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Variably Protease-Sensitive Prionopathy. Emerg Infect Dis 20: 2006–2014.) Handbook of Clinical Neurology, Vol. 153 (3rd series) Human Prion Diseases M. Pocchiari and J. Manson, Editors https://doi.org/10.1016/B978-0-444-63945-5.00010-6 Copyright © 2018 Elsevier B.V. All rights reserved Chapter 10 Variably protease-sensitive prionopathy SILVIO NOTARI1, BRIAN S. APPLEBY1,2,3,4, AND PIERLUIGI GAMBETTI1* 1Department of Pathology, Case Western Reserve University, Cleveland, OH, United States 2National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, United States 3Department of Neurology, Case Western Reserve University, Cleveland, OH, United States 4Department of Psychiatry, Case Western Reserve University, Cleveland, OH, United States Abstract Variably protease-sensitive prionopathy (VPSPr), originally identified in 2008, was further characterized and renamed in 2010. Thirty-seven cases of VPSPr have been reported to date, consistent with estimated prevalence of 0.7–1.7% of all sporadic prion diseases. The lack of gene mutations establishes VPSPr as a sporadic form of human prion diseases, along with sporadic Creutzfeldt–Jakob disease (sCJD) and spo- radic fatal insomnia. Like sCJD, VPSPr affects patients harboring any of the three genotypes, MM, MV, and VVat the prion protein (PrP) gene polymorphic codon 129, with VPSPr VVaccounting for 65% of all VPSPr cases. Distinguishing clinical features include a median 2-year duration and presentation with psy- chiatric signs, speech/language impairment, or cognitive decline. Neuropathology comprises moderate spongiform degeneration, PrP amyloid miniplaques, and a target-like or plaque-like PrP deposition. The abnormal PrP associated with VPSPr typically forms an electrophoretic profile of five to seven bands (according to the antibody) presenting variable protease resistance depending on the 129 genotype. The familial prion disease associated with the V180I PrP gene mutation which harbors an abnormal PrP with similar electrophoretic profile might serve as a model for VPSPr. Transmission to animals has definitively established VPSPr as a prion disease. Because of its recent identification, rarity, and the elusiveness of its abnormal PrP, VPSPr remains largely understudied. INTRODUCTION immunohistochemical techniques. However, they were negative following biochemical analysis by gel electro- Variably protease-sensitive prionopathy (VPSPr) was TSE phoresis and immunoblotting of PrP , a test that is typ- originally described in 2008 based on a study of 11 US ically performed following treatment with proteinase subjects (Gambetti et al., 2008). The identification of this TSE K (PK) given the common PrP protease resistance rare and clinically rather indistinct novel condition, in prion diseases. Enhanced analyses demonstrated the and its prompt independent validation that followed, TSE presence of a peculiar form of PrP that was particu- was made possible by the existence of many national larly sensitive to PK digestion and displayed a distinctive prion surveillance centers worldwide dedicated to the multiple-band profile upon immunoblotting. examination and tissue banking of prion diseases. Genetic analysis established that all subjects were During regular examination of acquired cases at the homozygotes for the codon valine (V) at position 129 US National Prion Disease Pathology Surveillance of the prion protein (PrP) gene, the site of a common Center (NPDPSC), it was noted that in rare but recurring and nonpathogenic methionine polymorphism, M129V cases, brain tissues tested positive for the presence of (Parchi et al., 1999; Gambetti et al., 2003, 2011). More- abnormal, disease-related prion protein (PrPTSE)by over, no mutation was found in and adjacent to the coding *Correspondence to: Pierluigi Gambetti, Department of Pathology, Case Western Reserve University, Cleveland, OH, USA. E-mail: [email protected] 176 S. NOTARI ET AL. region of the PrP gene where genetic mutations reside in estimated that VPSPr accounts for one death per 4 years inherited prion diseases, thus defining VPSPr as a spo- in the 60 million UK population. Adding together the radic prion disease (Gambetti et al., 2003, 2008; Kong unpublished cases stored by the US and UK prion sur- et al., 2004). A subsequent study (Zou et al., 2010) veillance centers brings the total number of known reporting 15 additional cases from the United States VPSPr cases worldwide to at least 77. However, it is and Italy established that all three M129V genotypes, likely that VPSPr is underreported, given that in most MM, MV, and VV, not just VV, were affected in VPSPr. cases it is initially misdiagnosed as one of the non- This property makes VPSPr the only sporadic human Alzheimer dementias, conditions in which autopsies prion disease that affects the three 129 genotypes besides are not regularly performed (Puoti et al., 2012). sporadic Creutzfeldt–Jakob disease (sCJD) (Chapter 9). This second study also revealed that PrPTSE resistance to DEFINITION PK treatment varied according to the 129 genotype. This finding led to the amendment of the disease label VPSPr is a novel sporadic prion disease, which may from the original protease-sensitive prionopathy (PSPr) account for almost 2% of all sporadic prion diseases. – in the first 2008 publication to the current VPSPr Similar to sporadic Creutzfeldt Jakob disease (sCJD), (Gambetti et al., 2008; Zou et al., 2010). VPSPr affects individuals harboring each of the three Two additional VPSPr features emerged. First, VPSPr genotypes at codon 129 of the PrP gene, thus segregating prevalence in the three 129 genotypes was found to be VPSPr into three subtypes: MM, MV, and VV. The MM 11%, MV 24%, VV 65% (Table 10.1), which is almost M129V genotype slightly affects disease phenotype TSE the opposite of that associated with sCJD (MM 68%, MV and PrP features. Overall, mean age at onset is 16%, VV 16%) (Collins et al., 2006), indicating that the 70 and duration 2 years. Clinical presentation often role played by the 129 genotype is different in the two dis- includes one or more of three sets of signs: psychiatric eases.Second, severalVPSPrpatients haveafamily history abnormalities, speech/language impairment, and cogni- of cognitive impairment, which raises the possibility of a tive decline (Table 10.1). Histopathologic features genetic component in VPSPr. Unfortunately, no genetic include moderate cortical and subcortical spongiform or neuropathologic examination has been performed on degeneration (SD) and miniplaques in the cerebellum, cognitively impaired relatives of VPSPr patients. while PrP immunostaining often reveals a distinctive target-like granular pattern. Depending on the antibody used, PrPTSE forms a five- or seven-band ladder-like EPIDEMIOLOGY electrophoretic profile with increasing protease resis- To date, 37 cases of VPSPr have been published. They tance from VV to MM subtypes. include 25 from the United States (Gambetti et al., 2008; Zou et al., 2010; Cannon et al., 2014), five from CLINICAL FEATURES the United Kingdom (Head et al., 2009, 2010, 2013); Demographics two each from Italy and Spain (Giaccone et al., 2007; Rodríguez-Martínez et al., 2010, 2012; Zou et al., VPSPr is unique given its departure from the clinical 2010), and one each from Austria, Germany, and The aspects typically observed in other human prion diseases. Netherlands (Krebs et al., 2007; Jansen et al., 2010; The clinical diagnosis of VPSPr is difficult because of its Assar et al., 2015). One of the US cases was diagnosed nonspecific clinical presentation and noncontributory incidentally at autopsy of a 93-year-old neurologically diagnostic tests that are typically suggestive of prion asymptomatic individual (Ghoshal et al., 2015). As for disease. the M129V polymorphic genotype, the 37 cases include The polymorphism at codon 129 of the PrP gene 24 VV homozygotes, nine MV heterozygotes, and four affects many aspects of this prion disease, including sus- MM homozygotes. In addition, the US NPDPSC lists a ceptibility to the disease, age at onset, illness duration, total of 57 cases of VPSPr (inclusive of the 25 published) clinical symptoms, and diagnostic test results from a total of 3279 sporadic prion disease cases, which (Table 10.2). Contrary to sCJD, the majority of VPSPr would estimate the VPSPr prevalence at 1.7% among all cases are homozygous for valine at codon 129 (65%), sporadic prion diseases (US National Prion Disease and the minority are homozygous for methionine Pathology Surveillance Center, 2017). Thirteen VPSPR (11%) (Table 10.2). VPSPr is typically a mid- to late-life cases are stored by the National CJD Surveillance and illness with a mean age at onset of 70 years (range 48–87 Research Unit in the United Kingdom, which by the years) (Puoti et al., 2012). The presence of valine at same calculation would result in a 0.7% prevalence of codon 129 seemingly has a dose–effect relationship VPSPr there (UK National CJD Research and toward a younger age at onset (mean age at onset: Surveillance Unit, 2017). Head et al. (2013) have VV ¼ 67, MV ¼ 74, MM ¼ 78 years) (Table 10.2). Table 10.1 Classification of variably protease-sensitive prionopathy Clinical feature Histopathology SDa PrP immunostaining patterna 129 Onset Course subtype N (years) (months) Type of presentationb C. cort BG Cereb C. cortex Cereb MMc 366 56 Parkinsonian, ataxic, cognitive ++ ++ + Granular, plaque-like of various sizes Granular, small (55–78) (41–78) plaque-like MV 9 73 Æ 37 Psychiatric, parkinsonian, +++ +++ Æ Fine granular with rarer larger granule or Amyloid (65–81)
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