The epidemiological, clinical, and laboratory features of sporadic Creutzfeldt-Jakob disease patients in China: surveillance data from 2006 to 2010

Background

Creutzfeldt-Jakob disease (CJD) is a rare, rapidly progressive fatal central nervous system disorder, which consists of three main catalogues: sporadic, familial, and iatrogenic CJD.

Methodology/Principal Findings

In China, the surveillance for CJD started in 2006, covering 12 provincial Centers for Disease Control and Prevention (CDCs) and 15 hospitals. From 2006 to 2010, 624 suspected patients were referred to China CJD surveillance. The epidemiological, clinical and laboratory features of sporadic CJD (sCJD) were analysed. Both groups of probable and possible sCJD showed highest incidences in the population of 60 to 69 year-olds. The most common presenting symptoms were progressive dementia and mental-related symptoms (neurological symptoms including sleeping turbulence, depression, anxiety and stress). Among the four main clinical manifestations, myoclonus was more frequently observed in the probable sCJD patients. About 2/3 of probable sCJD cases showed positive 14-3-3 in CSF and/or periodic sharp wave complexes (PSWC) in electroencephalography (EEG). The presence of myoclonus was significantly closely related with the appearance of PSWC in EEG. Polymorphisms of codon 129 in PRNP of the notified cases revealed a highly predominant M129M genotype in Han Chinese. Among 23 genetic human prion diseases, ten were D178N/M129M Fatal familial insomnia (FFI) and five were T188K genetic CJD (gCJD), possibly indicating a special distribution of gCJD-related mutations in Han Chinese.

Conclusion

From the period of 2006 to 2010, 261 patients were diagnosed as sCJD and 23 patients were diagnosed as genetic human prion diseases in China. The epidemiological, clinical and laboratory analysis data were consistent with the characteristics of sporadic CJD, which provide insight into the features of CJD in China.     

Analysis of the advantage features of Beijing surveillance network for Creutzfeldt-Jakob disease

ABSTRACT. Since 2006, China has conducted the surveillance program for Creutzfeldt-Jakob disease (CJD) and other subtypes of prion diseases covering 12 provinces. In this study, the characteristics and special role of Beijing CJD surveillance network in the national CJD surveillance system were analyzed. Based on the registered permanent resident places, all reporting suspected CJD cases and diagnosed CJD cases via Beijing CJD surveillance network between 2006 and 2013 were grouped as the cases from Beijing and from outside of Beijing. Both numbers of the suspected and diagnosed CJD cases via Beijing CJD surveillance network constantly increased along with the years, totally 532 reporting cases and 192 diagnosed CJD cases were obtained in the past 8 y. About 75% of suspected and diagnosed CJD cases via Beijing CJD surveillance network came from other provinces, mainly from neighboring provinces. Altogether, 46 different hospitals in the Beijing region have reported suspected CJD cases to the CJD surveillance system during the period from 2006 to 2013. Five hospitals continually reported suspected CJD cases during those 8 y and 5 other hospitals had reported cases except for 1 to 2 y. Additionally, we found that the diagnosed CJD patients from Beijing region had less numbers of hospital transfer and shorter interval from the disease onset to the final diagnosis than those outside of Beijing. It indicates that as the most important component, Beijing CJD surveillance network functions more actively, which supplies the special medical services not only for Beijing residents but also for patients from all of China.     

Analysis of the advantage features of Beijing surveillance network for Creutzfeldt-Jakob disease

ABSTRACT. Since 2006, China has conducted the surveillance program for Creutzfeldt-Jakob disease (CJD) and other subtypes of prion diseases covering 12 provinces. In this study, the characteristics and special role of Beijing CJD surveillance network in the national CJD surveillance system were analyzed. Based on the registered permanent resident places, all reporting suspected CJD cases and diagnosed CJD cases via Beijing CJD surveillance network between 2006 and 2013 were grouped as the cases from Beijing and from outside of Beijing. Both numbers of the suspected and diagnosed CJD cases via Beijing CJD surveillance network constantly increased along with the years, totally 532 reporting cases and 192 diagnosed CJD cases were obtained in the past 8 y. About 75% of suspected and diagnosed CJD cases via Beijing CJD surveillance network came from other provinces, mainly from neighboring provinces. Altogether, 46 different hospitals in the Beijing region have reported suspected CJD cases to the CJD surveillance system during the period from 2006 to 2013. Five hospitals continually reported suspected CJD cases during those 8 y and 5 other hospitals had reported cases except for 1 to 2 y. Additionally, we found that the diagnosed CJD patients from Beijing region had less numbers of hospital transfer and shorter interval from the disease onset to the final diagnosis than those outside of Beijing. It indicates that as the most important component, Beijing CJD surveillance network functions more actively, which supplies the special medical services not only for Beijing residents but also for patients from all of China.     

Characteristics of Korean patients with suspected Creutzfeldt-Jakob disease with 14-3-3 protein in cerebrospinal fluid: Preliminary study of the Korean Creutzfeldt-Jakob disease active surveillance program

Although Korea had a national surveillance system for Creutzfeldt-Jakob disease (CJD), it was mainly dependent on attending physician''s reports. Thus, little prospective data about the epidemiology, characteristics, and final diagnoses of suspected patients were available. We have established a nationwide network for the active surveillance of patients with suspected CJD. When the requested cerebrospinal fluid (CSF) samples tested positive for 14-3-3 protein, we investigated the clinical characteristics of the corresponding patients and followed them until their final diagnoses were confirmed. A total of 218 samples were requested for CSF assays from May 2010 to August 2012, and 106 (48.6%) were positive for 14-3-3 protein. In 89 patients with complete clinical data, 38 (42.7%) were diagnosed with probable CJD and the estimated annual occurrence of CJD was 16.3 persons-per-year. The most common diagnoses of the remainder were central nervous system infection and any-cause encephalopathy. Non-CJD subjects showed worse initial consciousness levels than CJD patients. This preliminary study showed that the number of reported cases of CJD and the true positivity rates of CSF 14-3-3 protein assays were both low in Korea. An active surveillance system is urgently needed to provide the latest nationwide epidemiological data of CJD.     

Characteristics of Korean patients with suspected Creutzfeldt-Jakob disease with 14-3-3 protein in cerebrospinal fluid: Preliminary study of the Korean Creutzfeldt-Jakob disease active surveillance program

Abstract

Although Korea had a national surveillance system for Creutzfeldt-Jakob disease (CJD), it was mainly dependent on attending physician's reports. Thus, little prospective data about the epidemiology, characteristics, and final diagnoses of suspected patients were available. We have established a nationwide network for the active surveillance of patients with suspected CJD. When the requested cerebrospinal fluid (CSF) samples tested positive for 14-3-3 protein, we investigated the clinical characteristics of the corresponding patients and followed them until their final diagnoses were confirmed. A total of 218 samples were requested for CSF assays from May 2010 to August 2012, and 106 (48.6%) were positive for 14-3-3 protein. In 89 patients with complete clinical data, 38 (42.7%) were diagnosed with probable CJD and the estimated annual occurrence of CJD was 16.3 persons-per-year. The most common diagnoses of the remainder were central nervous system infection and any-cause encephalopathy. Non-CJD subjects showed worse initial consciousness levels than CJD patients. This preliminary study showed that the number of reported cases of CJD and the true positivity rates of CSF 14-3-3 protein assays were both low in Korea. An active surveillance system is urgently needed to provide the latest nationwide epidemiological data of CJD.     

Analysis of the compliance and the related influence factors in the follow-up process of surveillance for Creutzfeldt-Jakob disease in China

Creutzfeldt-Jakob disease (CJD) is a kind of rare, rapidly progressive fatal central nervous system disorders. In China, the surveillance for CJD has started since 2006. As one of the major issues in CJD surveillance, the follow-up process via telephone plays important role in CJD diagnosis and surveillance. Although the follow-up process was conducted by the experiential staffs from CJD surveillance center in China CDC, it is frequently encountered that some interviewed family members do not cooperate well during follow-up. To screen the possible factors influence on the compliances of the interviewees during CJD follow-up, 11 independent variables from patient aspect and 4 variables from interviewee aspect were selected and a questionnaire was prepared. Based on 199 suspected sporadic CJD cases reported to CJD surveillance center in 2013, a telephone-inquiring was conducted and the degree of compliances of the interviewees were given as good, fair or poor. After screened with univariate analysis and evaluated ordinal logistic regression analysis, several indictors, such as the patient gender, CJD diagnosis, numbers of clinical symptoms, continual medical treatment after diagnosis, medical treatment mode, as well as the relationship with the patient and CJD knowledge of the interviewees, showed influence on the compliance in CJD follow-up process significantly. The data here provide for the first time the factors related with the compliances of the interviewed family members of the suspected CJD patients during follow-up process, which supplies useful clue for us to improve CJD follow-up process and increase the capacity of CJD surveillance.     

MRI findings are often missed in the diagnosis of Creutzfeldt-Jakob disease

Background

Establishing a confident clinical diagnosis before an advanced stage of illness can be difficult in Creutzfeldt-Jakob disease (CJD) but unlike common causes of dementia, prion diseases can often be diagnosed by identifying characteristic MRI signal changes. However, it is not known how often CJD-associated MRI changes are identified at the initial imaging report, whether the most sensitive sequences are used, and what impact MRI-diagnosis has on prompt referral to clinical trial-like studies.

Methods

We reviewed the MRI scans of 103 patients with CJD referred to the National Prion Clinic since 2007 and reviewed the presence of CJD-associated changes, compared these findings with the formal report from the referring centre and reviewed the types of sequence performed.

Results

In sCJD we found CJD-associated MRI changes in 83 of 91 cases (91% sensitivity). However, the referring centres documented CJD-associated MRI changes in 43 of the sCJD cases (47% sensitivity). The most common region not documented by referring centres was the cortex (23 of 68 sCJD cases), but there was a statistically significant discrepancy in all regions (p<0.0001). Patients in whom MRI abnormalities were missed by the referring hospital were more advanced at the time of recruitment to a clinical trial-like study (p=0.03).

Conclusions

CJD-associated MRI changes are often not documented on the formal investigation report at the referring centre. This is important as delay makes enrolment to clinical trials futile because of highly advanced disease. If a diagnosis of CJD is suspected, even if the initial imaging is reported as normal, a specialist MRI review either by an experienced neuroradiologist or by a prion disease specialist unit could facilitate earlier diagnosis.

     

Human prion diseases in the Netherlands (1998-2009): clinical, genetic and molecular aspects

Prion diseases are rare and fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. Based on a national surveillance program in the Netherlands we describe here the clinical, neuropathological, genetic and molecular characteristics of 162 patients with neuropathologically confirmed prion disease over a 12-year period (1998-2009). Since 1998, there has been a relatively stable mortality of Creutzfeldt-Jakob disease (CJD) in the Netherlands, ranging from 0.63 to 1.53 per million inhabitants per annum. Genetic analysis of the codon 129 methionine/valine (M/V) polymorphism in all patients with sporadic CJD (sCJD) showed a trend for under-representation of VV cases (7.0%), compared with sCJD cohorts in other Western countries, whereas the MV genotype was relatively over-represented (22,4%). Combined PrP(Sc) and histopathological typing identified all sCJD subtypes known to date, except for the VV1 subtype. In particular, a "pure" phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. The relative excess of MV cases was largely accounted for by a relatively high incidence of the MV 2K subtype. Genetic analysis of the prion protein gene (PRNP) was performed in 161 patients and showed a mutation in 9 of them (5.6%), including one FFI and four GSS cases. Iatrogenic CJD was a rare phenomenon (3.1%), mainly associated with dura mater grafts. Three patients were diagnosed with new variant CJD (1.9%) and one with variably protease-sensitive prionopathy (VPSPr). Post-mortem examination revealed an alternative diagnosis in 156 patients, most commonly Alzheimer's disease (21.2%) or vascular causes of dementia (19.9%). The mortality rates of sCJD in the Netherlands are similar to those in other European countries, whereas iatrogenic and genetic cases are relatively rare. The unusual incidence of the VV2 sCJD subtype compared to that reported to date in other Western countries deserves further investigation.     

Human Prion Diseases in the United States

Background

Prion diseases are a family of rare, progressive, neurodegenerative disorders that affect humans and animals. The most common form of human prion disease, Creutzfeldt-Jakob disease (CJD), occurs worldwide. Variant CJD (vCJD), a recently emerged human prion disease, is a zoonotic foodborne disorder that occurs almost exclusively in countries with outbreaks of bovine spongiform encephalopathy.This study describes the occurrence and epidemiology of CJD and vCJD in the United States.

Methodology/Principal Findings

Analysis of CJD and vCJD deaths using death certificates of US residents for 1979–2006, and those identified through other surveillance mechanisms during 1996–2008. Since CJD is invariably fatal and illness duration is usually less than one year, the CJD incidence is estimated as the death rate. During 1979 through 2006, an estimated 6,917 deaths with CJD as a cause of death were reported in the United States, an annual average of approximately 247 deaths (range 172–304 deaths). The average annual age-adjusted incidence for CJD was 0.97 per 1,000,000 persons. Most (61.8%) of the CJD deaths occurred among persons ≥65 years of age for an average annual incidence of 4.8 per 1,000,000 persons in this population. Most deaths were among whites (94.6%); the age-adjusted incidence for whites was 2.7 times higher than that for blacks (1.04 and 0.40, respectively). Three patients who died since 2004 were reported with vCJD; epidemiologic evidence indicated that their infection was acquired outside of the United States.

Conclusion/Significance

Surveillance continues to show an annual CJD incidence rate of about 1 case per 1,000,000 persons and marked differences in CJD rates by age and race in the United States. Ongoing surveillance remains important for monitoring the stability of the CJD incidence rates, and detecting occurrences of vCJD and possibly other novel prion diseases in the United States.     

Clinical and laboratory features of 14 young Chinese probable sCJD patients

Sporadic Creutzfeldt-Jakob disease (sCJD) occurs frequently in the relatively older population, mainly in the groups of 60–69 and 70–79 year-old. Since 2006 when China performed national CJD surveillance, 14 young probable sCJD patients below 40 year-old were identified, counting for 1.93% of all probable sCJD cases. The clinical features of young probable sCJD cases, including the onset feature, the presence of sCJD-associated signs and the clinical duration, are indistinguishable from those of older patients. Special sCJD-associated abnormalities on EEG and MRI were noticed in 7 and 10 cases. CSF 14–3–3 was positive in 7 cases. CSF RT-QuIC showed positive reactive curves in 9 cases, with short lag phases. PRNP sequencing did not find any mutation. Due to low rate of brain autopsy in China, performances of other CJD-associated examinations as much as possible are extremely important for the distinguish diagnosis of young probable sCJD patients.     

Neuropathology of variant Creutzfeldt-Jakob disease

The neuropathological features human prion diseases comprise spongiform change, neuronal loss, astrocytic and microglial proliferation and the accumulation of the abnormal isoform of prion protein (PrPRES) in the central nervous system. Variant Creutzfeldt-Jakob disease (CJD) is a novel human prion disease which appears to result from infection by the bovine spongiform encephalopathy (BSE) agent. The neuropathology of variant CJD shows morphological and immunocytochemical characteristics distinct from all other types of human prion disease, and is characterised by abundant florid and cluster plaques in the cerebrum and cerebellum, and widespread accumulation of PrPRES on immunocytochemistry. Spongiform change is most marked in the caudate nucleus and putamen, and the thalamus exhibits severe neuronal loss and gliosis, which is most marked in the posterior nuclei and correlates with the areas of high signal seen in the posterior thalamus on MRI examination of the brain. Western blot analysis of PrPRES on frozen brain tissue in variant CJD tissue shows a uniform isotype, with a glycoform ratio distinct from sporadic CJD. PrPRES accumulation is widespread in lymphoid tissues in vCJD. All cases of variant CJD are methionine homozygotes at codon 129 of the PrP gene. Histological and biochemical techniques will be required to identify cases of 'human BSE' in individuals who are MV or VV at codon 129 of the PrP gene. Continued surveillance is required to investigate this possibility in the UK and other countries where BSE has been reported.     

Can prion disease suspicion be supported earlier?: Clinical,radiological and laboratory findings in a series of cases

The subacute spongiform encephalopathies are prion diseases characterized by acute and rapid neurodegeneration that lead to the death of the patient within months to a few years. The epidemiology of CJD is complicated and the frequency in Mexico is unknown. We aim to describe the cases of prion disease in Mexico. Consecutive patients who met the diagnostic criteria by the WHO were enrolled. We describe 26 patients with clinical manifestations, imaging and laboratory studies compatible with prion disease. The mean age at onset was 52 years old. The main clinical manifestations were cognitive alterations (69%) followed by extrapyramidal movements (50%), abnormal cerebellar function (46%), behavioral alterations (46%), myoclonus (46%) and mood depression (23%), among other features. Half of the patients progressed rapidly to a state of akinetic mutism (53%). Only 2 (7.6%) patients had a family history of a similar disease. Time interval between onset and diagnosis varied between 71 days to 24 months, with a median of 6 months. The classical bilateral basal ganglia hyperintensities were present in the very early stage of the disease. Protein 14-3-3 immuneassay in the CSF was positive in all measured cases. Bilateral basal ganglia hyperintensities was the most important early finding, while protein 14-3-3 was a late finding and the results were usually obtained after the patient was discharged. Around 1.5 cases of CJD cases per year are reported in our country. When suspected, MRI can support the diagnosis earlier than other studies.Key words: Creutzfeldt-Jacob disease, prions     

14-3-3 and enolase abundances in the CSF of Prion diseased rats

ABSTRACT

Creutzfeldt-Jakob disease (CJD) is characterized by an extended asymptomatic preclinical phase followed by rapid neurodegeneration. There are no effective treatments. CJD diagnosis is initially suspected based upon the clinical presentation of the disease and the exclusion of other etiologies. Neurologic symptoms are assessed in combination with results from cerebrospinal fluid (CSF) biomarker abundances, electroencephalography (EEG), magnetic resonance imaging (MRI), and in some countries, real-time quaking-induced conversion (RT-QuIC). Inconsistencies in sensitivities and specificities of prion disease biomarker abundance in CSF have been described, which can affect diagnostic certainty, but the utility of biomarkers for prognosis has not been fully explored. The clinical presentation of CJD is variable, and factors such as prion protein polymorphic variants, prion strain, and other genetic or environmental contributions may affect the disease progression, confounding the appearance or abundance of biomarkers in the CSF. These same factors may also affect the appearance or abundance of biomarkers, further confounding diagnosis. In this study, we controlled for many of these variables through the analysis of serial samples of CSF from prion-infected and control rats. Prion disease in laboratory rodents follows a defined disease course as the infection route and time, prion strain, genotype, and environmental conditions are all controlled. We measured the relative abundance of 14-3-3 and neuron-specific enolase (NSE) in CSF during the course of prion infection in rats. Even when disease-related, environmental and genetic variables were controlled, CSF 14-3-3 and NSE abundances were variable. Our study emphasizes the considerable diagnostic and prognostic limitations of these prion biomarkers.     

The Features of Genetic Prion Diseases Based on Chinese Surveillance Program

Objective

To identify the features of Chinese genetic prion diseases.

Methods

Suspected Creutzfeldt-Jakob disease (CJD) cases that were reported under CJD surveillance were diagnosed and subtyped using the diagnostic criteria issued by the WHO. The general information concerning the patient, their clinical, MRI and EEG data, and the results of CSF 14-3-3 and PRNP sequencing were carefully collected from the database of the national CJD surveillance program and analyzed using the SPSS 11.5 statistical software program.

Results

Since 2006, 69 patients were diagnosed with genetic prion diseases and as having 15 different mutations. The median age of the 69 patients at disease onset was 53.5 years, varying from 19 to 80 years. The majority of patients displaying clinical symptoms were in the 50–59 years of age. FFI, T188K gCJD and E200K were the three most common subtypes. The disease appeared in the family histories of 43.48% of the patients. The clinical manifestations varied considerably among the various diseases. Patients who carried mutations in the N-terminus displayed a younger age of onset, were CSF 14-3-3 negative, had a family history of the condition, and experienced a longer duration of the condition. The clinical courses of T188K were significantly shorter than those of FFI and E200K gCJD, while the symptoms in the FFI group appeared at a younger age and for a longer duration. Moreover, the time intervals between the initial neurologist visit to the final diagnosis were similar among patients with FFI, T188K gCJD, E200K gCJD and other diseases.

Conclusion

The features of Chinese genetic prion diseases are different from those seen in Europe and other Asian countries.     

Review. The origin of the prion agent of kuru: molecular and biological strain typing

Kuru is an acquired human prion disease that primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. The central clinical feature of kuru is progressive cerebellar ataxia and, in sharp contrast to most cases of sporadic Creutzfeldt-Jakob disease (CJD), dementia is a less prominent and usually late clinical feature. In this regard, kuru is more similar to variant CJD, which also has similar prodromal symptoms of sensory disturbance and joint pains in the legs and psychiatric and behavioural changes. Since a significant part of the clinicopathological diversity seen in human prion disease is likely to relate to the propagation of distinct human prion strains, we have compared the transmission properties of kuru prions with those isolated from patients with sporadic, iatrogenic and variant CJD in both transgenic and wild-type mice. These data have established that kuru prions have prion strain properties equivalent to those of classical (sporadic and iatrogenic) CJD prions but distinct from variant CJD prions. Here, we review these findings and discuss how peripheral routes of infection and other factors may be critical modifiers of the kuru phenotype.     

Dengue viruses activity in Piauí, Brazil

The present paper reports a laboratory investigation performed between the years of 2000 and 2002 to study a virological surveillance program introduced in the state of Piauí to support an epidemiological survey of the disease. Dengue virus type 3 (DENV-3) existence in the state was detected in May 2002 when a high number of dengue cases due to DENV-1 and DENV-2 were reported. An assessment on the population knowledge about the disease and its transmission showed that almost 50% of the population were still unaware of the epidemiological features of dengue.     

Transmission of human prion diseases to rodents

PrP genotypes of human prion diseases were closely related to deposition types of PrP^Sc, clinico-pathologic phenotypes and transmission rates to rodents. Wild type CJD with 129M/M, iatrogenic cases, and hereditary CJD with V1801, E200K, and M232R showed synaptic type deposition of PrP^Sc, similar phenotypes and, except for V1801, similar transmission rates. One patient with fatal familial insomnia transmitted the disease to mice. Plaque type deposition of PrP^Scinduced various phenotypes, such as GSS or Alzheimer's disease-like dementia, usually with a longer clinical course than CJD. Experimental transmission was positive from one-third of the cases with P102L but negative from other mutation cases with PrP plaques. Polymorphism at codon 129 may modify phenotypes as well as transmission rates.     

Overview and evaluation of 15 years of Creutzfeldt-Jakob disease surveillance in Belgium, 1998-2012

Background

In 1998, following the detection of variant Creutzfeldt-Jakob disease (vCJD) in the UK, Belgium installed a surveillance system for Creutzfeldt-Jakob disease (CJD). The objectives of this system were to identify vCJD cases and detect increases in CJD incidence. Diagnostic confirmation of CJD is based on autopsy after referral by neurologists. Reference centres perform autopsies and report to the surveillance system. The aim of this study was to assess whether the system met its objectives and to assess its acceptability.

Methods

For 1999–2010, we linked surveillance data with hospital discharge data. We calculated the proportion of CJD suspected patients who died in hospitals and were captured by the surveillance system. We surveyed stakeholders on knowledge of the surveillance system, referral practices and acceptability. We compared proportions using the chi-square test and investigated variables associated with capture using a multivariable logistic regression model.

Results

On average 60 % of hospitalised patients who died with suspected CJD were captured by the surveillance system. This proportion did not significantly differ over the years (p?=?0.1). The odds of capture significantly decreased with every 1 year increase in age (OR?=?0.95, 95 % CI 0.92–0.98, p?=?0.001). Eleven percent of surveyed neurologists would not refer suspect vCJD cases for autopsy, nor contact a reference centre for diagnostic support. Sixty-one percent of surveyed neurologists were not familiar with the surveillance system. Awareness of the existence of the system did not impact referral behaviour (p?=?0.18). CJD and vCJD surveillance were considered important by the majority of stakeholders.

Conclusions

Although 40 % of the suspect CJD cases were not referred for autopsy, our data suggest that the Belgian CJD surveillance system meets one of its main objectives: it can detect changes in CJD incidence. However, we do not have sufficient evidence to conclude that the system meets its second objective of detecting vCJD cases arising in Belgium. Although not well known, the system was considered acceptable by its stakeholders.

     

Iatrogenic and sporadic Creutzfeldt-Jakob disease in 2 sisters without mutation in the prion protein gene

ABSTRACT

Human genetic prion diseases have invariably been linked to alterations of the prion protein (PrP) gene PRNP. Two sisters died from probable Creutzfeldt-Jakob disease (CJD) in Switzerland within 14 y. At autopsy, both patients had typical spongiform change in their brains accompanied by punctuate deposits of PrP. Biochemical analyses demonstrated proteinase K-resistant PrP. Sequencing of PRNP showed 2 wild-type alleles in both siblings. Retrospectively, clinical data revealed a history of dural transplantation in the initially deceased sister, compatible with a diagnosis of iatrogenic CJD. Clinical and familial histories provided no evidence for potential horizontal transmission. This observation of 2 siblings suffering from CJD without mutations in the PRNP gene suggests potential involvement of non-PRNP genes in prion disease etiology.     

Molecular genetics of human prion diseases in Germany

Human prion diseases may be acquired as infectious diseases, they may be inherited in an autosomal dominant fashion or occur sporadically. Mutations and polymorphisms in the sequence of the coding region of the prion protein gene (PRNP) have been established as an important factor in all of these three types of prion diseases. Therefore, a total of 578 patients with suspect prion diseases referred to the German Creutzfeldt-Jakob disease (CJD) surveillance unit over a period of 4.5 years have been examined for mutations and polymorphisms in the coding region of PRNP. We found 40 cases with a missense mutation previously reported as pathogenic. Amongst these, the aspartate to asparagine change at codon 178 (D178N) was the most common mutation. All of these cases carried the D178N mutation in coupling with methionine at codon 129, resulting in the typical fatal familial insomnia (FFI) genotype. Most cases with pathogenic mutations were not found in the group of clinically "probable" cases according to established clinical criteria, supporting the notion that inherited prion diseases often exhibit atypical features. Two novel missense mutations (T188R and P238S) and several silent polymorphisms were found, demonstrating the quality of our screening procedure based on a modified version of the single-stranded conformational polymorphism technique. In "definite" CJD cases with no pathogenic mutation, the patients clinically classified as "probable" were mostly homozygous for methionine at the common polymorphism at codon 129, whereas there was a marked over-representation of patients homozygous for valine amongst those clinically classified as "possible". This large study on suspect cases of human prion diseases in Germany clearly shows that PRNP genetics is essential for a comprehensive analysis of prion diseases.