disease has declined but a few cases still occur as a result of the long incubation periods in this condition, which may exceed 50 years.(5) The term Creutzfeldt-Jakob disease was introduced by Spielmeyer in 1922 bringing together the case reports published by Creutzfeldt and Jakob. Several of these cases would not meet modern diagnostic criteria for CJD and indeed it was not until the demonstration of transmissibility allowed diagnostic criteria to be reassessed and refined that a clear diagnostic entity developed. All these diseases share common histopathological features; the classical triad of spongiform vacuolation (affecting any part of the cerebral grey matter), astrocytic proliferation, and neuronal loss, may be accompanied by the deposition of amyloid plaques.
Aetiology
Prion diseases of both humans and animals are associated with the accumulation in the brain of an abnormal, partially proteaseresistant, isoform of a host-encoded glycoprotein known as prion protein (PrP). The disease-related isoform, PrPSc, is derived from its normal cellular precursor, PrPC, by a post-translational process that involves a conformational change. PrPC is rich in α-helical structure while PrPSc appears to be predominantly composed of β-sheet structure. According to the ‘protein-only’ hypothesis,(6) an abnormal PrP isoform(7) is the principal, and possibly the sole, constituent of the transmissible agent or prion. PrPSc is hypothesized to act as a conformational template, promoting the conversion of PrPC to further PrPSc. PrPC appears to be poised between two radically different folding states, and α- and β-forms of PrP can be inter-converted in suitable conditions.(8) Soluble β-PrP aggregates in physiological salt concentrations to form fibrils with morphological and biochemical characteristics closely similar to PrPSc. A molecular mechanism for prion propagation can now be proposed.(8) Prion replication, with recruitment of PrPC into the aggregated PrPSc isoform, may be initiated by a pathogenic mutation (resulting in a PrPC predisposed to form β-PrP) in inherited prion diseases, by exposure to a ‘seed’ of PrPSc in acquired cases, or as a result of the spontaneous conversion of PrPC to β-PrP (and subsequent formation of aggregated material) as a rare stochastic event in sporadic prion disease.
The human PrP gene (PRNP) is a single copy gene located on the short arm of chromosome 20 and was an obvious candidate for genetic linkage studies in the familial forms of CJD and GSS, which both showed an autosomal dominant pattern of disease segregation. A turning point in understanding the human prion diseases was the identification of mutations in the prion protein gene in familial CJD and GSS in 1989. The first mutation to be identified in PRNP was in a family with CJD and constituted a 144 bp insertion into the coding sequence.(9) A second mutation was reported in two families with GSS and genetic linkage was confirmed between this missense variant at codon 102 and GSS, confirming that GSS was an autosomal dominant Mendelian disorder.(10) Uniquely, these diseases are therefore both inherited and transmissible. Current evidence suggests that around 15 per cent of prion diseases are inherited and over 30 coding mutations in PRNP are now recognized.
With the exception of the rare iatrogenic CJD cases mentioned above, most prion disease occurs as sporadic CJD. While, by definition, there will not be a family history in sporadic cases, mutations are seen in occasional apparently sporadic cases, as with a late-onset disease the family history may not be apparent or non-paternity may occur. However, in the majority of sporadic CJD cases there is neither a coding mutation nor a history of iatrogenic exposure. Human prion diseases can therefore be subdivided into inherited, sporadic, and acquired forms. However, a common PrP polymorphism at residue 129, where either methionine or valine can be encoded, is a key determinant of genetic susceptibility to acquired and sporadic prion diseases, the large majority of which occur in homozygous individuals.(11,12) This protective effect of PRNP codon 129 heterozygosity is also seen in some of the inherited prion diseases.
The aetiology of sporadic CJD remains unclear. It has been speculated that these cases might arise from somatic mutation of PRNP or spontaneous conversion of PrPC to PrPSc as a rare stochastic event. The alternative hypothesis, in which such cases arise as a result of exposure to an environmental source of either human or animal prions, is not supported by epidemiological evidence.(13)
A major problem for the ‘protein-only’ hypothesis of prion propagation has been how to explain the existence of multiple isolates or strains of prions, with distinct biological properties. Understanding how a protein-only infectious agent could encode such phenotypic information has been of considerable biological interest. However, it is now clear that prion strains can be distinguished by differences in the biochemical properties of PrPSc. Prion strain diversity appears to be encoded by differences in PrP conformation and pattern of glycosylation.(14) A molecular strain
typing approach based on these characteristics has allowed the identification of four main types amongst CJD cases, sporadic and iatrogenic CJD being of PrPSc types 1-3, while all vCJD cases are associated with a distinctive type 4 PrPSc type.(14,15) A similar PrPSc type to that seen in vCJD is seen in BSE and BSE when transmitted to several other species. Such molecular strain typing strongly supported the hypothesis that vCJD was human BSE. This conclusion was strengthened by subsequent transmission studies of vCJD into both transgenic and conventional mice which argued that cattle BSE and vCJD were caused by the same strain.(16,17) Such studies are allowing a molecular classification of human prion diseases. Two such classifications are in use: no internationally agreed classification has yet emerged and it is likely that additional PrPSc types or strains will be identified.(15,18) Molecular classification may well open new avenues of epidemiological investigation and offer insights into causes of ‘sporadic’ CJD. The ability of a protein to encode a disease phenotype has important implications in biology, as it represents a non-Mendelian form of transmission. It would be surprising if this mechanism had not been used more widely during evolution such that prion biology may prove to be of far wider relevance.
typing approach based on these characteristics has allowed the identification of four main types amongst CJD cases, sporadic and iatrogenic CJD being of PrPSc types 1-3, while all vCJD cases are associated with a distinctive type 4 PrPSc type.(14,15) A similar PrPSc type to that seen in vCJD is seen in BSE and BSE when transmitted to several other species. Such molecular strain typing strongly supported the hypothesis that vCJD was human BSE. This conclusion was strengthened by subsequent transmission studies of vCJD into both transgenic and conventional mice which argued that cattle BSE and vCJD were caused by the same strain.(16,17) Such studies are allowing a molecular classification of human prion diseases. Two such classifications are in use: no internationally agreed classification has yet emerged and it is likely that additional PrPSc types or strains will be identified.(15,18) Molecular classification may well open new avenues of epidemiological investigation and offer insights into causes of ‘sporadic’ CJD. The ability of a protein to encode a disease phenotype has important implications in biology, as it represents a non-Mendelian form of transmission. It would be surprising if this mechanism had not been used more widely during evolution such that prion biology may prove to be of far wider relevance.
Transmission of prion diseases between different mammalian species is limited by a so-called ‘species barrier’. Early studies of the molecular basis of the species barrier argued that it principally resided in differences in PrP primary structure between the species from which the inoculum was derived and the inoculated host. Transgenic mice expressing hamster PrP were, unlike wild-type mice, highly susceptible to infection with hamster prions.(19) That most sporadic and acquired CJD occurred in individuals homozygous at PRNP polymorphic codon 129 supported the view that prion propagation proceeded most efficiently when the interacting PrPSc and PrPC were of identical primary structure.(12) However, it has been long recognized that prion strain type affects ease of transmission to another species. Interestingly, with BSE prions the strain component to the barrier seems to predominate, with BSE not only transmitting efficiently to a range of species, but maintaining its transmission characteristics even when passaged through an intermediate species with a distinct PrP gene.(20) The term ‘species-strain barrier’ or simply ‘transmission barrier’ may be preferable.(21) Both PrP amino acid sequence and strain type affect the 3D structure of glycosylated PrP which will presumably, in turn, affect the efficiency of the protein-protein interactions thought to determine prion propagation.
Mammalian PrP genes are highly conserved. Presumably only a restricted number of different PrPSc conformations (that are highly stable and can therefore be serially propagated) will be permissible thermodynamically and will constitute the range of prion strains seen in mammals. While a significant number of different such PrPSc conformations may be possible amongst the range of mammalian PrPs, only a subset of these would be allowable for a given single mammalian PrP. Substantial overlap between the favoured conformations for PrPSc derived from species A and species B might therefore result in relatively easy transmission of prion diseases between these two species, while two species with no preferred PrPSc conformations in common would have a large barrier to transmission (and indeed transmission would necessitate a change of strain type). According to such a conformational selection model(21) of a prion transmission barrier, BSE may represent a thermodynamically highly favoured PrPSc conformation that is permissive for PrP expressed in a wide range of different species, accounting for the remarkable promiscuity of this strain in mammals. Contribution of other components to the species barrier are possible and may involve interacting co-factors which mediate the efficiency of prion propagation, although no such factors have yet been identified.
Additional data has further challenged our understanding of transmission barriers.(22) The assessment of species barriers has relied on the development of a clinical disease in inoculated animals. However, it is now clear that subclinical prion infections are sometimes established on prion inoculation of a second species.(23) Such animals harbour high levels of prion infectivity but do not develop clinical disease during a normal lifespan. The existence of such subclinical carrier states of prion infection has important potential animal and public health implications and argues against direct neurotoxicity of prions.
The transmission barrier between cattle BSE and humans cannot be directly measured but can be modelled in transgenic mice expressing human PrPC, which produce human PrPSc when challenged with human prions. Long-term transmission studies have been carried out using such ‘humanized’ mice to both to characterize the distinct prion strains causing human disease and to model human susceptibility to infection with BSE and other prions.(24) While these transgenic mouse models have been able to faithfully propagate human prion strains(14,16,25) and recapitulate the characteristic neuropathology of vCJD,(26) there are important caveats in extrapolating from such animal models to human susceptibility. However, these studies have found a much higher infection rate in transgenic mice expressing human PrP M129 than mice expressing human PrP V129 when challenged with either BSE or vCJD prions, and demonstrated that BSE prion infection can produce disease phenotypes resembling sporadic CJD infection of these mice and also novel prion strain phenotypes. Most recently, these studies have argued that the vCJD phenotype may only be expressed in the presence of the M form of human PrP.(27) While this would imply that only those humans expressing human PrP M129 may develop the vCJD phenotype, this does not mean that VV individuals are completely resistant to BSE prion infection— but rather that if infected they would show a different phenotype.(27) Modelling of susceptibility of the MV genotype suggests that several different phenotypes, all distinct from vCJD, may be possible when infected with BSE or vCJD prions.(28)
Clinical features and diagnosis
The human prion diseases can be divided aetiologically into inherited, sporadic, and acquired forms with CJD, GSS, and kuru now seen as clinicopathological syndromes within a wider spectrum of disease. Kindreds with inherited prion disease have been described with phenotypes of classical CJD, GSS, and also with other neurodegenerative syndromes including fatal familial insomnia. Some kindreds show remarkable phenotypic variability which can encompass both CJD- and GSS-like cases as well as other cases which do not conform to either CJD or GSS phenotypes and which indeed readily mimic, and are frequently misdiagnosed as, many other neurodegenerative conditions. Inherited prion diseases are a frequent cause of pre-senile dementia and a family history is not always apparent: PRNP should be analysed in all suspected cases of CJD, and considered in all early-onset dementia and ataxias. Cases diagnosed by PRNP analysis have been reported which are not only
clinically atypical but which lack the classical histological features entirely. Significant clinical overlap exists with familial Alzheimer’s disease, Pick’s disease, frontal lobe degeneration of non-Alzheimer type, and amyotrophic lateral sclerosis with dementia. Although classical GSS is described below it now seems more sensible to designate the familial illnesses as inherited prion diseases and then to subclassify these according to mutation. Acquired prion diseases include iatrogenic CJD, kuru, and now vCJD. Sporadic prion diseases at present consist of CJD and atypical variants of CJD. Cases lacking the characteristic histological features of CJD have been transmitted. As there are at present no equivalent aetiological diagnostic markers for sporadic prion diseases to those for the inherited diseases, it cannot yet be excluded that more diverse phenotypic variants of sporadic prion disease exist. The key clinical features and investigations for the diagnosis of prion disease are given in the Table 4.1.4.1.
clinically atypical but which lack the classical histological features entirely. Significant clinical overlap exists with familial Alzheimer’s disease, Pick’s disease, frontal lobe degeneration of non-Alzheimer type, and amyotrophic lateral sclerosis with dementia. Although classical GSS is described below it now seems more sensible to designate the familial illnesses as inherited prion diseases and then to subclassify these according to mutation. Acquired prion diseases include iatrogenic CJD, kuru, and now vCJD. Sporadic prion diseases at present consist of CJD and atypical variants of CJD. Cases lacking the characteristic histological features of CJD have been transmitted. As there are at present no equivalent aetiological diagnostic markers for sporadic prion diseases to those for the inherited diseases, it cannot yet be excluded that more diverse phenotypic variants of sporadic prion disease exist. The key clinical features and investigations for the diagnosis of prion disease are given in the Table 4.1.4.1.
Table 4.1.4.1 Diagnosis of prion disease | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Sporadic prion disease CJD
The core clinical syndrome of classic CJD is of a rapidly progressive multifocal dementia usually with myoclonus. The onset is usually in the 45-75-year age group with peak onset between 60 and 65 years. The clinical progression is typically over weeks progressing to akinetic mutism and death often in 2-3 months. Around 70 per cent of cases die in under 6 months. Prodromal features, present in around a third of cases, include fatigue, insomnia, depression, weight loss, headaches, general malaise, and ill-defined pain sensations. In addition to mental deterioration and myoclonus, frequent additional neurological features include extrapyramidal signs, cerebellar ataxia, pyramidal signs, and cortical blindness. About 10 per cent of cases present initially with cerebellar ataxia.
Routine haematological and biochemical investigations are normal although occasional cases have been noted to have raised serum transaminases or alkaline phosphatase. There are no immunological markers and acute phase proteins are not elevated. Examination of the cerebrospinal fluid is normal 14-3-3 protein is usually elevated in CJD and is a useful adjunct to diagnosis in the appropriate clinical context.(29) It is also positive in recent cerebral infarction or haemorrhage and in viral encephalitis, although these conditions do not usually present diagnostic confusion with CJD. It may also be elevated in rapidly progressive Alzheimer’s disease, which may be difficult to clinically distinguish from CJD. Neuronal specific enolase (NSE) and S-100b may be also elevated although also are not specific for CJD and represent markers of neuronal injury(30,31) Neuroimaging with CT or MRI is crucial to exclude other causes of subacute neurological illness but MRI has become increasingly useful in diagnosis of sporadic CJD, showing high signal in the striatum and/or cerebral cortex in FLAIR or diffusion-weighted images.(32) Cerebral and cerebellar atrophy may be present in longer duration cases. The electroencephalogram (EEG) may show characteristic pseudoperiodic sharp wave activity, which is very helpful in diagnosis but present only in around 70 per cent of cases. To some extent demonstration of a typical EEG is dependent on the number of EEGs performed and serial EEG is indicated to try and demonstrate this appearance.
Prospective epidemiological studies have demonstrated that cases with a progressive dementia, and two or more of the following: myoclonus; cortical blindness; pyramidal, cerebellar, or extrapyramidal signs; or akinetic mutism in the setting of a typical EEG nearly always turn out to be confirmed as histologically definite CJD if neuropathological examination is performed.
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