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Title: Clinico-pathological phenotypes of sporadic CJD in relation to PpPres type
Author: Mackay, Graham
ISNI:       0000 0004 2745 7553
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2012
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Introduction: Sporadic CJD (sCJD) has a varied clinical and pathological phenotype. This variability is felt to be influenced by patients' genotype at codon 129 on the prion protein gene (PRNP); and has associations with PrPres protein type. There is a polymorphism at codon 129 of PRNP, which results in three genotypes (MM, MV, VV). Additionally, the protease resistant protein (PrPres) seen in patients with CJD can also be classified according to certain biochemical characteristics. The protein types are determined by their mobility on western blot electrophoresis and their degree of glycosylation (type 1, 2a, 2b). In 1996, Parchi and Gambetti categorised cases by sub-types relating to these findings (broadly speaking: MM1, MM2, MV1, MV2, VV1 and VV2) suggesting this as an explanation for the clinical and pathological diversity of the condition (Parchi 1996). Relatively recently a significant minority of patients have been found to have both PrPres protein types present in the brain. Two recent papers have proposed a revised classification system, taking into account the co-occurrence phenomenon, suggesting there are further distinct groups of patients with sCJD (Cali 2009, Parchi 2009). Methods: 108 patients referred to the UK CJD surveillance system, confirmed to have had sporadic CJD at post-mortem, were included in the study. All cases had PRNP genetic analysis to exclude genetic CJD and establish their codon 129 status. Biochemical analysis of disease-associated prion protein via western blot was undertaken in the temporal, parietal and occipital lobes and the thalamus in all patients. A structured assessment of the clinical features seen both at presentation and during the patients' illness was undertaken. A summary of the pathological findings for the patients was also recorded. The clinical and pathological features were then analysed for the relative influence of the codon 129 genotype, protein typing and the combination of the two as the revised sub-type, according to the 2009 Parchi classification system. Results: 26 out of 108 patients had mixed PrP isotypes on western blot analysis. On comparing the most common of these mixed groups [MM 1(+2)] with those patients with the same genotype and predominant protein type [MM1], there were subtle differences in the clinical phenotype and pattern of investigation results. However, the major clinical findings were the same. In general, there was a trend towards increased disease duration with increasing relative ratios of type 2 proteins. On reviewing the pathological findings there were no findings unique to any genotype-isotype sub-group. Conclusions: While there were differing trends, the lack of distinct clinical or pathological findings by genotype-isotype sub-type suggest that these groups do not represent unique strains of prions, but rather groupings over a spectrum of disease. Therefore, more detailed biochemical analysis leading to a revised classification may be more accurate, but currently adds limited useful extra clinical information.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Creutzfeldt-Jakob disease