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Introduction: Human prion diseases are progressive, fatal neurological conditions linked to conformational changes in the structure of the prion protein. Prion diseases may be sporadic (sporadic Creutzfeldt-Jakob disease or sCJD, Sporadic Fatal Insomnia), acquired (variant CJD, iatrogenic CJD, kuru) or genetic (genetic prion disease, gPD). gPD is due to a disease-specific point or octapeptide repeat insertion (OPRI) mutation in the prion protein gene (PRNP). Numerous different PRNP mutations have been described. In some cases of gPD the phenotype may closely resemble that of sCJD, and it can be impossible to distinguish sporadic from genetic cases without genetic screening. The clinico-pathological phenotype of gPD is highly variable, both between different mutations and even within families carrying the same mutation. This variability can be partly explained by a polymorphism at codon 129 of PRNP. Codon 129 encodes either methionine or valine, and the status of both the mutated and wild-type alleles may influence disease susceptibility and phenotype. Codon 129 may also affect the manifestations of sporadic and acquired prion disease. Homozygosity for methionine at codon 129 is over-represented in both sporadic CJD (sCJD) and variant CJD (vCJD); indeed all definite or probable clinical cases of vCJD seen to date have been homozygous for methionine. Other polymorphisms of PRNP have been found in a small number of patients with sporadic and variant CJD. The significance of these polymorphisms has not been fully investigated. It is likely that other, as yet unidentified, genetic factors also play a role in influencing susceptibility to prion diseases and the clinico-pathological phenotype. A recent genome wide association study of vCJD patients found codon 129 to be the main genetic risk factor for vCJD, but did identify other candidate loci that may contribute to disease susceptibility. Work is in progress to carry out genomic screens for other, novel polymorphisms in 309 patients with sCJD and 118 patients with vCJD. Aims: The aims of the work described in this MD thesis are: 1) To review all cases of gPD on the database of the National Creutzfeldt-Jakob Disease Research and Surveillance Unit. The clinico-pathological phenotype, investigative findings and family history will be reviewed in detail. The findings will be compared with those cases of gPD previously described, in particular with cases seen in other European countries. The incidence and prevalence of these diseases in the UK will also be assessed. 2) To review cases of sCJD and vCJD with novel PRNP polymorphisms of uncertain significance. The clinico-pathological phenotype will be reviewed in detail to attempt to establish if these novel polymorphisms exert any influence over disease susceptibility or phenotype. Results: 159 cases of gPD were identified between 1970 and 2009, representing 7.8% of the prion disease (of any type) cases referred to the NCJDRSU over this time period. 17 different PRNP haplotypes were identified: P102L-129M, P105L-129V, A117V-129V, S132I-129M, Y163X, D167G-129M, D178N-129M, D178N-129V, E200K-129M, D202N-129V, V210I-129M, Q212P-129M, 2-OPRI, 4-OPRI, 5- OPRI, 6-OPRI, 7-OPRI. The clinicopathological phenotypes were highly variable and often difficult to distinguish from sCJD. The highest number of cases was caused by the 6-OPRI, most of which belonged to a single kindred. Several cases in the 4-OPRI group were found to share an additional risk allele, rsl029273C. In may be that this mutation is not pathogenic unless this risk allele is also present. This raises the possibility that other as yet unidentified genetic risk factors exist which influence gPD susceptibility and clinicopathological phenotype. Overall 61.4% of cases tested had a positive cerebrospinal fluid (CSF) 14-3-3, 90.0% an elevated SI00b, 23.1% had Magnetic Resonance Imaging (MRI) of the brain showing basal ganglia or cortical high signal, and 18.1% had an electroencephalogram (EEG) showing triphasic periodic complexes. A positive family history of prion disease was present in 57.9% of cases. Discussion: The range of point mutations and OPRI seen in the UK is considerable, but the majority of cases were due to 6-OPRI, E200K, or PI 02L. The UK differs from the rest of the world in that E200K is not the commonest mutation, due to the presence of a large British kindred with the 6-OPRI. Even within the larger kindreds, the clinicopathological phenotype remained very variable. Some distinctive features which may act as pointers towards gPD were found, such as a linear pattern of PrPSc deposition in the cerebellum seen in E200K-129M cases. Analysing the data in the smaller groups should be done with caution, and further large international studies are needed in order to truly determine the influence of factors such as codon 129 status. As with other forms of prion disease, there is an excess of individuals with methionine homozygosity at codon 129. It is unclear whether or not PRNP mutations in cis with valine at codon 129 will result in prion disease at an older age or with a different phenotype, or if these are not actually pathogenic in this genetic context. In the case of 4-OPRI, it appears that an additional risk allele is required for the development of disease, and it remains to be seen if other additional genetic factors will be found to influence disease susceptibility and phenotype. A relatively small percentage of cases had EEGs showing periodic triphasic waves, or basal ganglia or cortical high signal on MRI. CSF SI00b was more sensitive than 14-3-3, the reverse of the pattern seen in sCJD. A pattern of a negative 14-3-3 and a very high SI00b should lead to suspicions of gPD. The current diagnostic criteria for gPD are relatively strict, and may exclude some individuals who have neuropathologically confirmed prion disease (without PRNP genotyping) and several second degree relatives with gPD. This is a potential problem, especially as the neuropathological appearances cannot be relied upon to distinguish sporadic from genetic disease. Particular attention should be paid to the family history and any subtle unusual neuropathological appearances to try and reduce the risk of gPD cases being missed. In conclusion, gPD remains a difficult condition to diagnose and study. Large systematic collaborative studies are essential to increase our understanding of these rare conditions. |
