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.     

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.     

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.     

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     

散发性Creutzfeldt-Jakob病患者10例prion基因研究

目的 检测10例Creutzfeldt-Jakob病（CJD）患者prion基因（PRNP）外显子突变情况.方法 抽取患者外周静脉血,提取DNA,PCR法扩增PRNP外显子后直接测序,并用限制性内切酶Nsp Ⅰ检测PRNP 129位点密码子基因型.结果 2例肯定CJD患者中,1例PRNP检测未见异常,另1例PRNP第729碱基G被C取代（729G→C）,使编码prion第211个氨基酸的密码子GAG变成了GAC,翻译后第211个氨基酸由谷氨酸变为天冬氨酸（E211D）.8例很可能CJD患者中,2例PRNP第751碱基G被A取代（751G→A）,使编码prion第219个氨基酸的密码子GAG变成了AAG,翻译后第219个氨基酸由谷氨酸变为赖氨酸（E219K）.10例CJD患者PRNP 129位点密码子基因型都是甲硫氨酸纯合型.结论 1例肯定CJD患者的prion基因外显子存在一种新的点突变E211D,这很可能是导致遗传prion病发生的原因.2例很可能CJD患者的prion基因突变E219K,与M129V同属于基因多态性,而不是致病原因.prion基因检测有助于prion病的诊断.     

Familial Creutzfeldt-Jakob disease with a novel 120-bp insertion in the prion protein gene

The clinical course, neuropathological features, and genetic findings in 3 members of a German family carrying a novel 120-bp insertion in the prion protein (PrP) gene are described. Genetic analysis of the mutated allele revealed a sequence of five extra octapeptide repeats, distinct from those of the two previously reported families with an insertion of this size. There was distinctive variation in the clinical course and the onset and duration of the illness in the documented subjects. Neuopathological evaluation showed neuronal loss and gliosis in the neocortex of the 3 examined cases; spongiform degeneration was found in 2 of them. PrP immunoreactivity of unusual morphology and distinct distribution was present in the cerebellem and neocortex ("blurred staining") of 2 examined cases. One subject showed features usually found in sporadic Creutzfeldt-Jacob disease with a punctate type of PrP deposition in the cerebellum. In addition, there were some plaque-like PrP aggregates morophologically similar to the other 2 cases in the molecular layer of the cerebellum, and unusual Prp immunoreactivity ("fleecy staining") was found in the neocortex. The clinicopathological heterogeneity in the documented family is in accordance with the phenotypic variability associated with previously reported insertions.     

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.     

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.     

Diffusion-weighted MRI in familial Creutzfeldt-Jakob disease with the codon 200 mutation in the prion protein gene

Magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) has been reported to be a useful tool for early diagnosis of sporadic Creutzfeldt-Jakob disease (CJD). We report MRI findings with DWI, as well as with fluid-attenuated inversion recovery (FLAIR) and T1-weighted imaging (T1WI), in a case of familial CJD with a mutation at codon 200 of the prion protein gene. DWI in this patient showed high signal intensity in the basal ganglia and the cerebral cortex, similar to findings in sporadic CJD. In addition, T1WI showed areas of high signal intensity bilaterally in the globus pallidus. Despite the clinical diversity and atypical laboratory findings seen in familial CJD with the codon 200 mutation, these neuroimaging studies suggest that common regional distributions and a common pathogenesis might underlie the clinical progression both in sporadic CJD and in familial CJD with the codon 200 mutation in the prion protein gene. DWI abnormalities may be characteristic features that should be considered in the diagnosis of familial as well as of sporadic CJD.     

Inherited Creutzfeldt-Jakob disease in a British family associated with a novel 144 base pair insertion of the prion protein gene.

A case of familial Creutzfeldt-Jakob disease associated with a 144 base pair insertion in the open reading frame of the prion protein gene is described. Sequencing of the mutated allele showed an arrangement of six octapeptide repeats, distinct from that of a recently described British family with an insertion of similar size. Thirteen years previously the brother of the proband had died from "Huntington's disease", but re-examination of his neuropathology revealed spongiform encephalopathy and anti-prion protein immunocytochemistry gave a positive result. The independent evolution of at least two distinct pathological 144 base pair insertions in Britain is proposed. The importance of maintaining a high index of suspicion of inherited Creutzfeldt-Jakob disease in cases of familial neurodegenerative disease is stressed.     

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.     

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.     

New haplotype of familial Creutzfeldt-Jakob disease with a codon 200 mutation and a codon 219 polymorphism of the prion protein gene in a Japanese family

We report a new haplotype of familial Creutzfeldt-Jakob disease (CJD) with a codon 200 mutation and a codon 219 polymorphism of the prion protein gene in a Japanese family. There were four cases diagnosed with CJD neuropathologically, one of which was identified with a codon 200 mutation (glutamic acid to lysine) and a codon 219^Lys polymorphism on the same allele. Clinicopathologically, two cases had a long clinical course, whereas the others were similar to the cases with a codon 200 mutation. Three cases was diagnosed with the panencephalopathic-type CJD neuropathologically and the other was diagnosed with the subacute spongiform encephalopathy, a subtype of CJD. We consider that the clinicopathological features in familial CJD are not steadily uniform and that it is impossible to state definitely from this study whether the codon 219 polymorphism influences the clinicopathological aspects in familial CJD with a codon 200 mutation (glutamic acid to lysine). Received: 10 August 1998 / Revised: 2 December 1998, 30 May 1999 / Accepted: 31 May 1999     

Allele-specific sequencing confirms novel prion gene polymorphism in Creutzfeldt-Jakob disease

We analyzed the prion protein coding sequence in a familial Creutzfeldt-Jakob disease patient who did not have any of the currently recognized prion protein mutations. Denaturing gradient gel electrophoresis indicated that the prion protein coding sequence was heterozygous at least one location. We isolated each allele by denaturing gradient gel electrophoresis and directly sequenced. We found a DNA polymorphism at codon 178 that predicted the amino acid substitution, aspartate----asparagine. Whether this represents a benign polymorphism or pathogenic mutation will depend on analysis of the functional consequences of this change. Denaturing gradient gel electrophoresis and allele-specific sequencing proved to be efficient means of analyzing sequence polymorphisms in this gene.     

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     

Review: Creutzfeldt-Jakob disease: prion protein type, disease phenotype and agent strain

The human transmissible spongiform encephalopathies or human prion diseases are one of the most intensively investigated groups of rare human neurodegenerative conditions. They are generally held to be unique in terms of their complex epidemiology and phenotypic variability, but they may also serve as a paradigm with which other more common protein misfolding disorders might be compared and contrasted. The clinico-pathological phenotype of human prion diseases appears to depend on a complex interaction between the prion protein genotype of the affected individual and the physico-chemical properties of the neurotoxic and transmissible agent, thought to comprise of misfolded prion protein. A major focus of research in recent years has been to define the phenotypic heterogeneity of the recognized human prion diseases, correlate this with molecular-genetic features and then determine whether this molecular-genetic classification of human prion disease defines the biological properties of the agent as determined by animal transmission studies. This review seeks to survey the field as it currently stands, summarize what has been learned, and explore what remains to be investigated in order to obtain a more complete scientific understanding of prion diseases and to protect public health.