Creutzfeldt-Jakob disease in a patient with an R208H mutation of the prion protein gene (PRNP) and a 17-kDa prion protein fragment

A case of Creutzfeldt-Jakob disease (CJD) with a rare mutation of the prion protein (PrP) gene (PRNP) at codon 208 (R208H) is described. By comparison with two preceding reports, the case described here displayed two distinct biochemical and neuropathological features. Western blot analysis of brain homogenates showed, in addition to the commonly observed three bands of abnormal protease-resistant PrP isoform (PrP^Sc), an additional band of about 17 kDa. Neuropathological examination of the post mortem brain revealed tau pathology in the hippocampus and entorhinal cortex, as well as ballooned neurons in the cortex, hippocampus and subcortical gray matter.     

The Braak hypothesis in prion disease with a focus on Creutzfeldt–Jakob disease

This review considers whether the Braak hypothesis on protein propagation could account for prion disease, particularly Creutzfeldt–Jakob disease (CJD). In CJD, we can speculate on the pathological onset region to some degree in reference to the clinical symptoms and magnetic resonance imaging findings. Although relating the Braak hypothesis to prion disease is not straightforward, the following could be proposed based on experimental and previously reported case observations. Pathogenic abnormal prion protein (PrP) deposition in the central nervous system (CNS) probably begins several months or years before clinical symptom onset, signifying the potentiality of a preclinical stage, similar to α-synuclein deposition in Parkinson's disease (PD) and amyloid-β/tau deposition in Alzheimer's disease (AD). Unlike in PD and AD, the initial clinical symptoms of CJD vary by case, and thus the onset lesions must also be various and multiple in the CNS. Based on the pathological findings, particularly of PrP deposition extensively observed in the CNS gray matter of autopsy cases, it could be speculated that in the early disease stage, including the preclinical stage, abnormal PrP spreads from the onset region without directionality or hierarchy. Because each CNS region shows either vulnerability to or resistance against PrP deposition and pathological progression in prion disease, the lesion distribution shows system degeneration. Although pathologically combined cases of type 1 and type 2 PrP patterns are often recognized, type 1 and type 2 PrP patterns must never shift toward each other during the disease course; in other words, the original type of PrP deposition in each region presumably remains unchanged in each case. According to the several observations and corresponding speculations, there are at least partial similarities between prion disease and protein propagation, as explained by the Braak hypothesis, in terms of pathological lesion progression, but several noted contradictions preclude the hypothesis from comprehensively accounting for prion disease.     

Prion disease with a 144 base pair insertion: unusual cerebellar prion protein immunoreactivity

Sporadic, acquired, and genetic human prion diseases are characterized neuropathologically by distinct deposition patterns of the abnormal, disease-associated form of the prion protein (PrP^sc). In addition to mutations in the prion protein gene (PRNP), PrP^sc immunostaining patterns correlate with molecular phenotypes of prion diseases defined by the PRNP polymorphism at codon 129 and with protease-resistant PrP classified by Western blotting. Some point or insertional PRNP mutations share similar clinical and neuropathological phenotypes, whereas others show great variability even within the same family. Here we report a patient who presented clinically as sporadic Creutzfeldt-Jakob disease (CJD). Histologically moderate spongiform change was seen in cerebral and cerebellar cortical areas. Neuronal loss was restricted mainly to the occipital cortex and the basal ganglia. Surprisingly, numerous eosinophilic globular structures were noted in the molecular layer and the parahippocampal gyrus. These globules showed intense PrP immunopositivity using anti-PrP antibodies against different epitopes. They were stained with PAS but lacked congophilia and birefringence in polarized light. Ultrastructurally, globules were composed of 21-nm-thick intermingled filaments without dense core. Genetic analysis revealed a PRNP 144 base pair insertion. Our case reinforces the importance of molecular genetic diagnosis, especially in those patients who lack a family history of prion disease and show unusual neuropathological changes. It also widens the phenotypic spectrum of prion diseases. The phenotypic variability within the same mutation suggests further, yet uncharacterized, genetic or epigenetic influence on phenotype in these diseases.     

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.     

Prion protein amyloidosis with divergent phenotype associated with two novel nonsense mutations in PRNP

Stop codon mutations in the gene encoding the prion protein (PRNP) are very rare and have thus far only been described in two patients with prion protein cerebral amyloid angiopathy (PrP-CAA). In this report, we describe the clinical, histopathological and pathological prion protein (PrP^Sc) characteristics of two Dutch patients carrying novel adjacent stop codon mutations in the C-terminal part of PRNP, resulting in either case in hereditary prion protein amyloidoses, but with strikingly different clinicopathological phenotypes. The patient with the shortest disease duration (27 months) carried a Y226X mutation and showed PrP-CAA without any neurofibrillary lesions, whereas the patient with the longest disease duration (72 months) had a Q227X mutation and showed an unusual Gerstmann-Sträussler-Scheinker disease phenotype with numerous cerebral multicentric amyloid plaques and severe neurofibrillary lesions without PrP-CAA. Western blot analysis in the patient with the Q227X mutation demonstrated the presence of a 7 kDa unglycosylated PrP^Sc fragment truncated at both the N- and C-terminal ends. Our observations expand the spectrum of clinicopathological phenotypes associated with PRNP mutations and show that a single tyrosine residue difference in the PrP C-terminus may significantly affect the site of amyloid deposition and the overall phenotypic expression of the prion disease. Furthermore, it confirms that the absence of the glycosylphosphatidylinositol anchor in PrP predisposes to amyloid plaque formation.     

Creutzfeldt–Jakob disease with E200K PRNP mutation: a case report and revision of the literature

Creutzfeldt–Jakob disease (CJD) is typically characterized by rapidly progressive dementia and myoclonus, and it is caused by a conformational change of the prion protein. The heritable forms are associated with mutation in the gene encoding the prion protein (PRNP). We report a 63-year-old Italian woman harboring the E200K PRNP mutation. Electroencephalogram, cerebrospinal fluid analysis, PRNP gene sequencing, histopathologic examination, immunohistochemical studies, and Western blotting analysis confirmed the diagnosis of CJD. Pyramidal involvement was the first sign and the prominent clinical feature. Later on, she developed also myoclonus, ataxia, spastic tetraplegia, and at last dementia with akinetic mutism. Usually, signs of degeneration of the pyramidal tracts occur in a small number of patients as the disease advances. Our report supports the variability of the clinical expression of the E200K genetic CJD. Further studies are needed to understand the molecular basis underlying the phenotypic variability among patients carrying this mutation.     

Mutation in the prion protein gene at codon 232 in Japanese patients with Creutzfeldt-Jakob disease: a clinicopathological,immunohistochemical and transmission study

We describe the clinical, neuropathological, immunohistochemical and transmission findings in three patients with Creutzfeldt-Jakob disease (CJD) with a substitution from methionine to arginine at codon 232 (M232R) in the prion protein (PrP) gene. The patients with M232R presented clinically with rapidly progressive dementia, myoclonus, and periodic synchronous discharges in the electroencephalogram. These findings were mostly consistent with those for sporadic CJD. All patients reached the stage of akinetic mutism between 2 and 6 months, and died between 4 and 24 months after the onset of the disease. Histopathological examination revealed spongiform changes, neuronal loss and severe astrocytosis. Immunohistochemical staining for PrP showed diffuse gray matter staining, including synaptic structures. However, no plaque-type PrP deposition was observed in the affected brain tissue sections. The brain homogenates from two patients were successfully transmitted to experimental animals. Since the same mutation was not found in 100 healthy control individuals, the mutation might be associated with the disease. The clinicopathological and experimental transmission studies of CJD patients with this PrP gene mutation may thus help us to determine both phenotypic variations and the potential infectivities in different forms of prion diseases. Received: 27 December 1995 / Revised, accepted: 25 March 1995     

A novel mutation I215V in the PRNP gene associated with Creutzfeldt–Jakob and Alzheimer’s diseases in three patients with divergent clinical phenotypes

Genetic human prion diseases are autosomal dominant disorders associated with different mutations in the PRNP gene that are manifested as distinct clinical phenotypes. Here, we report a new pathogenic missense mutation (c.[643A>G], p.[I215V]) in the PRNP gene associated with three pathologically confirmed cases: two of Creutzfeldt–Jakob disease (CJD) and one of Alzheimer’s disease (AD) in two different families from the same geographical region in Spain. This mutation has not been found in any of more than 2,000 control cases studied. It represents a conservative amino acid change, and the same change is observed in the PRNP gene from other species. The two CJD cases were homozygous at codon 129 (M/M), but showed divergent clinical phenotypes with onset at ages 55 and 77 years and illness durations of 15 and 6 months, respectively. The postmortem neuropathological analysis of these cases showed homogeneous features compatible with CJD. Interestingly, the AD case (a brother of one of the CJD cases) was heterozygous at codon 129 (M/V). No familiar history was documented for any of the cases, suggesting a de novo mutation, or a partial, age-dependent penetration of the mutation, perhaps related to codon 129 status. This new mutation extends the list of known pathogenic mutations responsible for genetic CJD, reinforces the clinical heterogeneity of the disease, and advocates for the inclusion of PRNP gene examination in the diagnostic workup of patients with poorly classifiable dementia, even in the absence of family history.     

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.     

An autopsy case of Creutzfeldt‐Jakob disease with a V180I mutation of the PrP gene and Alzheimer‐type pathology

We report an autopsy case of Creutzfeldt‐Jakob disease with a codon 180 point mutation of the prion protein gene (PRNP). A 77‐year‐old woman developed gait instability, followed by dementia and limb/truncal ataxia. She became akinetic and mute 18 months and died of pneumonia 26 months after the disease onset. Analysis of the PRNP gene revealed a codon 180 point mutation. Post‐mortem examination revealed marked spongiosis, neuronal loss, and astrocytic gliosis in the cerebral cortex. Mild to moderate spongiosis and neuronal loss were observed in the limbic cortex and basal ganglia. There was no spongiform change in the hippocampus, brain stem or cerebellum. Many senile plaques and neurofibrillary tangles were found, and the Braak stages were stage C and stage IV, respectively. Immunostaining for prion protein (PrP) revealed granular (synaptic‐type) and patchy PrP deposition in the cerebral cortex and especially in the hippocampus. Most patchy PrP deposits were colocalized with amyloid β plaques, but some of them were isolated. The relatively strong PrP deposition and coexistence of Alzheimer‐type pathology of this case are remarkable. We suppose that amyloid β plaques might act as a facilitating factor for PrP deposition.     

A case of sporadic Creutzfeldt-Jakob disease with a Gerstmann-Sträussler-Scheinker phenotype but no alterations in the PRNP gene

We report here an unusual sporadic case of Creutzfeldt-Jakob disease (CJD) characterized by an abundance of prion protein (PrP)-immunopositive kuru and multicentric but not florid plaques. Molecular genetic analysis of the PRNP open reading frame region spanning codons 8–221 was performed. Neither deletion nor insertion mutations were detected in the repeat area of the PRNP. No pathogenic mutation was found in the sequenced region between codon 108–221. Restriction analysis of the amplified fragment using restriction endonucleases DdeI, PvuII and AluI did not show any of the previously described pathogenic mutations at codon 102, 105, and 117 associated with Gerstmann-Sträussler-Scheinker (GSS). The patient was heterozygous for the methionine/valine coding triplet at polymorphic codon 129 of the PRNP gene by sequence, restriction endonuclease analysis and hybridization with allele-specific nucleotides. Furthermore, hybridization with ³²P-labeled allele-specific oligonucleotides confirmed the absence of pathogenic mutations at codons 102, 200 and 178. Such a case may present a missing “link” between sporadic CJD and familial GSS.     

Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects.

Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease-resistant prion protein (PrP(Sc)) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrP(Sc) properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrP(Sc) deposition. Seventy percent of subjects showed the classic CJD phenotype, PrP(Sc) type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru-plaque variants, associated to PrP(Sc) type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrP(Sc) type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrP(Sc) type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrP(Sc) in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants.     

Cell-to-cell transmission of non-prion protein aggregates

Neurodegenerative disorders such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and Creutzfeldt-Jakob disease (CJD) are characterized by progressive accumulation of protein aggregates in selected brain regions. Protein misfolding and templated assembly into aggregates might result from an imbalance between protein synthesis, aggregation and clearance. Although protein misfolding and aggregation occur in most neurodegenerative disorders, the concept of spreading and infectivity of aggregates in the CNS has, until now, been confined to prion diseases such as CJD and bovine spongiform encephalopathy. Emerging evidence, however, suggests that prion-like spreading, involving secreted proteins such as amyloid-β and cytosolic proteins such as tau, huntingtin and α-synuclein, can occur in other neurodegenerative disorders. The underlying molecular mechanisms and the therapeutic implications of the new data are discussed in this article.     

Involvement of the peripheral nervous system in human prion diseases including dural graft associated Creutzfeldt-Jakob disease

OBJECTIVE: To investigate abnormal prion protein (PrP) deposition in the peripheral nervous system (PNS) in human prion diseases. METHODS: Eight patients with prion diseases were examined: three with sporadic Creutzfeldt-Jakob disease (sCJD), two with dural graft associated CJD (dCJD), one with Gerstmann-Straussler-Scheinker disease (GSS) with a PrP P102L mutation (GSS102), and two with a P105L mutation (GSS105). An atypical case of sCJD with PrP plaques in the brain presented clinically with peripheral neuropathy, and showed demyelination in 12% of the teased fibres of the sural nerve. The PNS was investigated by immunohistochemical and western blotting analyses of PrP. RESULTS: In immunohistochemical studies, granular PrP deposits were detected in some neurones of dorsal root ganglia and a few fibres of peripheral nerves and spinal posterior roots in one sCJD and two dCJD patients, but not in GSS102 or GSS105 patients. The atypical case of sCJD with peripheral neuropathy showed no obvious PrP deposition in the nerves. Western blotting analysis of the PNS from the dCJD patients revealed a small amount of protease K resistant PrP in the dorsal root ganglia and peripheral nerves. CONCLUSIONS: Abnormal PrP deposition occurs in the dorsal root ganglia and peripheral nerves in sCJD and dCJD. The PrP deposits in the PNS are not correlated with clinical manifestation of peripheral neuropathy in CJD.     

Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) and Alzheimer’s disease (AD) share clinical, neuropathological, and pathogenetic features. To investigate eventual mutual influences, we screened prominently affected neocortex from 110 neuropathologically proven CJD patients for Alzheimer-type pathology with anti-β/A4, Bielschowsky and anti-tau (immuno)stains. The neuropathological classification of Alzheimer-type pathology was made according to the CERAD criteria. Results were controlled by comparison with Alzheimer-type changes in sections from the same cortical areas in 110 sex- and age-matched non-demented control patients. For comparison, the control patients were also classified according to the CERAD neuropathology criteria as if they had been demented. Alzheimer-type tissue changes as in definite and probable CERAD AD occur in 10.9% of the CJD patients and 19.1% of control patients (P = 0.11). The median age of CJD and control patients with CERAD AD is 72 and 68 years, respectively, which differs significantly from the median ages of 64 and 63 years, respectively, in the non-AD/CJD and non-AD control patients. Since CERAD criteria include “presence of other neuropathological lesions likely to cause dementia”, an AD diagnosis in CJD patients (all of whom are demented) is solely based on densities of neuritic plaques. Similar Alzheimer-type changes in even higher frequency, however, are also present in elderly non-demented controls. Thus, the coexistence of Alzheimer-type pathology in CJD most likely represents an age-related change. Deposits of prion protein (PrP) frequently accumulate at the periphery of β/A4 plaques. The presence of β/A4 amyloid in the brain may influence PrP morphogenesis. Received: 18 November 1997 / Revised, accepted: 11 February 1998     

Creutzfeldt-Jakob disease with a novel extra-repeat insertional mutation in the PRNP gene

The authors investigated two unrelated patients with Creutzfeldt-Jakob disease (CJD) with clinical features of sporadic CJD (sCJD) carrying one extra octapeptide repeat in the prion protein (PrP) gene (PRNP). A synaptic type PrP distribution throughout the cerebral gray matter and plaque-like PrP deposits in the subcortical gray structures were detected immunocytochemically. The different patterns of PrP deposition were associated with distinct types of protease-resistant PrP, similar to type 1 and type 2 of sCJD. The features suggest that this insertion is a pathogenic mutation.     

Distribution of prion protein in German patients with Creutzfeldt-Jakob disease is different from that in Japanese patients

We investigated the distribution of prion protein (PrP) in 14 German patients with sporadic Creutzfeldt-Jakob disease (CJD) and compared it with that observed in Japanese patients. Immunohistochemical study revealed diffuse gray matter stainings including synaptic structures in all cases. In addition, 4 patients showed plaque-type deposition which was very rarely observed among sporadic Japanese patients without known mutation of the PrP gene but with valine at codon 129. A higher incidence of PrP plaques in German sporadic CJD may be related to the racial difference in the PrP gene.     

Neuropathological and biochemical criteria to identify acquired Creutzfeldt‐Jakob disease among presumed sporadic cases

As an experimental model of acquired Creutzfeldt‐Jakob disease (CJD), we performed transmission studies of sporadic CJD using knock‐in mice expressing human prion protein (PrP). In this model, the inoculation of the sporadic CJD strain V2 into animals homozygous for methionine at polymorphic codon 129 (129 M/M) of the PRNP gene produced quite distinctive neuropathological and biochemical features, that is, widespread kuru plaques and intermediate type abnormal PrP (PrP^Sc). Interestingly, this distinctive combination of molecular and pathological features has been, to date, observed in acquired CJD but not in sporadic CJD. Assuming that these distinctive phenotypic traits are specific for acquired CJD, we revisited the literature and found two cases showing widespread kuru plaques despite the 129 M/M genotype, in a neurosurgeon and in a patient with a medical history of neurosurgery without dura mater grafting. By Western blot analysis of brain homogenates, we revealed the intermediate type of PrP^Sc in both cases. Furthermore, transmission properties of brain extracts from these two cases were indistinguishable from those of a subgroup of dura mater graft‐associated iatrogenic CJD caused by infection with the sporadic CJD strain V2. These data strongly suggest that the two atypical CJD cases, previously thought to represent sporadic CJD, very likely acquired the disease through exposure to prion‐contaminated brain tissues. Thus, we propose that the distinctive combination of 129 M/M genotype, kuru plaques, and intermediate type PrP^Sc, represents a reliable criterion for the identification of acquired CJD cases among presumed sporadic cases.     

A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann�CStr?ussler�CScheinker disease phenotype: comparison with similar cases from the literature

Human prion diseases can be sporadic, inherited or acquired by infection and show considerable phenotypic heterogeneity. We describe the clinical, histopathological and pathological prion protein (PrP^Sc) characteristics of a Dutch family with a novel 7-octapeptide repeat insertion (7-OPRI) in PRNP, the gene encoding the prion protein (PrP). Clinical features were available in four, neuropathological features in three and biochemical characteristics in two members of this family. The clinical phenotype was characterized by slowly progressive cognitive decline, personality change, lethargy, depression with anxiety and panic attacks, apraxia and a hypokinetic-rigid syndrome. Neuropathological findings consisted of numerous multi- and unicentric amyloid plaques throughout the cerebrum and cerebellum with varying degrees of spongiform degeneration. Genetic and molecular studies were performed in two male family members. One of them was homozygous for valine and the other heterozygous for methionine and valine at codon 129 of PRNP. Sequence analysis identified a novel 168?bp insertion [R2?CR2?CR2?CR2?CR3g?CR2?CR2] in the octapeptide repeat region of PRNP. Both patients carried the mutation on the allele with valine at codon 129. Western blot analysis showed type 1 PrP^Sc in both patients and detected a smaller ~8?kDa PrP^Sc fragment in the cerebellum in one patient. The features of this Dutch kindred define an unusual neuropathological phenotype and a novel PRNP haplotype among the previously documented 7-OPRI mutations, further expanding the spectrum of genotype?Cphenotype correlations in inherited prion diseases.     

Prion diseases, update]

In prion diseases, genotypic classification has been useful to understand the clinical course and pathological changes. However, among patients with the same prion protein (PrP) genotype, there are variations in the pathological and clinical phenotype. Recently, PrP typing was proposed by the molecular weight of protease-resistant PrP (PrPres). Combined with genotype and PrPres typing, sporadic Creutzfeldt-Jakob disease (CJD) could be classified precisely. In addition, we found the fragmented PrP molecules to differentiate between dura-classic CJD and dura-plaque type CJD. We report herein that the fragmented PrP is a useful marker to classify human prion diseases, and also a clue to analyze abnormal PrP structures. The fragmented PrP was detected in patients with classic-type CJD, sporadic thalamic-type CJD, familial CJD with codon 200 or 232 mutation, or familial Gerstmann-Straussler syndrome (GSS) with codon 102 mutation. Among patients with type-1 abnormal PrP, the transmission study was successful in sporadic CJD with type 1 PrPres and the fragment PrP, but not in CJD without the fragmented PrP. Thus, in the prion field, type-specific PrP structure contributes to the clinicopathology and transmissibility.