Human prion diseases in The Netherlands : clinico-pathological, genetic and molecular aspects

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are invariably fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. In humans, TSEs comprise three major groups showing a wide phenotypic heterogeneity: Creutzfeldt-Jakob disease (CJD), Gerstmann-Str䵳sler-Scheinker (GSS) disease and fatal insomnia (FI). In The Netherlands, a national surveillance program was established in 1997 to monitor the incidence of both existing and emerging forms of prion diseases, in particular new variant CJD (vCJD), which is causally related to bovine spongiform encephalopathy (BSE) in cattle. The aim of the work described in this thesis is to describe the clinical, neuropathological, genetic and prion protein characteristics of all 162 patients with neuropathologically confirmed prion diseases in The Netherlands, diagnosed over a 12-year period (1998-2009). Since 1998, there has been a relatively stable incidence of Creutzfeldt-Jakob disease (CJD) in The Netherlands, ranging from 0.63 to 1.53 per million inhabitants per annum. Genetic analysis of the codon 129 methionine/valine (M/V) polymorphism in the prion protein gene in all patients with sporadic CJD (sCJD) showed an over-representation of the MV genotype (22.4%) and an under-representation of VV (7.0%) cases, compared with sCJD cohorts in other Western countries. Combined biochemical and histopathological typing studies identified all sCJD subtypes known to, except for the VV1 subtype. In particular, a “pure” phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. The relative excess of MV cases was largely accounted for by a relatively high incidence of the MV 2K subtype. Genetic analysis of the prion protein gene (PRNP) was performed in 161 patients and showed a mutation in 9 of them (5.6%), including one familial FI and four GSS cases. Four mutations had not been described before, including two insertional mutations and two very rare nonsense mutations (Y226X and Q227X, the latter confirming that the absence of the glycosylphosphatidylinositol anchor in the prion protein predisposes to amyloid plaque formation). Iatrogenic CJD was a rare phenomenon (3.1%), mainly associated with dura mater grafts. Three patients were diagnosed with vCJD (1.9%) and one with the recently described variably protease-sensitive prionopathy. Post-mortem examination revealed an alternative diagnosis in 156 patients, most commonly Alzheimer’s disease (21.2%) or vascular causes of dementia (19.9%). Many of these patients had been referred on the basis of a positive 14-3-3 protein assay in cerebrospinal fluid or because of electro-encephalogram findings suggestive of CJD, indicating that care must be taken in the interpretation of such ancillary investigations. The incidence and mortality rates of sCJD in The Netherlands are similar to those in other European countries, whereas iatrogenic and genetic cases are relatively rare. The unusual incidence of the MV 2K and VV2 sCJD subtypes deserves further investigation. The results of the studies presented in this thesis not only provide important epidemiological data for the Dutch population, but also add to an increasing body of knowledge with respect to molecular and genetic determinants of phenotypic variability in human prion diseases