Epidemiological characteristics of human prion diseases
© Chen and Dong. 2016
Received: 22 January 2016
Accepted: 4 May 2016
Published: 2 June 2016
Human prion diseases are a group of transmissible, progressive, and invariably fatal neurodegenerative disorders, which include Kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia. Human prion diseases affect approximately 1–2 persons per million worldwide annually, occurring in sporadic, inherited, and acquired forms. These diseases have attracted both scientific and public attention not only because of their mysterious pathogen, but also due to their considerable threat to public health since the emergence of the variant CJD.
There are still no specific therapeutic and prophylactic interventions available for prion diseases, thus active surveillance of human prion diseases is critical for disease control and prevention. Since 1993, CJD surveillance systems have been established in many countries and regions, and several long-term multinational cooperative projects have been conducted.
In this paper, the epidemiological characteristics of various human prion diseases and the active surveillance systems pertaining to them in different countries and regions are summarized and reviewed.
KeywordsPrion disease Epidemiology Creutzfeldt-Jakob disease Surveillance
Please see Additional file 1 for translations of the abstract into the six official working languages of the United Nations.
Human prion diseases, also named transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders, which include Kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). These various subtypes have different characteristics based on the onset times/durations of the disease, genetic/family histories of the patients, clinical manifestations, neuropathology, and scrapie-like prion protein (PrPSc) molecular features [1, 2]. It is widely accepted that TSEs result from the conformational conversion of a normal cellular prion protein (PrPC) into an abnormal misfolded pathological form (PrPSc). An accumulation of PrPSc leads to the onset of TSEs, which attack the central nervous system, resulting in progressive neuronal degeneration and neuronal vacuolation .
Currently, Kuru is virtually extinct due to a ban on ritualistic cannibalism in the area of Papua New Guinea where it was endemic. Most of the human prion diseases are CJD, which consist of three main catalogues: sporadic, genetic, and acquired . Approximately 85–90 % of CJD cases occur sporadically and affect 1–1.5 people per million annually . Familial/genetic CJD (fCJD/gCJD) account for about 10 % of CJD cases worldwide . Acquired prion diseases include variant CJD (vCJD) and iatrogenic CJD (iCJD), and are observed in 2–5 % of CJD cases. Depending on the origin of the causative agent, human prion diseases can be divided into two groups: caused by prions originating internally, such as in the case of fCJD/gCJD, GSS, and FFI; or infected by external prions, such as in the case of Kuru, iCJD, and vCJD .
The pathogenesis of sporadic CJD (sCJD) is little known. Many case–control studies on the risk factors for sCJD have been conducted, with varying results, but no consistent data are available [7–12]. However, the opportunity of external prion infection is still not easy to be excluded definitely during long life-span .
As there are no specific therapeutic and prophylactic interventions available for prion diseases, active surveillance is critical for the control and prevention of human prion diseases, especially those diseases caused by animal-derived prion agents. Since 1993, many national CJD surveillance systems have been established and several multinational cooperative organizations have also been set up for CJD surveillance and research [14–18]. In the present review, the epidemiological characteristics of various subtypes of human prion diseases and the active surveillance systems pertaining to them are summarized and discussed.
Epidemiological characteristics of human prion diseases
CJD was first described in the early 1920s [19, 20]. The predominant subtype of human prion diseases, sCJD, occurs equally in both sexes with a peak age of onset between 60 and 69 years [21–23]. sCJD occurs all year round, with no seasonal specificity. Typical clinical symptoms include progressive dementia, accompanied by visual and cerebellum function abnormalities, myoclonia, pyramidal and extrapyramidal dysfunction, or akinetic mutism [2, 21]. The duration of sCJD cases is relatively short. The median survival time of Chinese sCJD cases is 7.1 months (range: 1.0–23.3) and 78.5 % of patients die within one year of onset . These data are comparable with that of Western countries but differ to data from Japan. A study conducted by the European CJD Surveillance Network (EuroCJD) involving 2,451 sCJD patients, who died between 31 December 1992 and 31 December 2002, revealed that the median survival time was five months (range: 1–81) and that 85.8 % of patients died within one year of onset . In Argentina, the median disease duration of sCJD (calculated using 150 definite and probable cases from available data) is 4.6 months (range: 1–70) . On the contrary, a survey by the Japanese CJD surveillance program showed significantly longer disease durations in Japanese patients with prion diseases (most of them with the sCJD subtype), in which the mean disease duration of 855 patients was 17.4 months and only 46.0 % died within one year of onset. This is likely attributed to the country’s healthcare system, which provides intensive life-sustaining treatment for patients . There is no accessible data for sCJD cases in South Asia or Africa.
Genetic human prion diseases
The human gene encoding for the prion protein (PrP), PRNP, is located on chromosome 20p12 in humans. To date, more than 40 mutations in the PRNP gene have been directly linked to familial prion diseases, including fCJD/gCJD, GSS, and FFI . These mutations include point mutations in the PRNP sequence, and octapeptide repeat insertions or deletions in PrP’s N-terminus. Several epidemiological surveys report that some patients with genetic prion diseases lack definite family history [33, 34].
The distribution of genetic prion diseases in European and East Asians countries
Total (n = 420)
China (n = 62)
Japan (n = 216)
Korea (n = 15)
Total (n = 293)
P < 0.001
P < 0.01
P < 0.001
P < 0.001
P < 0.001
P < 0.001
P < 0.001
P < 0.001
P < 0.05
P < 0.01
The distribution and frequency of mutations in the PRNP gene causing GSS are also clearly distinct between Caucasians and East Asians. Although the most common mutation causing GSS in Caucasian and East Asian patients is P102L, the mutation P105L is only observed in East Asian populations, especially in the Japanese, while the mutation A117V is exclusively reported in Caucasians.
FFIs caused by the mutation D178N in the PRNP gene associated with the M129 genotype have been reported worldwide. However, there are also clear geographical and race-associated variations. FFI is predominant in some regions of Europe, such as in Spain and Germany, where 56.8 % (25/44) and 25 % (17/68) of genetic prion diseases are FFI, respectively . It is worth emphasizing that FFI cases are common in the Han Chinese population, which reaches to the first most common PRNP mutation in all identified mutations associated with genetic prion diseases in China , revealing a distinct profile compared with those in Japan and Korea (see Table 1). A study further addressing PRNP mutations among different ethnic groups is warranted.
The age at onset of genetic prion diseases is often earlier than that of sCJD, ranging from 30 to 55 years for gCJD, 40 to 60 years for GSS, and 20 to 72 years for FFI . Although gCJD cases with point mutations have an earlier median age of death compared with that of sCJD cases, there is no difference between gCJD cases with point mutations and sCJD in the mean duration of the disease [44–46]. Meanwhile, gCJD cases with extra insertional octarepeat sequences, as well as GSS and FFI cases often have a relatively protracted duration of illness in Caucasians [34, 47, 48]. Relatively long clinical durations are also observed in Chinese FFI cases  and Japanese GSS patients .
In addition to these disease-related mutations, polymorphisms have also been described in PrP [32, 50]. In particular, single nucleotide polymorphisms (SNPs) at codons 129 and 219 of the PRNP gene represent susceptibility factors for human prion diseases [51, 52]. The pattern of SNP at codon 129 greatly varies between Caucasians and East Asians. An overwhelming percentage of East Asians (92 % to 94 %) exhibit methionine/methionine homozygote at codon 129 (M129M), but a much lower percentage of Caucasians have this polymorphism (32 % to 45 %) . Homozygosity at codon129 (M/V polymorphism) is a strong risk factor for the development of sCJD in Caucasians [15, 53–55]. Moreover, all vCJD cases with clinical symptoms and genetic analysis worldwide are M129M homozygous . Homozygosity at a different PRNP polymorphism, E219K, seems to also be a risk factor for the development of sCJD in Korean and Japanese populations, but not in Caucasian populations [16, 52, 57–59]. In addition, PRNP codon 129 polymorphism has obvious effects on the clinical, neuropathological, and pathogenic features of prion disease. For instance, in the population with the D178N mutation in the PRNP gene, the codon 129 polymorphism determines the type of disease: people with the M129M mutation suffer from FFI and those with the M129V mutation acquire gCJD [60, 61].
The clinicopathological features of dura mater graft-associated iCJD cases resemble those of sCJD cases. However, in Japan, approximately one third of these cases have atypical features (slow progression, non-characteristic electroencephalogram tracings, plaque deposition, and an atypical prion protein molecular signature on Western blots), suggesting the possibility of two different types of infectious agents [71, 72]. The incubation periods are in the range of 1.3 to 30 years (mean: 12) worldwide . The clinicopathological features of hGH-related iCJD cases resemble those of Kuru. The incubation periods vary from five to 42 years worldwide (mean:17) . Those with the M129M mutation are at risk for acquiring hGH-related iCJD in France and in the US, but not in the UK [68, 73, 74].
Surveillance of human prion diseases
Besides these major CJD surveillance networks, there are several other CJD surveillance and/or research groups intra- and internationally, including CJD surveillance in Central and Eastern European countries . NeuroPrion, which aims to structure and integrate the efforts of the main European prion research teams for the effective management of prion diseases is funded by the European Commission and has been operating since 2003 . In 1997, the National Prion Disease Pathology Surveillance Center of the US was established at the Case Western Reserve University  and the following year, the Canadian CJD surveillance system was initiated by the Public Health Agency of Canada . In 1999, the CJD Surveillance Committee was established at the Kanazawa University of Japan, which started carrying out surveillance of CJD nationwide . The CJD surveillance program in the Republic of Korea was established in 2001 and it is supported by the Korean CDCs . In 2006, the China CJD surveillance program was initiated, which is supported by the Chinese CDC .
CJD surveillance systems have some unique features compared with other public health surveillance systems. One is that due to a lack of approved biomarkers for CJDs, specific types of clinical and laboratory approaches are critical to effectively diagnose and monitor CJDs. The other is that CJD surveillance systems are primarily dependent on reports from physicians, especially neurologists and neuropathologists in regional hospitals and medical centers where first visit for most patients. Thus, the experiences of these specialists directly determine the quality of the collected specimens, such as accurate identify the clinical manifestations of CJD or supply the appropriate specimens to CJD surveillance center. Both aspects seriously impact the sensitivity of CJD surveillance.
Human prion diseases are invariably fatal neurodegenerative disorders. The emergence of the novel prion strain, which include the causative agent of vCJD, has created an important public health concern. New prion strains continually emerge in livestock, and their threats to other domestic animals and humans are uncertain and need long-term evaluation and assessment. Strategies for early diagnosis of and therapies to treat human prion diseases remain unavailable. Therefore, except for developing treatment for prion diseases, the most feasible method to prevent these diseases from spreading, either via human-to-human or zoonotic transmission, is active surveillance and improving the sensitivity and specificity of laboratory diagnostic procedures. This will require more clinicians and experts participating in regional, national, and global systems by investing more of an effort toward reliable and accurate diagnostic methods for the control of prion diseases.
bovine spongiform encephalopathy
center for disease control and prevention
European Creutzfeldt-Jakob disease surveillance network
familial Creutzfeldt-Jakob disease
fatal familial insomnia
genetic Creutzfeldt-Jakob disease
iatrogenic Creutzfeldt-Jakob disease
methionine/methionine homozygote at codon 129
human gene encoding for the major prion protein
- PrPC :
cellular prion protein
- PrPSc :
scrapie-like prion protein
sporadic Creutzfeldt-Jakob disease
single nucleotide polymorphism
transmissible spongiform encephalopathies
variant Creutzfeldt-Jakob disease
This work was supported by the Chinese National Natural Science Foundation Grants (81401670), the China Mega-Project for Infectious Diseases (2011ZX10004-101, 2012ZX10004215), and the SKLID Development Grant (2012SKLID102).
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