Abstract
A national system for surveillance of prion diseases (PrDs) was established in Japan in April 1999. Here, we analyzed the relationships among prion protein gene (PRNP) mutations and the clinical features, cerebrospinal fluid (CSF) markers, and pathological characteristics of the major genotypes of genetic PrDs (gPrDs). We retrospectively analyzed age at onset and disease duration; the concentrations and incidences of 14-3-3 protein, tau protein, and abnormal prion protein (PrPSc) in the CSF of 309 gPrD patients with P102L, P105L, E200K, V180I, or M232R mutations; and brain pathology in 32 autopsied patients. Three clinical phenotypes were seen: rapidly progressive Creutzfeldt-Jakob disease (CJD), which included 100% of E200K cases, 70% of M232R, and 21% of P102L; slowly progressive CJD, which included 100% of V180I and 30% of M232R; and Gerstmann-Sträussler-Scheinker disease, which included 100% of P105L and 79% of P102L. PrPSc was detected in the CSF of more than 80% of patients with E200K, M232R, or P102L mutations but in only 39% of patients with V180I. V180I was accompanied by weak PrP immunoreactivity in the brain. Patients negative for PrPSc in the CSF were older at disease onset than positive patients. Patients with mutations associated with high 14-3-3 protein levels in the CSF typically had synaptic deposition of PrP in the brain and a rapid course of disease. The presence of small PrP protein fragments in brain homogenates was not correlated with other clinicopathological features. Positivity for PrPSc in the CSF may reflect the pathological process before or at disease onset, or abnormality in the secretion or metabolism of PrPSc. The amount of 14-3-3 protein in the CSF likely indicates the severity of the pathological process and accompanying neuronal damage. These characteristic features of the CSF in cases of gPrD will likely facilitate accurate diagnosis and clinicopathological study of the various disease subtypes.
Highlights
Genetic prion diseases are classified into three major phenotypes: fatal familial insomnia (FFI), Gerstmann-StrausslerScheinker disease (GSS), and genetic Creutzfeldt-Jakob disease
The range in median age at onset was wider for our patients than was that of genetic PrDs (gPrDs) patients in European countries [2]; our youngest group of patients was 44.3 years at an average disease onset, and our oldest group of patients was 76.5 years at an average (Figure 1A and Table S2)
Clinical variation is observed, more than 60% of the gPrD cases we examined had mutations of V180I, P105L, and M232R; these mutations were mostly reported from Japan [3]
Summary
Genetic prion diseases (gPrDs) are classified into three major phenotypes: fatal familial insomnia (FFI), Gerstmann-StrausslerScheinker disease (GSS), and genetic Creutzfeldt-Jakob disease (gCJD). These diseases are characterized by disease-specific mutations in the prion protein gene (PRNP), some of which are inherited in an autosomal dominant fashion. The frequency of gPrDs and the proportion of each PRNP mutation differ from country to country. In Japan, where a nationwide surveillance system for PrDs was established in April 1999, a 10year review of PrDs was published in 2010 [3]. Several of the mutations detected, namely V180I, P105L, and M232R, are seen almost exclusively in patients from Japan
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