Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification

Abstract

Six subtypes of sporadic Creutzfeldt-Jakob disease with distinctive clinico-pathological features have been identified largely based on two types of the abnormal prion protein, PrP Sc , and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein. The existence of affected subjects showing mixed phenotypic features and concurrent PrP Sc types has been reported but with inconsistencies among studies in both results and their interpretation. The issue currently complicates diagnosis and classification of cases and also has implications for disease pathogenesis. To explore the issue in depth, we carried out a systematic regional study in a large series of 225 cases. PrP Sc types 1 and 2 concurrence was detected in 35% of cases and was higher in MM than in MV or VV subjects. The deposition of either type 1 or 2, when concurrent, was not random and always characterized by the coexistence of phenotypic features previously described in the pure subtypes. PrPSc type 1 accumulation and related pathology predominated in MM and MV cases, while the type 2 phenotype prevailed in VVs. Neuropathological examination best identified the mixed types 1 and 2 features in MMs and most MVs, and also uniquely revealed the cooccurrence of pathological variants sharing PrP Sc type 2. In contrast, molecular typing best detected the concurrent PrP Sc types in VV subjects and MV cases with kuru plaques. The present data provide an updated disease classification and are of importance for future epidemiologic and transmission studies aimed to identify etiology and extent of strain variation in sporadic Creutzfeldt-Jakob disease.

Drug resistance confounding prion therapeutics

“…However, the rapid acquisition of IND24 resistance and the strainspecific efficacy of the compounds, combined with the observation that some CJD patients may harbor more than one prion strain (reviewed in ref. 37), indicate that a single therapeutic agent may not be sufficient to treat individuals with prion diseases.…”

Imaging of prion diseases

“…The abnormal protein accumulates in the intra and/or the extra-cellular compartments and induces neuronal dysfunction. On histological examination, the four major human subtypes of prion diseases, sCJD, GSS, FI and vCJD exhibit similar neuropathological features namely spongiform degeneration of the gray matter neuronal loss, gliosis, and deposits of insoluble PrP Sc ; with varying degrees of severity and anatomical distribution (4). The term spongiform is used to describe vacuoles representing focal swellings of axonal and dendritic neuronal processes.…”

“…Another factor is the protein type, either 1 or 2, based on the pattern of migration on Western blot after limited proteolysis. These two variables taken together provide the basis for the molecular classification into six subtypes of CJD, which correlates with different clinical, paraclinical, and neuroimaging presentations (Table 2) (4,6,7). This molecular classification is still evolving and a new classification has been recently proposed taking into account the fact that the two main types of prion proteins may coexist (4).…”

“…However, other neurological symptoms may confound the initial clinical diagnosis, such as weakness, extrapyramidal symptoms, alien hand syndrome, sensory and visual disturbances (1). Nonspecific symptoms including fatigue, headache, sleep disturbance, vertigo, and behavioral changes may precede the development of frank progressive cognitive decline (1,4). Other less frequent patterns of clinical presentation are also recognized, among them the Heidenhain variant is known for the predominant visual symptoms preceding the emergence of other clinical manifestations ( Fig.…”

Glycosylphosphatidylinositol Anchoring Directs the Assembly of Sup35NM Protein into Non-fibrillar, Membrane-bound Aggregates

“…The cross-␤ arrangement yields characteristic reflections by fiber diffraction and typically stains with the amyloid-specific dyes Thioflavin T or S and Congo Red (17)(18)(19)(20). In most instances, PrPSc is membrane-bound as granular, diffuse, nonfibrillar structures, with amyloid plaques only manifesting in certain TSE diseases, such as kuru, Gerstmann-StrausslerScheinker disease, variant Creutzfeldt-Jakob disease, and a minority of sporadic Creutzfeldt-Jakob disease cases (14,(21)(22)(23)(24)(25). The effect of GPI anchoring of PrP on TSE pathogenesis and infectivity has been investigated using a transgenic mouse that expresses PrPC lacking a GPI anchor (26,27).…”