Variably protease‐sensitive prionopathy: A new sporadic disease of the prion protein

Abstract

Objective The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Methods Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Results Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with “variably protease-sensitive prionopathy” (VPSPr). None of the subjects had mutations in the PrP gene coding region. Interpretation Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease.

Variably protease‐sensitive prionopathy presenting within ALS/FTD spectrum

“…The patient who presented primary with ALS carried MM at PRNP codon 129 while the patient with FTD‐ALS was VV. In VPSPr, the most frequent genotype is VV (65%) and 60% of patients may have symptoms mimicking FTD 1. In contrast, among less frequent genotypes, MV (23%) and MM (12%), motor signs are more common.…”

“…Typical clinical features include rapidly progressive dementia, cerebellar, extrapyramidal, pyramidal, and visual signs. In 2008, a novel sporadic variably protease‐sensitive prionopathy (VPSPr) was described 1. VPSPr differs from classical CJD in its clinical presentation with prominent aphasia, ataxia, and parkinsonian signs; a longer disease duration of up to 45 months; and by a unique ladder‐like electrophoretic profile of proteinase K (PK)‐resistant PrP sc fragments 1.…”

“…In 2008, a novel sporadic variably protease‐sensitive prionopathy (VPSPr) was described 1. VPSPr differs from classical CJD in its clinical presentation with prominent aphasia, ataxia, and parkinsonian signs; a longer disease duration of up to 45 months; and by a unique ladder‐like electrophoretic profile of proteinase K (PK)‐resistant PrP sc fragments 1. Despite the frequent finding of pyramidal signs in CJD,2, 3, 4 we are not aware of reports of VPSPr presenting simultaneous upper and lower motor neuron (MN) dysfunction, as in ALS, and as we present here.…”

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study

“…However, the sensitivity and specificity of such testing during the pre-clinical incubation period or in chronic carriers (who may have a distinct pathogenesis which conceivably might not involve the same degree of lymphoreticular colonization) are unknown. Although peripheral tissue involvement in recently identified cases of variable protease-sensitive prionopathy [42][43][44][45] has not yet been defined, the apparent rarity of this condition would not be expected to confound estimates of UK vCJD prevalence.…”

Modeling Amyloid Diseases in Fruit Fly Drosophila Melanogaster

“…However, increasing evidence argues against the neurotoxicity of PrP Sc . Significant pathology and/or clinical dysfunction develop with little accumulation of PrP Sc [Flechsig et al, 2000;Manson et al, 1999] and some familial prion diseases are not transmissible, and are not accompanied by the accumulation of protease resistant PrP [Brown et al, 1994;Rodríguez-Martínez et al, 2010;Tateishi & Kitamoto, 1995;Zou et al, 2010]. Thus, it is not clear whether specific conformers are associated with neuronal dysfunction and degeneration [Solomon et al, 2010].…”