Type 1 protease resistant prion protein and valine homozygosity at codon 129 of PRNP identify a subtype of sporadic Creutzfeldt-Jakob disease

A man was studied with sporadic Creutzfeldt-Jakob disease (sCJD) who had serial cortical syndromes evolving over 15 months without significant ataxia, prominent myoclonus, or periodic complexes on EEG examinations. This clinical phenotype correlated with a predominantly cortical and striatal distribution of lesions and accumulation of protease resistant prion protein with relative sparing of the brainstem or cerebellum. No amyloid plaques were seen and prion protein (PrP) immunohistochemistry only demonstrated very faint granular deposits in the cerebral cortex. Molecular analysis showed homozygosity for valine at codon 129 in the prion protein gene (PRNP) and protease resistant prion protein type 1 deposition. The comparison of molecular and clinicopathological features of the present case with those previously reported in sCJD, indicates that valine homozygosity at codon 129 and type 1 protease resistant prion protein are associated with a distinct phenotypic variant of sCJD. The data also support the view that the PRNP codon 129 polymorphism and the physicochemical properties of the protease resistant prion protein are major determinants of phenotypic variability in sCJD.     

MRI characteristics of sporadic CJD with valine homozygosity at codon 129 of the prion protein gene and PrPSc type 2 in Japan

Two Japanese sporadic Creutzfeld-Jakob disease (sCJD) patients with valine homozygosity at codon 129 of the prion protein gene and protease-resistant prion protein (PrP(Sc)) type 2 (VV2) are described. In contrast with Western countries, this type of sCJD is very rare in Japan. In 123 sCJD cases, only two were recognised as VV2 by the Japanese CJD surveillance committee. The clinical symptoms and pathological findings of the patients were similar to those of European and US patients. The noteworthy finding of diffusion weighted MRI (DWI) was that an abnormal high intensity covered a wide range of the thalamus including the dorsomedial nucleus, the pulvinar, and the ventral anterior, lateral, and posterolateral nuclei. This thalamic pattern has not been recognised in sCJD with methionine homozygosity and PrP(Sc) type 1 (MM1) or methionine/valine heterozygosity and PrP(Sc) type 1 (MV1) which comprises the vast majority of sCJD. This finding may be characteristic to VV2 and may distinguish it from MM1, MV1, and variant CJD. DWI can provide a very important clue for the antemortem diagnosis of VV2 subjects.     

散发性克-雅病PrP基因129密码子基因型与临床表型14例研究

目的：探讨散发性克－雅病（Creutzfeldt-Jakob disease,CJD)PrP基因129位点密码子基因型与临床表型的关系。方法：对14例散发性CJD患者进行PrP基因129例密码子的检测，并与临床表现进行了分析。结果：（1）根据诊断标准，14例散发性CJD中8例诊断为肯定CJD，6例诊断为很可能CJD。（2）8例诊断肯定CJD组中，PrP基因129例位点密码子为甲硫氨酸纯合型6例，甲充氨酸／缬氨酸2例，6例诊断很可能CJD组的PrP基因129密码子均为甲硫氨酸纯合型。（3）12例PrP基因129位点为甲硫氨酸纯合型的患者以认知障碍起病8例，共济失调1例；视觉障碍2例；肌阵挛1例，病程最长20个月，最短2．5个月，病程中有癫痫5例，肌阵挛6周，视觉障碍6例。7例有典型周期性同步放电（PSD）脑电改变。（4）2例甲硫氨酸／缬氨型患者均以共济失调起病。2个月后才出现痴呆，病理程分析为16个月和20个月，均无典型的PSD。（2）本组散发性CJDPrP基因129位点密码子甲硫氨酸／甲硫氨酸，甲硫氨酸／缬氨酸，分布比例与日本相同，但与西方不同，而且没有缬氨酸纯合型。     

Creutzfeldt-Jakob disease, prion protein gene codon 129VV, and a novel PrPSc type in a young British woman

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is an acquired prion disease causally related to bovine spongiform encephalopathy that has occurred predominantly in young adults. All clinical cases studied have been methionine homozygotes at codon 129 of the prion protein gene (PRNP) with distinctive neuropathological findings and molecular strain type (PrP(Sc) type 4). Modeling studies in transgenic mice suggest that other PRNP genotypes will also be susceptible to infection with bovine spongiform encephalopathy prions but may develop distinctive phenotypes. OBJECTIVE: To describe the histopathologic and molecular investigation in a young British woman with atypical sporadic CJD and valine homozygosity at PRNP codon 129. DESIGN: Case report, autopsy, and molecular analysis. SETTING: Specialist neurology referral center, together with the laboratory services of the MRC [Medical Research Council] Prion Unit. Subject Single hospitalized patient. MAIN OUTCOME MEASURES: Autopsy findings and molecular investigation results. RESULTS: Autopsy findings were atypical of sporadic CJD, with marked gray and white matter degeneration and widespread prion protein (PrP) deposition. Lymphoreticular tissue was not available for analysis. Molecular analysis of PrP(Sc) (the scrapie isoform of PrP) from cerebellar tissue demonstrated a novel PrP(Sc) type similar to that seen in vCJD (PrP(Sc) type 4). However, this could be distinguished from the typical vCJD pattern by an altered protease cleavage site in the presence of the metal ion chelator EDTA. CONCLUSIONS: Further studies will be required to characterize the prion strain seen in this patient and to investigate its etiologic relationship with bovine spongiform encephalopathy. This case illustrates the importance of molecular analysis of prion disease, including the use of EDTA to investigate the metal dependence of protease cleavage patterns of PrP(Sc).     

A novel phenotype in familial Creutzfeldt-Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein.

A novel phenotype of familial Creutzfeldt-Jakob disease (CJD) with mutated codon 200 of the prion protein gene (PRNP) coupled with the valine codon 129 (E200K-129V haplotype) has two features never observed in subjects carrying the pathogenic mutation coupled with the methionine codon 129 (E200K-129M haplotype): (1) plaque-like prion protein (PrP) deposits in the cerebellum and (2) type 2 protease-resistant prion protein (PrP(res)). This observation further underlines the role of codon 129 on the mutated PRNP allele in modulating the phenotype of familial prion diseases.     

Autopsy case of Creutzfeldt–Jakob disease with Met/Val heterozygosity at codon 129 and type 1 protease‐resistant prion protein presenting some florid‐type plaques and many Kuru plaques in the cerebellum

We report an atypical case of CJD. The clinical course was similar to a classic CJD phenotype, but histopathological study revealed several florid‐type plaques in the amygdale and abundant Kuru plaques in the cerebellum that are atypical of classic CJD. Molecular analysis showed methionine/valine heterozygosity at codon 129 and no pathogenic mutation in the coding region of the prion protein gene. Western immunoblots revealed type 1 protease‐resistant prion protein (PrPres), and a ration analysis of PrPres showed a high ratio of the diglycosylated form and a low ratio of the non‐glycosylated form. Our case could not be precisely classified in any of Parchi’s six variants. It suggests the existence of some factors that determine the phenotypic variability other than the codon 129 genotypes in the PrP gene or the physicochemical properties of PrPres.     

Distinctive cerebellar immunoreactivity for the prion protein in familial (E200K) Creutzfeldt-Jakob disease

We have compared the immunomorphological spectrum of the deposition of the disease-associated prion protein (PrP(Sc)) in the cerebral and cerebellar cortex of 32 Creutzfeldt-Jakob disease (CJD) patients with the PrP gene (PRNP) E200K mutation to 45 sporadic CJD and 14 other genetic prion disease cases. PrP deposits correlate with the genotype at the methionine/valine (MV) polymorphic codon 129. While the diffuse/synaptic and patchy/perivacuolar PrP deposits and PrP plaques have a similar distribution and correlation with the genotype at codon 129 as in sporadic CJD, an additional peculiar PrP immunostaining pattern occurs in the cerebellum in 81% E200K mutation brains including 93% of M129M, 71% of M129V, but not in the single V129V case. It is localized to the molecular layer and consists of coarse granular PrP deposits arranged in a stripe-like manner predominantly perpendicular to the surface, closely resembling the parasagittal arborization of climbing fibers. Our results suggest that (1) the type of PrP deposits in the cerebellum may suggest genetic disease and the need for genetic testing; and (2) the peculiar stripes of PrP deposits might reflect selective vulnerability of cerebellar structures.     

Inherited prion disease caused by the V210I mutation: transmission to transgenic mice.

OBJECTIVE: To describe the clinical and neuropathologic profile and determine the strain characteristics of familial Creutzfeldt-Jakob disease (fCJD) caused by a point mutation of the PRNP gene at codon 210 that results in a valine-to-isoleucine substitution in the prion protein (PrP). METHODS: The clinicopathologic features of four individuals from the United States who died of fCJD(V210I) were compared. Transgenic (Tg) mice expressing a chimeric human-mouse PrP transgene were inoculated with brain extracts from three fCJD(V210I) cases, sporadic CJD (sCJD), fCJD(E200K), and fatal familial insomnia (FFI), to compare prion strain characteristics. RESULTS: The clinicopathologic profile of fCJD(V210I) was variable among cases but shared similarities with sCJD. The pattern of PrP(Sc) deposition in the brains of Tg mice was similar to that caused by sCJD but different from that associated with fCJD(E200K) or FFI. CONCLUSIONS: Each of these prion diseases is characterized by a rapidly progressive dementia with myoclonus, periodic complexes on EEG, and spongiform change without PrP plaque deposition in the brain. The occurrence of a different PrP(Sc) phenotype with each PRNP mutation argues that each respective amino acid sequence substitution produces a different prion strain.     

Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA

The current classification of human sporadic prion diseases recognizes six major phenotypic subtypes with distinctive clinicopathological features, which largely correlate at the molecular level with the genotype at the polymorphic codon 129 (methionine, M, or valine, V) in the prion protein gene and with the size of the protease-resistant core of the abnormal prion protein, PrP(Sc) (i.e. type 1 migrating at 21?kDa and type 2 at 19?kDa). We previously demonstrated that PrP(Sc) typing by Western blotting is a reliable means of strain typing and disease classification. Limitations of this approach, however, particularly in the interlaboratory setting, are the association of PrP(Sc) types 1 or 2 with more than one clinicopathological phenotype, which precludes definitive case classification if not supported by further analysis, and the difficulty of fully recognizing cases with mixed phenotypic features. In this study, we tested the inter-rater reliability of disease classification based only on histopathological criteria. Slides from 21 cases covering the whole phenotypic spectrum of human sporadic prion diseases, and also including two cases of variant Creutzfeldt-Jakob disease (CJD), were distributed blindly to 13 assessors for classification according to given instructions. The results showed good-to-excellent agreement between assessors in the classification of cases. In particular, there was full agreement (100?%) for the two most common sporadic CJD subtypes and variant CJD, and very high concordance in general for all pure phenotypes and the most common subtype with mixed phenotypic features. The present data fully support the basis for the current classification of sporadic human prion diseases and indicate that, besides molecular PrP(Sc) typing, histopathological analysis permits reliable disease classification with high interlaboratory accuracy.     

Sporadic Creutzfeldt-Jakob disease in a young Dutch valine homozygote: atypical molecular phenotype

A case of sporadic Creutzfeldt-Jakob disease (sCJD) is described in a young Dutch protein prion gene (PRNP) codon 129 valine homozygote. Certain clinical and molecular features of this case overlap those of variant CJD. The case highlights possible difficulties in the differential diagnosis of vCJD and the more rare sCJD subtypes based on molecular features alone.     

A traceback phenomenon can reveal the origin of prion infection

The transmission of prions to animals with incongruent prion protein (PrP) gene (referred to as cross‐sequence transmission) results in a relatively long incubation period and can generate a new prion strain with unique transmissibility designated as a traceback phenomenon. For example, cross‐sequence transmission of bovine spongiform encephalopathy (BSE) prions to human generated variant Creutzfeldt‐Jakob disease (vCJD) prions which retained the transmissibility to mice expressing bovine PrP. This finding suggests that traceback studies could enable us to identify the origin of prions. There are two distinct phenotypes in dura mater graft‐associated Creutzfeldt‐Jakob disease (dCJD), with the majority represented by a non‐plaque‐type of dCJD (np‐dCJD) and the minority by a plaque‐type of dCJD (p‐dCJD). To identify the origin of p‐dCJD, we performed a traceback study using mice expressing human PrP with methionine homozygosity (129M/M) or valine homozygosity (129V/V) at polymorphic codon 129. The characteristics of p‐dCJD such as the accumulation of abnormal isoform of PrP (PrP^Sc) intermediate in size between type 1 and type 2, and plaque‐type PrP deposition in the brain were maintained after transmission to the 129M/M mice. Furthermore, the 129V/V mice were more susceptible to p‐dCJD prions than the 129M/M mice and produced type 2 PrP^Sc that were identical in size to those from the 129V/V mice inoculated with sporadic CJD prions from a patient with 129V/V and type 2 PrP^Sc (sCJD‐VV2). In addition, we performed intracerebral transmission of sCJD‐VV2 prions to the 129M/M mice as an experimental model for p‐dCJD. These 129M/M mice showed the accumulation of the intermediate type PrP^Sc and plaque‐type PrP deposition in the brain. These results suggest that p‐dCJD could be caused by cross‐sequence transmission of sCJD‐VV2 prions to individuals with the 129M/M genotype.     

A novel phenotype of sporadic Creutzfeldt-Jakob disease

An atypical case of sporadic Creutzfeldt-Jakob disease (CJD) is described in a 78-year-old woman homozygous for methionine at codon 129 of the prion protein (PrP) gene. The neuropathological signature was the presence of PrP immunoreactive plaque-like deposits in the cerebral cortex, striatum and thalamus. Western blot analysis showed a profile of the pathological form of PrP (PrP(Sc)) previously unrecognised in sporadic CJD, marked by the absence of diglycosylated protease resistant species. These features define a novel neuropathological and molecular CJD phenotype.     

Clinical and genetic features of human prion diseases in Catalonia: 1993–2002

We describe the clinical and genetic characteristics of the 85 definite or probable human prion diseases cases died between January 1993 and December 2002 in Catalonia (an autonomous community of Spain, 6 million population). Seventy-three (86%) cases were sporadic Creutzfeld-Jakob diseases (sCJD) (49 definite, 24 probable), with a median age at onset of 66 years. The clinical presentation was dementia in 29 cases, ataxia in 14 and visual symptoms in five. The median survival was 3 months. The 14-3-3 assay was positive in 93% cases, 62% presented periodic sharp wave complexes (PSWC) in EEG but only 18% the typical signs on MRI. Forty-eight sCJD were studied for codon 129 PRNP polymorphism: 69% were methionine/methionine (M/M), 14.5% valine/valine (V/V) and 16.5% M/V. Six out of seven V/V cases did not present PSWC and in two survival was longer than 20 months. Eleven cases (13%) were genetic: five familial fatal insomnia and six familial CJD (fCJD). Up to four (67%) fCJD lacked family history of disease, two presented seizures early at onset and one neurosensorial deafness. The only iatrogenic case was related to a dura mater graft. No case of variant CJD was registered. The study confirms in our population the consistent pattern reported worldwide on human prion diseases. Atypical features were seen more frequently in sporadic 129 V/V CJD and fCJD cases.     

Sporadic Creutzfeldt-Jakob disease with MM1-type prion protein and plaques

The authors report a 75-year-old woman with atypical sporadic Creutzfeldt-Jakob disease (CJD) characterized by MM1-type prion protein (PrP) (methionine homozygosity at codon 129 in the PrP gene and type-1 protease-resistant PrP) and PrP plaques. This patient is the first case of sporadic CJD with plaque-forming MM1-type PrP, suggesting either a shared prion strain with the plaque-forming subset of dural graft-associated CJD or shared host genetic factors that are unrelated to the PrP genotype.     

Clinicopathological phenotype of codon 129 valine homozygote sporadic Creutzfeldt-Jakob disease

The naturally occurring polymorphism at codon 129 of the human prion protein gene (PRNP) influences susceptibility to sporadic Creutzfeldt-Jakob Disease (CJD); the majority of the patients are methionine homozygotes at this locus, while valine homozygotes represent only 10% of cases. The aim was to study the clinical and neuropathological phenotype of sporadic CJD in valine homozygotes, to estimate the reliability of current clinical diagnostic criteria, and to identify any consistent and distinct features. Twelve cases of sporadic CJD with a codon 129 valine homozygote genotype were identified at the National CJD Surveillance Unit in Edinburgh. In addition to a retrospective clinical analysis, tissue blocks were stained by conventional techniques and by immunocytochemistry for prion protein. Frozen brain tissue was available from five cases for Western blot analysis of PrPRES, which in all cases showed a type 2 mobility. The cases included four males and eight females, average age 63.6 years, with a mean duration of illness of 6 months. Eleven patients presented with ataxia, and none had the characteristic EEG changes found in sporadic CJD. The neuropathological phenotype comprised spongiform change and prion protein immunopositivity most marked in the subcortical grey matter and cerebellum, prion protein positive plaque-like deposits in all regions, laminar deposition of prion protein in the cerebral cortex, and hippocampal involvement (which is seldom reported in sporadic CJD). In conclusion, these cases exhibited a fairly uniform phenotype, which is relatively distinct from sporadic CJD in methionine homozygotes, and thus diagnosis may be difficult using existing clinical criteria.     

A subtype of sporadic prion disease mimicking fatal familial insomnia.

OBJECTIVE: To establish a variant of sporadic prion disease as the sporadic form of fatal familial insomnia (FFI). BACKGROUND: FFI is a recently described prion disease characterized clinically by severe sleep impairment, dysautonomia, and motor signs, and pathologically by atrophy of thalamic nuclei, especially the medial dorsal and anterior ventral, and of the inferior olive. FFI is linked to the D178N mutation coupled with the methionine codon at position 129 in the prion protein gene (PRNP). It is also identified by the properties of the abnormal prion protein (PrP(Sc)), which has the relative molecular mass of 19 kDa, corresponding to the so-called type 2, and a marked underrepresentation of the unglycosylated form relative to the diglycosylated and monoglycosylated forms. METHODS: Clinical, pathologic, PrP(Sc), and PRNP data from 5 subjects with a sporadic prion disease phenotypically similar to FFI were collected and analyzed. RESULTS: All 5 subjects had a disease clinically similar and histopathologically virtually identical to FFI. PrP(Sc) type 2 was present in all subjects in amount and distribution similar to those of FFI. However, the PrP(Sc) did not show the striking underrepresentation of the unglycosylated isoform of the protein that is characteristic of FFI. Moreover, none of the subjects had the D178N PRNP mutation but all were homozygous for methionine at codon 129. CONCLUSION: This condition is likely to represent the sporadic form of FFI and the term "sporadic fatal insomnia" is proposed.     

Increased incidence of sporadic Creutzfeldt-Jakob disease on the island of Crete associated with a high rate of PRNP 129-methionine homozygosity in the local population

Since the spring of 1997, when the Neurology Department of the University Hospital of Crete admitted its first patient, nine cases (eight neuropathologically confirmed and one probable) of sporadic Creutzfeldt-Jakob disease (sCJD) have been recorded. This represents an annual incidence five-fold higher than expected based on the island's population (0.54 million). Molecular analysis of the prion-protein gene (PRNP) showed no mutations in any of the seven CJD cases studied. Five patients (ages 64-88 years) were homozygous for methionine-129 of PRNP and showed the classic sCJD triad (subacute dementia, myoclonus, periodic electroencephalogram). Brains contained type 1 (unglycosylated 21.5 kDa band) protease-resistant prion protein (PrPres). Two patients (ages 56 and 57 years), both homozygous for valine-129, showed cerebellar ataxia and later dementia not associated with periodic electroencephalogram; brain PrPres was type 2. Genotyping of 205 Cretan controls showed that methionine-129 homozygosity, a susceptibility factor for sCJD, was significantly higher in this population than in other Caucasian populations (57.0% n = 205 vs. 41.5% n = 859, p < 0.0001). These data are the first to relate a high regional incidence rate for sCJD to the distribution of PRNP 129 genotypes in the local population; however, additional factors may be operational.     

Molecular basis of phenotypic variability in sporadc creudeldt-jakob disease

We sequenced the prion protein gene and studied the biochemical characteristics and the intracerebral distribution of protease-resistant prion protein with Western blot and immunohistochemistry in 19 cases of sporadic Creutzfeldt-Jakob disease. We identified four groups of subjects defined by the genotype at codon 129 of the prion protein gene, the site of a common methioninelvaline polymorphism, and two types of protease-resistant prion proteins that differed in size and glycosylation. The four Creutzfeldt-Jakob disease groups showed distinct clinicopathological features that corresponded to previously described variants. The typical Creutzfeldt Jakob disease phenotype or myoclonic variant and the Heidenhain variant were linked to methionine homozygosity at codon 129 and to “type 1” protease-resistant prion protein. The atypical and rarer variants such as that with dementia of long duration, the ataxic variant, and the variant with kuru plaques were linked to different genotypes at codon 129 and shared the “type 2” protease-resistant prion protein. Our data indicate that the sporadic form of Creutzfeldt-Jakob disease comprises a limited number of variants. The methionine/valine polymorphism at codon 129 of the prion protein gene and two types of protease-resistant prion proteins are the major determinants of these variants. These findings suggest the existence of prion strains in humans and provide the molecular basis for a novel classification of sporadic Creutzfeldt-Jakob disease.     

EEG in Creutzfeldt-Jakob disease.

Electroecenphalography (EEG) is an integral part of the diagnostic process in patients with Creutzfeldt-Jakob disease (CJD). The EEG has therefore been included in the World Health Organisation diagnostic classification criteria of CJD. In sporadic CJD (sCJD), the EEG exhibits characteristic changes depending on the stage of the disease, ranging from nonspecific findings such as diffuse slowing and frontal rhythmic delta activity (FIRDA) in early stages to disease-typical periodic sharp wave complexes (PSWC) in middle and late stages to areactive coma traces or even alpha coma in preterminal EEG recordings. PSWC, either lateralized (in earlier stages) or generalized, occur in about two-thirds of patients with sCJD, with a positive predictive value of 95%. PSWC occur in patients with methionine homozygosity and methionine/valine heterozygosity but only rarely in patients with valine homozygosity at codon 129 of the prion protein gene. PSWC tend to disappear during sleep and may be attenuated by sedative medication and external stimulation. Seizures are an uncommon finding, occurring in less than 15% of patients with sCJD. In patients with iatrogenic CJD, PSWC usually present with more regional EEG findings corresponding to the site of inoculation of the transmissible agent. In genetic CJD, PSWC in its typical form are uncommon, occurring in about 10%. No PSWC occur in EEG recordings of patients with variant CJD.     

Clinical range and MRI in Creutzfeldt-Jakob disease with heterozygosity at codon 129 and prion protein type 2.

A 68 year old woman with sporadic Creutzfeldt-Jakob disease is described, who neither showed characteristic EEG abnormalities nor a positive test of the neuronal protein 14-3-3 or neuron specific enolase (NSE) in CSF, despite a clinical presentation with ataxia of cerebellar type, rapidly progressive dementia, myoclonus, and marked hyperintense signal abnormalities in the deep cortical layers and the basal ganglia on T2 and diffusion weighted MRI. Moreover she showed atypical clinical features with a syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) and a peripheral sensorimotor polyneuropathy. Whether these disturbances are independent of Creutzfeldt-Jakob disease or a feature of it is discussed. It has recently been shown that in Creutzfeldt-Jakob disease different clinical and pathological phenotypes correlate with the polymorphism at codon 129 of the prion protein gene (PRNP) and the type of the protease resistant fragment that accumulates in the brain. According to the new classification at least six sporadic variants of Creutzfeldt-Jakob disease exist. The molecular genetic analysis showed heterozygosity of PRNP at codon 129 for methionine and valine and the presence of PrP(CJD) type 2 in the brain of this patient. As a new feature of changes on MRI, striking cortical changes of hyperintense signals are described in diffusion weighted as well as T2 weighted MRI that directly correlate with the histomorphological spongy degeneration of the brain in this region. In cases of rapidly progressive dementia, Creutzfeldt-Jakob disease always needs to be considered even if unusual features are present and current diagnostic criteria are not in favour of this disease.