http://repub.eur.nl/res/aut/32889/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/31240/ 2011-08-01T00:00:00Z A rare case of Gerstmann-Sträussler-Scheinker disease in a 36-year-old Dutch man is reported. The clinical phenotype was characterized by slowly progressive cognitive decline, later followed byataxia and parkinsonism. Neuropathologic findings consisted of numerous amyloid plaques in the cerebellum, which showed positive staining for the abnormal prion protein (PrPSc). In addition, there were tau accumulations around numerous amyloid deposits in the cerebral cortex, striatum, hippocampal formation, and midbrain. There was nospongiform degeneration. Western blot analysis showed the co-occurrence of 2 distinct abnormal prion protein species comprising anunglycosylated, protease-resistant fragment of approximately 8 kd, which was found to be truncated at both N- and C-terminal ends by epitope mapping, and a detergent-insoluble but protease-sensitive form of full-length PrPSc. Sequence analysis disclosed a mutation at codon 131 of the prion protein gene (PRNP), resulting in a valine-for-glycine substitution (G131V). The patient was heterozygous at the polymorphic codon 129 and carried the mutation on the methionine allele. To our knowledge, this is the second family worldwide in which this mutation has been identified. Gerstmann-Sträussler-Scheinker disease should be considered in patients with a clinical diagnosis of familial frontotemporal dementia. Copyright http://repub.eur.nl/res/pub/27388/ 2010-02-01T00:00:00Z Stop codon mutations in the gene encoding the prion protein (PRNP) are very rare and have thus far only been described in two patients with prion protein cerebral amyloid angiopathy (PrP-CAA). In this report, we describe the clinical, histopathological and pathological prion protein (PrPSc) characteristics of two Dutch patients carrying novel adjacent stop codon mutations in the C-terminal part of PRNP, resulting in either case in hereditary prion protein amyloidoses, but with strikingly different clinicopathological phenotypes. The patient with the shortest disease duration (27 months) carried a Y226X mutation and showed PrP-CAA without any neurofibrillary lesions, whereas the patient with the longest disease duration (72 months) had a Q227X mutation and showed an unusual Gerstmann-Sträussler-Scheinker disease phenotype with numerous cerebral multicentric amyloid plaques and severe neurofibrillary lesions without PrP-CAA. Western blot analysis in the patient with the Q227X mutation demonstrated the presence of a 7 kDa unglycosylated PrPScfragment truncated at both the N- and C-terminal ends. Our observations expand the spectrum of clinicopathological phenotypes associated with PRNP mutations and show that a single tyrosine residue difference in the PrP C-terminus may significantly affect the site of amyloid deposition and the overall phenotypic expression of the prion disease. Furthermore, it confirms that the absence of the glycosylphosphatidylinositol anchor in PrP predisposes to amyloid plaque formation. http://repub.eur.nl/res/pub/24909/ 2009-12-01T00:00:00Z An atypical case of inherited Creutzfeldt-Jakob disease (CJD) is described in a 35-year-old Dutch woman, homozygous for methionine at codon 129 of the prion protein gene (PRNP). The clinical phenotype was characterised by slowly progressive cognitive decline and parkinsonism. Neuropathological findings consisted of scanty spongiosis and only faint to absent immunohistochemical staining for the abnormal prion protein, PrPSc, with patchy deposits in the cerebellar cortex. Purkinje cells were abnormally located in the molecular layer of the cerebellum. Western blot analysis showed the cooccurrence of PrPSctypes 1 and 2 with an unusual distribution. Sequence analysis disclosed a novel 120 bp insertion in the octapeptide repeat region of the PRNP, encoding five additional R2 octapeptide repeats. These features define an unusual neuropathological phenotype and novel genotype, further expanding the spectrum of genotype-phenotype correlations in inherited prion diseases and emphasising the need to carry out pre-mortem PRNP sequencing in all young patients with atypical dementias.