Using this system, we found a new mutation of the PrP gene in a patient with pathologically confirmed Creutzfeldt-Jakob disease and a negative family history for dementia.
Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrP(Sc) type 2 and methionine homozygosity.
Gerstmann-Sträussler-Scheinker syndrome caused by the P102L mutation in the prion protein gene (GSS102) is usually characterized by the onset of slowly progressive cerebellar ataxia, with dementia occurring much later.
GSS and PrP-CAA are associated with point mutations of the prion protein gene (PRNP); these conditions show a broad spectrum of clinical presentation, the main signs being ataxia, spastic paraparesis, extrapyramidal signs and dementia.
There was a significant correlation between clinical symptoms and the neuroanatomical distribution of prion protein-immunoreactive aggregates, i.e. subtentorial predominance in ataxia vs cortical predominance in dementia.
Investigation of these patients, including two with neuropathologically verified AD and one with post-mortem confirmed CJD, did not reveal an alternative aetiology for their dementia.
This variant GSS with codon 105 mutation has been found in four pedigrees, only in Japan up to the present, and the clinicopathological phenotype is summarized as follows: (1) onset at age 38-48, with a duration of 7-11 years, (2) prominent spastic paraparesis, associated with dementia and ataxia, (3) numerous amyloid plaques in the cerebral cortex, (4) amorphous PrP deposits with neuronal loss in the deep cortical layers, and (5) minor change of cerebellum.
Moreover, since selective thalamic dementia with the PrP 178Asn mutation and fatal familial insomnia share clinical and histopathologic features, we propose that they are the same disease.
We developed gene panel based technologies to assess 16 genes known to harbour mutations causal of dementia and combined these with PCR based assessments of the C9orf72 hexanucleotide repeat expansion and the octapeptide repeat region of PRNP.
In this study, we screened the PRNP gene to evaluate the frequency of PRNP mutations and their correlations with clinical phenotype in 185 sporadic neurodegenerative dementia cases and 310 control subjects.
The APOBEC-related mutations were higher in healthy controls than in cases suffering from neurodegeneration, with the exception of the dementia group with the prion protein gene (PRNP) MV genotype.
Patients with an alternative diagnosis and those with sCJD were of similar age, sex and frequency of dementia but CJD mimics had a longer clinical history.