Prion diseases

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Prion diseases

The designation of prion diseases as a distinct nosologic category is based on the elucidation of a novel molecular pathology that is common to several disorders previously known as spongiform encephalopathies, unconventional viral infections, or transmissible dementias. These include the following human diseases:

Common to all of these diseases are:


The prion diseases have a common molecular pathology that involves the conversion of a normal cellular protein called prion protein (PrP) into an abnormal isoform (Fig. 32.1). Most evidence implicates the abnormal protein as the transmissible factor; evidence is lacking for the involvement of DNA or RNA in the infective process.



Agent of transmissible spongiform encephalopathy (TSE) with unconventional properties. The term does not have structural implications other than that a protein is an essential component

PrPC or PrP sen

The naturally occurring form of the mature PRNP gene product. Its presence in a given cell type is necessary, but not sufficient, for replication of the prion. The terms PrPC (cellular PrP) and PrPsen (proteinase-sensitive) are both used (Fig. 32.2).

PrPSc (other terms PrP res or PrPCJD)

‘Abnormal’ form of the mature Prnp gene product (Fig. 32.3). Partly resistant to digestion by proteinase K. Believed to differ from PrPC conformationally. Often considered to be the transmissible agent or prion. The designations PrPSc (from scrapie, the spongiform encephalopathy of sheep); PrPCJD (CJD-associated PrP); PrPres (protease resistant); PrP*, and PrPP have all been used for this form of PrP.

‘Protein-only’ hypothesis

This maintains that the prion is devoid of informational nucleic acid, and that the essential pathogenic component is protein (or glycoprotein). Genetic evidence indicates that the protein is an abnormal form of PrP. The association with other non-informational molecules (such as lipids or glycosaminoglycans) is not excluded.

PrP in normal function and disease

PrPC (‘cellular’ PrP)

In prion disease PrPSc (abnormal, disease-associated PrP) accumulates within cells, and also outside cells in the form of amyloid.

image The accumulated PrPSc is abnormal in that it is relatively resistant to degradation in vitro by proteinase K – this property is the basis of detection of abnormal PrP by immunohistochemical techniques.

image According to the template-directed refolding hypothesis (Fig. 32.4), exogenously added PrPSc serves as a template for the conversion of PrPC into more PrPSc. This conformational change is kinetically controlled in that a high activation-energy barrier prevents spontaneous conversion at detectable rates.

image The seeding (or nucleated crystallization) model (Fig. 32.4) hypothesizes that the conversion is reversible. PrPSc stabilizes when it form a crystal-like seed. Once a seed is formed, further monomers add rapidly.

image Mutations in PrPC increase the likelihood of conversion to PrPSc although as familial TSEs arise quite late in life this presumably remains a relatively rare event. Sporadic CJD may also come about through spontaneous conversion of PrPC to PrPSc, although the likelihood of this occurring is much lower. In both cases the formation of PrPSc initiates a conversion cascade.

Prion strains

Distinct prion strains can be identified with characteristic patterns of CNS pathology and distinct incubation times. Such strains can be stably propagated in experimental animals that are homozygous for their PrP genes (Fig. 32.5).

Differences in the pattern of PrP glycosylation

Research has revealed variations in the pattern of PrP glycosylation in CJD and in spongiform encephalopathies in animals. Western blot analysis of PrP from affected brain tissue shows three bands, corresponding to protein with two, one, or no attached polysaccharide chains (Fig. 32.6).


32.6 Glycoforms of PrP and electrophoretic patterns of prion protein in western blots. Left: PrP has two glycosylation sites and can exist in diglycosylated, monoglycosylated and unglycosylated forms. During the conversion to PrPSc, the glycans (glycosylation trees) are preserved. Right: To detect PrPSc in a Western blot, the tissue homogenate (which contains both PrPC and PrPSc) needs to be treated with proteinase K to digest the protease-sensitive PrPC but retain the partially protease resistant PrPSc, leaving a fragment of approximately 142 amino acids. Separation of the ~142-AA fragment by western blotting reveals three bands. The types of PrPSc can be further characterized according to the amino acid – methionine (M) or valine (V) – that is encoded at position 129 in PrP by each of the patient’s two PRPN alleles. The combination of electrophoretic mobility and codon 129 genotyping allows discrimination between different types human of CJD: types 1, 2, 3 or MM1/VV1 and MM2/MV2/VV2 are seen in sporadic CJD, Kuru and iatrogenic CJD, while a distinct, highly characteristic diglycosylation-dominant banding pattern is seen in vCJD, in BSE and other forms where BSE prions were transmitted accidentally or experimentally (type 4 or type MM2B). This diglycosylation-dominant banding pattern is regarded as strong evidence that BSE is the origin of vCJD. Variable glycotype patterns can be found in a single patient. A large, detailed study of 4200 samples from 200 brains showed that two types of PrP coexist in about 35% of sCJD cases. PrPSc types 1 and 2 co-occur more frequently in the MM than in the MV or VV genotypes. These molecular findings correlate to some extent to the histological phenotype. (Adapted from Parchi P, Strammiello R, Notari S, et al. Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification. Acta Neuropathol 2009; 118:659–671)

After deglycosylation, the underlying PrP fragment is generally of one of two sizes, running at 19 or 21 kDa. On the basis of size and glycosylation pattern, several types of PrPSc can be distinguished which are associated with different clinical and pathologic patterns of disease.

Prion diseases occur in several mammalian species in addition to man, the most notable being scrapie in sheep and bovine spongiform encephalopathy (BSE) in cattle.

In approximately 85% of cases, human prion diseases are sporadic. Rarely, prion disease is transmitted by accidental inoculation during a therapeutic procedure (iatrogenic CJD), or by endocannibalism (Kuru). In about 15% of cases, prion diseases are inherited in an autosomal dominant fashion.

The commonest phenotype of prion disease is CJD. Patients typically present with subtle motor signs, which herald severe cerebellar ataxia, and progress to global dementia in under 1 year. Criteria for the clinical diagnosis of CJD have been proposed and widely adopted (Table 32.1).

Several phenotypes of prion disease other than CJD have been identified (Table 32.2). In all of these, the mainstay of diagnosis is clinical examination supplemented by additional radiologic, electrophysiologic and neuropathologic investigations (Table 32.3).

Many patients in the late stage of neurodegenerative disease develop myoclonus, but the length of the history usually contrasts with the rapid progression of classic CJD. Some patients who have dementia with cortical Lewy bodies deteriorate rapidly and develop myoclonus, in which case CJD enters the clinical differential diagnosis. The possibility that many cases of dementia of uncertain etiology or dementia with atypical features may be due to undiagnosed prion disease is not supported by comprehensive necropsy studies.


Several point mutations and insertions have been identified in the PrP gene that increase the susceptibility of PrP to assume a pathologic conformation (Fig. 32.7).

Nomenclature of PrP gene mutations

This takes the form of disease phenotype (original amino acid, codon position, substituted amino acid), for example GSS (P102L).

Polymorphism at codon 129 acting as a susceptibility factor

In addition to these pathogenic mutations, a polymorphism at codon 129 (which codes for either valine or methionine) acts as a susceptibility factor, modulating the facility with which PrPC assumes an abnormal conformation when interacting with exogenous abnormal PrPP (see below). The frequency of this polymorphism in Caucasian populations is:

In the Japanese population the frequency is:

In studies of the PrP genotype in sporadic CJD, over 90% of cases are homozygous for either M or V at 129, suggesting that this homozygosity confers relative susceptibility to disease. 100% of patients diagnosed with vCJD are MM at codon 129. Having the same amino acid at this position may facilitate conversion of PrPC to PrPP when they interact. In familial disease the clinical and pathological phenotype can be affected by codon 129 (see fatal familial insomnia, below). It remains uncertain whether individuals who are 129 VV or MV will ever develop vCJD and, if they did, whether the clinical pattern of disease would be different from that of the presently characterized 129 MM cases.


The severity of abnormalities varies. In most cases, the pathologic changes described below are moderate to marked. Rarely, no abnormalities are demonstrable by standard histologic techniques. The neuropathologic manifestations depend upon whether the disease is sporadic, familial, or iatrogenic, and are modified by the nature of the PrP gene defect (if familial) and the codon 129 PrP genotype, and by the duration of the illness.


The brain may appear macroscopically normal, even in cases with long clinical histories. Most cases, however, show some atrophy (Fig. 32.8) and this may be severe, with a reduction in brain weight to as low as 850 g. In such cases, ventricular enlargement is marked and the atrophy often includes the caudate nucleus and thalamus. The hippocampus may be relatively spared, even in cases with severe atrophy elsewhere.

Atrophy of the cerebellar folia is common and the brain stem may appear atrophic in some cases. In general, loss of brain substance appears to be confined to the gray matter, and white matter is relatively spared, although this is not always the case (see panencephalopathic CJD, below). Meninges and blood vessels appear normal.