Human prion diseases

Human prion disease models have also been developed in mice [154,155]. Crossing the species barrier into an experimentally accessible animal system, the prions responsible for Creutzfeldt Jakob disease, new variant CJD, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia produce a reproducible time-dependent neuronal degeneration leading to death. 

Keohane C. The human prion diseases. A review with special emphasis on new variant CJD and comments on surveillance. Clin Exp Pathol 1999 47 125-132. 

Human prion disease most commonly presents with a sporadic etiology 793... 

Acquired human prion diseases include kuru and variant CJD 794 Prion protein polymorphism contributes genetic susceptibility to prion disease 794... 

Distinct PrPSc types are seen in human prion disease 799... 

The prion diseases are a closely related group of neuro-degenerative conditions which affect both humans and animals. They have previously been described as the subacute spongiform encephalopathies, slow virus diseases and transmissible dementias, and include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and the human prion diseases, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and kuru. Prion diseases are... 

Human prion diseases encompass the three etiological types of prion disease inherited, sporadic and acquired forms. 

Acquired human prion diseases include kuru and variant... 

Fig. 2. Primary structure of hamster PrP (Stahl et al., 1993). The first 22 residues at the N-terminus are the signal sequence. PrPc is completely digested by proteinase K, whereas the N-terminal sequence of PrPSc to residue 89 (arrow, closed head) is digested. — CHO indicates the glycosylation sites at residues 181 and 197 Gpi the glycosylpho-sphatidylinositol anchor at 231 and the N-terminal octarepeats. In one case of human prion disease, a stop codon was found at 145 (arrow, open head) (Kitamoto et al., 1993). HI, H2, H3, and H4 denote the predicted a-helices (Huang et al, 1994, 1996), and A-C denote the a-helices and SI, S2 the /(-strands determined by solution NMR (James et al, 1997).

Fig. 3. Classification of human prion diseases. Sporadic the transformation from PrPc (circle) to PrPSc (square) occurs without apparent cause. Familial a point mutation ( ) is thought to facilitate the transformation. Infectious the transformation arises via PrPSc which acts as a template. The kinetic equations are defined by Eigen (1996). The infectious form includes kuru, iatrogenic CJD (iCJD), variant CJD (vCJD first reported in 1996), bovine spongiform encephalopathy (BSE first reported in 1985), and scrapie. In the nucleation-dependent model, monomeric PrPc and PrPSc are in chemical equilibrium.

The human prion diseases include CJD, kuru, Gerstmann-Straussler-Scheinker (GSS), and fatal insomnia, which can be classified into three groups based on etiology (Table 29.1). 

Table 29.1. Origin and prevalence of tire human prion diseases.

Biochemical characterization of Prps<> reveals heterogeneity in the polypeptide patterns among the human prion diseases and this has been useful for the molecular classification of PrP " (reviewed by Gambetti et al., 2003). Limited proteinase K... 

Among the human prion diseases, Pi-p " polypeptide fragments can vary in number (typically 1 to 3), molecular weight, and the ratio of the three glycoforms. Based on these criteria, Prps<" is classified into three operational groups called type 1, type 2 (a and b), and GSS-type (Table 29.2, Figure... 

Epidemiology and Clinical Features of Human Prion Diseases... 

The sCJDMMl/sCJDMVl subtype displays either MM or MV at PrP codon 129 and type 1 PrP It is the most common subtype and accounts for 60-70% of all sporadic human prion disease. This sCJD subtype has a mean age at clinical onset of 65 years of age and the mean duration of clinical symptoms prior to death is approximately four months. The symptoms at clinical presentation can include cognitive impairment, widened gait or ataxia, behavioral signs (including depression, anxiety. 

The sCJDW2 subtype has a W at PrP codon 129 and type 2 PrP It is the second most common form of sCJD and accounts for 16% of all sporadic human prion disease. The mean age at onset is 60 years and the mean duration of the clinical phase is six months. Ataxia is the most common presenting symptom for this subtype. At later stages, dementia almost always develops and is accompanied by myoclonus and pyramidal signs. PSW on EEG is rare and CSF 14-3-3 is positive in 80% of cases. 

The sCJDWl subtype has W at PrP codon 129 and type 1 PrP % and it accounts for 1% of the sporadic cases. The mean age at onset is 39 years and the mean clinical duration is 15 months. This younger age of clinical onset is unusual for a sporadic human prion disease and more closely resembles the age of onset that is characteristic in vCJD. This subtype shows dementia at the early clinical stages and is followed by myoclonus and pyramidal signs. There is no PSW on EEG and the CSF 14-3-3 is positive in all cases tested. 

The familial prion diseases are inherited in an autosomal dominant manner and account for 10-15% of all human prion disease. They include familial CID (fCJD), GSS, and fatal familial insomnia (FH) (reviewed by Gambetti et al., 2003 and by Kong et al., 2003). The familial prion diseases are caused by pathogenic mutations in the PRNP coding sequence. To date, these include 24 mis-sense mutations that result in amino... 

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