朊蛋白疾病最新研究动态

朊蛋白疾病最新研究动态郭玉璞一、前言１９９６年３月２０日，英国海绵状脑病顾问委员会（ＳＥＡＣ）宣布确认了１０例前所未知的克－雅二氏病（ＣＪＤ）类型，称ＣＪＤ变异型，简称Ｖ－ＣＪＤ。有人认为Ｖ－ＣＪＤ可能与英国牛海绵状脑病（ｂｏｖｉｎｅｓｐｏｎｇｉｆｏ...     

我国Creutzfeldt-Jakob病的若干特殊性

目的通过本组资料，企图发现我国ＣｒｅｕｔｚｆｅｌｄｔＪａｋｏｂ病（ＣＪＤ）在临床与病理方面有不同于西方的若干特殊性。方法１５例经病理检查确诊的ＣＪＤ，６例进行免疫组化染色，７例进行鼠脑传递，５例进行ＰｒＰ基因检测。结果我国ＣＪＤ急性发病较多，急性发病者多表现抽搐或共济失调、病程短、脑萎缩不明显。结论我国ＣＪＤ确有不同于西方的若干特殊性，充分认识这些特殊性，对早期临床诊断，减少医源性传播有积极意义。     

我国Creutzfeldt—Jabob病的若干特殊性

目的 通过本组资料，企图发现我国Ｇｒｅｕｔｚｆｅｌｄｔ－Ｊａｂｏｂ病（ＣＪＤ）在临床与病理方面有不同于西方的若干特殊性。方法 １５例经病理检查确诊的ＣＪＤ，６例进行免疫组化染色，７例进行鼠脑传染，５例进行ＰｒＰ基因检测。结果 我国ＣＪＤ急性发病较多，急性发病者多表现抽搐或共济失调，病程短，脑萎缩不明显。结论我国ＣＪＤ确有不同于西方的若干特殊性，充分认识这些特殊性，对早期临床诊断，减少医源性传播有积     

脑活检证实的皮质-纹状体-脊髓变性的临床研究

目的：提高临床对Ｃｒｅｕｔｚｆｅｌｄｔ－Ｊａｋｏｂ氏病（ＣＪＤ）的认识。方法：５例被证实是ＣＪＤ，病理均有神经细胞海绵状空泡样变性等改变。结论：临床发现短期内痴呆进行性发展，伴有早期出现肌阵挛和脑电图有相应改变时应高度怀疑ＣＪＤ。及早行脑活检是早期诊断的方法之一。     

Creutzfldt—Jakob病临床,病理,免疫组化及动物传递的实验研究

经病理证实Ｃｒｅｕｔｚｆｌｄｔ－Ｊａｋｏｂ病（ＣＪＤ）９例，急性发病４例，亚急性４例，慢性１例。平均病程８．８个月，４例脑切片免疫组化染色阳性，另有３例脑活检组织匀浆接种于Ｃ５７ＢＬ／６０ｌａ，Ｂａｌｂ／ｃ和Ｗｉｓｔａｒ鼠脑内，分别于第二、三代发病，资料提示：（１）国人ＣＪＤ急性发病较多；（２）蛋白酶抗性蛋白免疫组化十分敏感，（３）ＣＪＤ脑组织活检可以成功地进行了动物接种。     

克罗伊茨费尔特——雅各布病人病人的脑电图

目的：了解克罗伊茨费尔特－雅各布病的脑电图特点。方法：对３４例ＣＪＤ病人经常规脑电描记并密切随访，动态观察脑电图的改变。结果：３例ＣＪＤ病人的脑电图均有短间隔周期性放电，疾病不同阶段有不同的特征性脑电图，结论：随着病情变化有相应脑电图特征，如在缺乏脑活检资料的情况下也可作出比较明确的ＣＪＤ诊断 。     

皮质-纹状体-脊髓变性病理与临床诊断☆(附5例临床分析)

目的　探讨皮质纹状体脊髓变性（ Ｃ Ｊ Ｄ） 的临床特点及诊断。方法　分析经病理证实的５ 例 Ｃ Ｊ Ｄ 的临床表现、光镜及超微检查结果。结果　５ 例均有典型 Ｃ Ｊ Ｄ 的临床表现，病理检查见神经细胞变性死亡，神经胶质细胞增生，无炎症性改变。超微检查除见上述改变外，还可见神经毡中膜性空泡内有卷曲的膜性碎片，部分髓鞘的轴突肿胀、空化。结论　本文５ 例 Ｃ Ｊ Ｄ 除引起中枢神经细胞胞体损害外，还可损害轴突，此病多为散发性，预后极差，目前无特效治疗。     

脑脊液14—3—3蛋白对Creutzfldt—Jakob病的诊断价值

目的 探讨脑脊液中１４－３－３蛋白质对Ｃｒｅｕｔｚｆｅｌｄｔ－Ｊａｋｏｂ病（ＣＪＤ）的诊断价值。方法 应用蛋白质印迹ＷｅｓｔｅｒｎＢｌｏｔ方法检测６１例病人的脑脊液中是否存在１４－３－３蛋白质,其中５例为ＣＪＤ病人,１８例为伴有痴呆症状的ＣＪＤ疾病,３８例为不伴有痴呆症状的神经系统疾病。在检测２例肯定的ＣＪＤ病人的不同条件下保存的脑脊液中１４－３－３蛋白质的稳定性。结果５例ＣＪＤ病人ＣＳＦ１４－     

Creutzfeldt－Jakob病临床、病理、免疫组化及动物传递的实验研究

经病理证实为Ｃｒｅｕｔｚｆｅｌｄｔ－Ｊａｋｏｂ病（ＣＪＤ）９例，急性发病４例，亚急性４例，慢性１例。平均病程８．８个月。４例脑切片免疫组化染色阳性。另有３例脑活检组织匀浆接种于Ｃ５７ＢＬ／６０ｌａ，Ｂａｌｂ／ｃ和Ｗｉｓｔａｒ鼠脑内。分别于第二、三代发病。资料提示：（１）国人ＣＪＤ急性发病较多；（２）蛋白酶抗性蛋白免疫组化十分敏感；（３）ＣＪＤ脑组织活检可以成功地进行动物接种。     

经动物传递和免疫组化证实的密码子129甲硫氨酸纯合子Creut …

目的 探讨Ｇｒｅｕｔｚｆｅｌｄｔ－Ｊａｂｋｏｂ病（ＣＪＤ）的生前诊断方法，ＣＪＤ患者基因型有否变异与病理改变和临床表现的关系，以及与免疫组化染色对朊蛋白在脑内沉积类型之间的关系。方法 取ＣＪＤ患者脑组织，用ＰｒＰ抗血清为第一抗体的免疫组化染色；并制成１５％重量容积比的脑匀浆，注入昆明小鼠脑内，观察１￣２年，发病小鼠脑亦经免疫组化染色。取患者静脉血分离白细胞提取ＤＮＡ，以特异引物扩增ＰｒＰ片段，常规     

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.     

Phenotypic similarities causing clinical misdiagnosis of pathologically-confirmed sporadic Creutzfeldt-Jakob disease as dementia with Lewy bodies

A patient fulfilling central, core and supportive clinical diagnostic criteria for dementia with Lewy bodies deteriorated rapidly in the absence of neuroleptic drug treatment, prompting suspicion of a diagnosis of sporadic Creutzfeldt-Jakob disease. At postmortem examination, the brain showed features typical of Creutzfeldt-Jakob disease of the MV1 subtype. We review the phenotypic overlap between dementia with Lewy bodies and Creutzfeldt-Jakob disease which may cause clinical misdiagnosis.     

Computed tomography findings in 15 cases of Creutzfeldt-Jakob disease with histological verification.

Computed tomography (CT) was normal in twelve of fifteen patients with definite Creutzfeldt-Jakob disease. In two patients CT showed mild sulcal widening, while marked ventricular enlargement and moderate cortical atrophy were seen in a patient who had both Creutzfeldt-Jakob disease and normal pressure hydrocephalus. No correspondence was observed between CT findings, severity of the clinical picture and postmorten gross brain examination. According to these results, a normal CT in a demented patient should suggest Creutzfeldt-Jakob disease. Conversely, CT is of value for the diagnosis of other potentially reversible illnesses clinically resembling Creutzfeldt-Jakob disease.     

Familial Creutzfeldt-Jakob disease with an R208H-129V haplotype and Kuru plaques

OBJECTIVE: To report the clinical and neuropathological features in the first patient seen, to our knowledge, with familial Creutzfeldt-Jakob disease and an R208H mutation associated with a Val/Val homozygosity at codon 129 in the prion protein gene (PRNP) and a type 2 protease-resistant prion protein. PATIENT AND RESULTS: A 61-year-old man with a long-standing history of memory loss and emotional disorders had an obvious behavioral change. Then he developed cerebellar ataxia, followed by cognitive decline. He had no myoclonus. Electroencephalography showed slow activity, and 14-3-3 protein detection was negative. Finally, the patient developed akinetic mutism and died 7 months after the onset of ataxia. Neuropathological examination showed severe spongiform changes in the frontal cortex and striatum and gliosis in the striatum and thalamus. Kuru plaques were noted in the cerebellum, notably in the molecular layer. Immunohistochemical findings showed granular, synaptic, perineuronal, and perivacuolar staining with antiprion antibodies. Kuru plaques were also stained. CONCLUSION: This study strengthens the linkage of the R208H mutation to Creutzfeldt-Jakob disease and points to some particular features such as Kuru plaques and long-standing psychiatric signs.     

Familial Creutzfeldt-Jakob disease without periodic EEG activity

Four members of a kindred with Creutzfeldt-Jakob disease are reported, in whom myoclonus did not develop and in whom serial electroencephalograms performed late in their illness failed to show periodic sharp wave complexes. Otherwise, the patients' disease duration, clinical features, and neuropathological findings were similar to those described in sporadic cases of Creutzfeldt-Jakob disease. Our findings and those reported by others suggest that periodic electroencephalographic activity may be rare in familial forms of Creutzfeldt-Jakob disease, as it is in other slow transmissible encephalopathies.     

Nonvasculitic autoimmune inflammatory meningoencephalitis imitating Creutzfeldt-Jakob disease

BACKGROUND: Nonvasculitic autoimmune inflammatory meningoencephalitis and Creutzfeldt-Jakob disease can present as rapidly progressive encephalopathies with similar clinical features. Slowing of background rhythm is an electroencephalographic characteristic shown by both, but persistent periodic sharp waves are more specific for Creutzfeldt-Jakob disease and have not been reported in nonvasculitic autoimmune inflammatory meningoencephalitis or related autoimmune meningoencephalitides. OBJECTIVE: To describe a patient with clinical (rapidly progressive myoclonus, dementia, and Parkinsonism) and electroencephalographic findings (persistent periodic sharp waves) that diagnostically suggest Creutzfeldt-Jakob disease. DESIGN AND SETTING: A case report at the Mayo Clinic Arizona, Scottsdale. RESULTS: The patient made a dramatic recovery with resolution of the periodic sharp wave complexes after treatment with high-dose corticosteroids. Our case is the first reported case of a patient with probable nonvasculitic autoimmune inflammatory meningoencephalitis and electroencephalographic periodic complexes suggestive of Creutzfeldt-Jakob disease. CONCLUSION: Rapidly progressive encephalopathy with periodic sharp wave complexes can be associated with a reversible autoimmune syndrome.     

Lithium-induced encephalopathy mimicking Creutzfeldt-Jakob disease

INTRODUCTION: Creutzfeldt-Jakob disease (CJD) has a poor prognosis. Certain clinical presentations can be suggestive yet mimic a curable disease. OBSERVATION: In the present study, we report the case of a 67-year-old man with a one-month history of progressive dementia, with myoclonic jerks and cerebellar syndrome suggesting a diagnosis of Creutzfeldt-Jakob encephalopathy. He had been treated for 9 years with lithium for a bipolar disorder. The results of the different investigations and the favorable course after discontinuation of lithium were in favor of the diagnosis of drug-induced Creutzfeldt-Jakob syndrome. CONCLUSION: This case illustrates the importance for researching a curable etiology in presence of clinical features suggesting a CJD.     

Demyelinating peripheral neuropathy in Creutzfeldt-Jakob disease.

We describe 2 patients of Jewish Libyan descent, who presented with a clinical syndrome compatible with Creutzfeldt-Jakob disease and who were found to have a mutation of codon 200 in the prion protein. The patients developed symptoms and signs of peripheral nerve involvement diagnosed by electrodiagnostic and histopathological studies as demyelinating neuropathy. This may be a rare manifestation of Creutzfeldt-Jakob disease.     

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.     

Patch-clamp Analysis of Synaptic Transmission to Cerebellar Purkinje Cells of Prion Protein Knockout Mice

The prion protein (PrP) plays a pivotal role in transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. Previous experiments have suggested that the normal cellular prion protein (PrP^C) is involved in synaptic function in the hippocampus. Here, we utilized the controlled recording conditions of the patch-clamp technique to investigate the synaptic function of prion protein in cerebellar Purkinje cells. By performing whole-cell and outside-out patch-clamp experiments in thin slices, we investigated synaptic transmission in prion protein knockout mice (PrP-null) and control animals. In PrP-null mice, the kinetics of GABA- and glutamate receptor-mediated currents showed no significant deviation from those in control animals. In contrast to previous results in hippocampal neurons, our findings support the view that synaptic transmission is unimpaired in prion protein-deficient mice.