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.     

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.     

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.     

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.     

Neuropathologic variants of sporadic Creutzfeldt-Jakob disease and codon 129 of PrP gene

OBJECTIVES: To determine the contribution of methionine/valine (Met/Val) polymorphism at codon 129 of the prion protein (PrP) gene in the neuropathologic pattern and mechanisms of lesion development in sporadic Creutzfeldt-Jakob disease. BACKGROUND: Creutzfeldt-Jakob disease is a transmissible spongiform encephalopathy characterized by a conformational change of PrP and a variety of PrP deposits in the brain, some of which aggregate into amyloid plaques. METHODS: The authors semiquantitatively assessed neuropathologic lesions and performed PrP immunolabeling in 70 patients (39 Met/Met, 11 Met/Val, 20 Val/Val) who had died in France between 1994 and 1998. RESULTS: Met/Met cases (mild lesions mostly involving the occipital areas, low PrP load, few focal PrP nonamyloid deposits, no amyloid plaques) contrasted with Met/Val cases (marked lesions especially in the parahippocampal gyrus, high PrP load, numerous amyloid plaques) and with Val/Val cases (younger patients, longer course of disease: 11.5 +/- 3 months, and distinct neuropathology: severe lesions heavily involving the hippocampal formation and basal ganglia, high PrP load, numerous focal nonamyloid deposits, rare amyloid plaques). The course of Val/Val patients younger than age 55 was particularly long (19.9 +/- 7 months), and the isocortex bore the brunt of the pathology, suggesting a distinct variety. CONCLUSIONS: Polymorphism at codon 129 modulates the phenotype of sporadic Creutzfeldt-Jakob disease. The Val genotype enhances the production of proteinase-resistant PrP, and the Met/Val genotype facilitates its aggregation into amyloid plaques.     

Double mutations at codon 180 and codon 232 of the PRNP gene in an apparently sporadic case of Creutzfeldt-Jakob disease

Several polymorphisms of the prion protein gene are associated with the occurrence of familial Creutzfeldt-Jakob disease. We described a 84-year-old Japanese man with neuropathologically verified Creutzfeldt-Jakob disease of apparently sporadic type. His clinical presentation was atypical in point of a very late age at onset and absence of periodic synchronous discharge on electroencephalography. The patient carried double hitherto undescribed mutations of the prion protein gene; at codon 180 on one allele and at codon 232 on another. The mutation at codon 180 abolishes the Tth111I cutting site, which may be misunderstood to represent codon 178 mutation on routine restriction fragment length polymorphism study.     

Gerstmann-Str?ussler-Scheinker disease with heterozygous codon change at prion protein codon 129]

A 53-year-old male was admitted to our hospital for progressive dementia and gait disturbance which had started at the age of 48. Examination indicated dementia, dysarthria, dysphagia, bilateral pyramidal signs, apraxia of the limbs, and extrapyramidal signs such as fine finger tremors, and rigidity of limbs. There were no cerebellar signs or myoclonus. His mother and elder brother showed similar symptoms and died at the ages of 53 and 50, respectively. EEG was normal. CT and MRI showed mild brain atrophy, but no cerebellar atrophy. T2 weighted image indicated low intensity areas covering bilateral caudate nuclei and putamina. A heterozygous amino acid change from methionine to valine was noted at codon 129 of the prion protein of the patient as well as in one of his son. The most likely diagnosis was Gerstmann-Str?ussler-Scheinker (GSS) disease without cerebellar atrophy. GSS may include a broad spectrum of brain pathology. Whether the codon change is associated with pathology without cerebellar atrophy is a problem that awaits further investigation.     

Polymorphism at codon 129 of the prion protein gene is not associated with sporadic AD

An association between cognitive performance in elderly people and variability in the codon 129 of the prion protein gene (PRNP) has been recently described. The authors analyzed this polymorphism in 278 sporadic AD patients and 268 cognitively normal control subjects. Analyses stratifying by APOE genotype, age, and gender failed to reveal any association between homozygosity for the 129 PRNP methionine or valine alleles and AD.     

Genotyping of the prion protein gene at codon 129

Sporadic, iatrogenic and new variant forms of Creutzfeldt-Jakob disease are associated with a predisposition for disease depending on a homozygosity at amino acid residue 129 of the prion protein gene (PRNP). A novel polymerase chain reaction/restriction digestion assay to screen for this polymorphism was developed and proved after comparison with a previously used method to be advantageous. Furthermore, for prevention of incorrect results an internal control for the restriction digestion was constructed. The feasibility of this method was tested in a cohort of 300 healthy Caucasian subjects. Of this normal population, 48.7% were heterozygous at codon 129, 43% homozygous for methionine and 8.3% for valine. Received: 22 July 1998 / Revised, accepted: 25 September 1998     

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.     

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 case of Creutzfeldt-Jakob disease with a point mutation of prion protein at codon 180]

A 67-year-old woman was admitted to our hospital with progressive aphasia. There was no family history of similar diseases or any history of dura transplantation. Cranial magnetic resonance imaging (MRI) showed high signal areas in the temporal and parietal cortex predominantly on the left side on both T2-weighted images and on diffusion-weighted images. There were no periodic synchronous discharges observed on the electroencephalogram. As prion protein gene codon 180 point mutation (Val/Ile) was detected, we diagnosed her as having Creutzfeldt-Jakob disease (CJD). The characteristics of CJD of this type differ from those of sporadic CJD. To date, few papers on CJD with point mutation of codon 180 have been reported from Japan.     

Codon 129 polymorphism of prion protein gene in sporadic Alzheimer's disease

Codon 129 polymorphism of the prion protein gene represents a major genetic risk factor for Creutzfeldt-Jakob disease (CJD). Both CJD and Alzheimer's disease (AD) are brain amyloidoses and it would be possible that codon 129 polymorphism plays a role in the susceptibility to AD. In order to investigate this polymorphism in AD the distribution of polymorphic codon 129 of the PRNP gene in 194 probable AD and 124 controls selected in Italy and 109 neuropathologically verified AD and 58 matched controls recruited in the USA was studied. No significant association was found for the PRNP polymorphism in AD compared to controls either in Probable or in Definite AD series even after stratification for APOE polymorphism. This study does not support a role of PRNP polymorphism as a susceptibility factor for AD.     

Familial Creutzfeldt-Jakob disease associated with a point mutation at codon 210 of the prion protein gene.

Creutzfeldt-Jakob disease (CJD), the most known human prion disease, is usually sporadic but approximately 15% of the cases are familial. To date, seven CJD cases with codon 210 mutation (GTT to ATT) have been reported in the literature. We describe a case of a 57 year-old woman who presented gait disturbances and rapidly progressive dementia, leading to death four months after onset. Electroencephalogram revealed periodic activity, diffusion-weighted magnetic resonance imaging showed hypersignal in basal ganglia, and test for 14-3-3 protein was strongly positive in the CSF. The complete prion protein gene coding region was sequenced after PCR amplification, showing a point mutation in codon 210. This is the first case of CJD with codon 210 mutation diagnosed in Brazil. We emphasize the role of genetic search for prion protein gene mutation, even in patients presenting clinical features resembling sporadic CJD.     

Correlation between prion protein gene codon 129 polymorphism and late-onset Alzheimer's disease

BACKGROUND:Studies addressing the correlation between prion protein gene codon 129 polymorphism,Alzheimer's disease,and cognitive disorders have mainly focused on Caucasians.However,prion protein gene codon 129 polymorphism is thought to also affect the Chinese Han and Wei populations.OBJECTIVE:To analyze the differences of prion protein gene codon 129 distribution among the elderly Chinese Han,East Asian,and Caucasian populations,and to study the correlation between prion protein gene codon 129 distribution and late-onset Alzheimer's disease.DESIGN,TIME AND SETTING:A gene polymorphism analysis was performed in the Institute of Geriatrics,General Hospital of Chinese PLA between January 2006 and January 2007.PARTICIPANTS:A total of 152 elderly Chinese Han people were selected from the Beijing Troop Cadre's Sanitarium.Among them,60 patients with late-onset Alzheimer's disease,with a mean age of (82±7) years (range 67-94 years) and disease course of (5.9±4.4) years,comprising 44 males with a mean age of (83±7) years and 16 females with a mean age of (78±7) years,were selected for the case group.An additional 92 healthy elderly subjects,with a mean of (76±9) years (range 60-94 years),comprising 76 males with a mean age of (77±9) years and 16 females with a mean age of (70±8) years,were selected for the control group.There were no significant differences in age and gender between the two groups (P>0.05).METHODS:DNA was extracted from peripheral blood leukocytes using routine phenol/chloroform methodology.Prion protein gene codon 129 polymorphism and ApoE polymorphism were measured using PCR-restriction fragment length polymorphism.The ApoEε allele was considered the standard for analyzing correlations between prion protein gene codon 129 polymorphism and late-onset Alzheimer's disease.MAIN OUTCOME MEASURES:Prion protein gene codon 129 distribution;correlation between genotypic frequency and allele frequency of prion protein gene codon 129 with Alzheimer's disease;relationship between methionine/methionine genotype of prion protein gene,ApoEε4 allele,gender,and age of Alzheimer's disease patients.RESULTS:Methionine/methionine genotypic frequency of prion protein gene codon 129 was 94.08% in the Chinese elderly population,and the methionine/valine genotypic frequency was 5.92%.However,valine/valine homozygotes were not determined.There was no significant difference in prion protein gene codon 129 polymorphism between the Chinese elderly and East Asian populations (P>0.05).However,there was a significant difference between the Chinese elderly and the Caucasian population (P<0.05).The methionine/methionine genotype for the positive and negative ApoEε4 alleles was a risk factor for increased incidence of Alzheimer's disease,but there was no significant difference between the positives and the negatives (odds ratio=1.33,95% confidence interval=0.32-5.49,P>0.05).CONCLUSION:Prion protein gene codon 129 distribution in the Chinese elderly was different from the Caucasian population,which suggested that the methionine/methionine genotype of prion protein gene codon 129 negatively correlated with late-onset Alzheimer's disease.     

Polymorphisms at codons 129 and 219 of the prion protein gene (PRNP) are not associated with sporadic Alzheimer's disease in the Korean population

Polymorphisms of prion protein gene ( PRNP ) at codons 129 and 219 play an important role in the susceptibility to Creutzfeldt-Jakob disease (CJD). Alzheimer's disease (AD) and prion diseases, such as CJD, are both characterized by the accumulation of abnormally folded proteins in the brain. An association between sporadic AD and the PRNP polymorphism at codon 129 has been reported in several studies, but other studies have failed to confirm an association. To investigate whether PRNP polymorphisms are associated with an increased risk for developing sporadic AD in the Korean population, we compared the genotype, allele, and haplotype frequencies of PRNP polymorphisms in 271 sporadic AD patients with those in 236 healthy Koreans. Our study does not show a significant difference in PRNP genotype, allele, and haplotype frequency at codons 129 and 219 between sporadic AD and normal controls. Analyses stratifying by age at disease onset, and gender also failed to reveal any association between these polymorphisms and sporadic AD. These results indicate that these PRNP polymorphisms have no direct influence on the susceptibility to sporadic AD in the Korean population.     

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。