Epidemiological characteristics of human prion diseases
Epidemiological characteristics of human prion diseases
Cao Chen1,2 and Xiao-Ping Dong1,2,3*
Abstract
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. Keywords: Prion disease,
Epidemiology, Creutzfeldt-Jakob disease, Surveillance
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 [13].
snip...
Epidemiological characteristics of human prion diseases sCJD 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 [24].
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 [25]. 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) [17]. 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 [26]. There is no accessible data for sCJD cases in South
Asia or Africa.
An international study on the epidemiologic characteristics of sCJD
involving 3,720 sCJD cases from nine European countries, as well as from
Australia and Canada, revealed that the overall annual mortality rate from sCJD
is 1.39 per million [27]. In Japan, the ageadjusted mortality rates have
increased from 1979 to 2004, with the annual mortality rate of 1.48 per million
in 2004 [28]. The Chinese CJD surveillance network reported that the annual CJD
morbidity rate in Beijing is 0.91 per million [29]. The recognition of CJD
clinically and the undertaking of national CJD surveillance influences a
country’s mortality rate. According to the latest data from the CJD
International Surveillance Network (formerly the EuroCJD), the countries with
the highest mean mortality rates per million from sCJD are France and
Switzerland (1.51 and 1.72, respectively). The mean mortality rates per million
from sCJD from 1993 to 2013 of some countries are shown in Fig. 1a; 16 out of 28
countries have a mean mortality rate per million greater than 1.0. Averaging the
annual data from all countries in the CJD International Surveillance Network
from 1993 to 2013 results in the mortality rates per million increased (see Fig.
1b). In the United States (US), the annual mortality rate is approximately one
per million based on data from 1979 to 2006 [30]. However, it is important to
note that most CJD cases from these data were European Americans (94.6 %) and
that the age-adjusted incidence of whites is 2.7 times higher than that of
African Americans (1.04 and 0.40, respectively) [30], and is also higher than
that of Native Americans and Alaska Natives (0.47) [31]. Although reasons for
such disparities are unclear, it is possible that genetic differences and/or
under diagnosis among non-white patients are two associated factors.
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 [32]. 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 and frequency of mutations in the PRNP gene vary
significantly among geographical areas and human races. In gCJD/fCJD, the three
most common PRNP mutations in European Caucasians, North Americans, and
Australians are E200K, V210I, and D178N/ 129 V [34]. Interestingly, E200K is the
only mutation in the PRNP gene reported in the Slovak population, whereas only
one E200K gCJD case was identified in the population of Switzerland between 1996
and 2002, and no E200K gCJD has been reported after this. The proportionate
incidence of the V210I mutation in the Italian population is obviously higher
than that in other ten countries (50 out of 69 V210I gCJD cases are observed in
Italy), according to data from the EuroCJD 1993–2002 [35]. In Japan, the most
frequently observed mutation in the PRNP gene is V180I, followed by E200K and
M232R [16], while the mutations T188K and E200K are most frequent in China [36].
Five mutations in codon 180, three in codon 200, two in codon 203, and two in
codon 232 have been identified in the Republic of Korea [37–42]. The frequency
of gCJD cases in the Republic of Korea is similar to that in Japan, but differs
from that in China (see Table 1) [43]. In addition, the V210I mutation is
prevalent in European countries but is rare in East Asian populations. M232R,
which is one of the most frequently described gCJDassociated mutations in the
Japanese, is rarely identified among Europeans.
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 [34]. 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 [36], 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 [43]. 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 [49] and Japanese GSS patients
[26].
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 %) [43]. 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
[56]. 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].
iCJD
In 1974, iatrogenic CJD (iCJD) was firstly described in a person who
received cadaveric corneal transplant from a patient with CJD [62]. Since then,
several cases of human prion disease have been confirmed to be associated with
iatrogenic transmission of CJD by the use of stereotactic intracerebral
electroencephalogram needles or neurosurgical instruments [63–67]. Additionally,
corneal grafts and the gonadotropin hormone [68, 69] can also cause iCJD.
Because of the long incubation time of iCJD, it is usually very difficult to
attribute the disease to a special medical service in the lifespan of a patient.
Therefore, the numbers of iCJD cases might be underestimated. Historically,
large outbreaks of human iCJD cases have been reported via two different medical
pathways: one is cadavericdura mater grafts [16], and the other is intramuscular
injection of contaminated cadaveric pituitary-derived human growth hormone (hGH)
and gonadotropin hormone [70]. Since the first identification of dura mater
graft-associated iCJD in 1987, at least 228 cases have been reported worldwide.
Nearly two thirds of cases come from Japan, with some European countries, such
as France, Spain, Germany, Italy, and the Netherlands, also reporting iCJD.
Cases have also been reported from Australia (five cases), South Africa (one
case), Argentina (one case), the US (four cases), and South Korea (two cases)
[68]. At least 226 hGH-related iCJD caseshave been reported worldwide, mostly in
France (119 cases), the United Kingdom, UK (65 cases) and the US (29 cases), and
a few cases in Brazil (two cases), New Zealand (six cases) and Qatar (one case)
[68]. The global distribution of iCJD cases associated with dura mater grafts
and the hGH is shown in Fig. 2. With the availability of recombinant hGH and the
initiation of separated processing of individual dura mater grafts, the
transmission pathways of these two kinds of iCJD have been successfully
eradicated and almost no new cases have been reported in the past few years
[70]. So far, there have been no reports of dura mater graft-associated or
hGH-related iCJD in China.
The clinicopathological features of dura mater graftassociated 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 [68]. The clinicopathological
features of hGH-related iCJD cases resemble those of Kuru. The incubation
periods vary from five to 42 years worldwide (mean:17) [68]. 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].
vCJD
The first 10 vCJD cases were reported in April 1996 in the UK [70, 75]. As
of April 2015, 229 vCJD cases have been reported from seven European (UK,
France, Spain, Republic of Ireland, Netherlands, Italy, and Portugal) and five
non- European countries or regions (US, Canada, Saudi Arabia, Japan, and
China-Taiwan). Among them, 177 cases were reported from the UK [76]. In 2000,
the annual number of deaths from vCJD in the UK reached a peak of 28. Since
2006, the annual deaths from vCJD have dramatically reduced, with 2–5 from 2006
to 2011, none in 2012, and only one in 2013 [77]. Since 2014, no more vCJD cases
have been reported (see Fig. 3). Outside of the UK, France is the most affected
country, with 27 vCJD cases reported from 1996 to 2014, which is thought to be
related to the peak in the volume of beef imports from the UK from 1985 to 1995
[78]. This potential relationship is shown by the peak of the number of deaths
from vCJD in France in 2005, five years after a similar peak in the number of
deaths occurred in the UK [78, 79]. Additionally, three East Asian vCJD cases
has been identified in Hong Kong SAR [80], Japan [81, 82], and China-Taiwan
[83]. All three are assumed to be imported cases from the UK due to patients who
either previously resided in or travelled to the UK bringing them in. The median
age of onset is 27 years (range: 12–74) and the median duration of the disease
is 14 months in the UK (range: 6–40). In France, despite a median age of onset
is 35 years (range: 18–57), which is higher than in the UK, all other data are
similar [84]. The disease duration in Asians (mean 28.3, range 14–43 months)
seems to be longer than in patients in the UK and France [83]. A further study
supports the hypothesis that a single strain of infectious agent is responsible
for all vCJD infections [85]. Probable secondary transmission of vCJD via blood
transfusions has been reported [86]. Animal experiments have shown that the
M129V heterozygote is less sensitive to the transmission of vCJD and bovine
spongiform encephalopathy (BSE) agents [87, 88]. Thus, vCJD with long incubation
periods in individuals with M129V and V129Vgenotypes and secondary iatrogenic
transmission of vCJD are still serious public health concerns [89–93].
Surveillance of human prion diseases
Due to the impact that the BSE outbreak and the emergence of vCJD has had
on public health, many countries and regions have initiated or re-initiated
their surveillance programs for human prion diseases. Initially, two major
surveillance networks for human prion diseases were created by the European
Commission. One is the EuroCJD established in 1993 by seven countries (Austria,
France, Germany, Italy, Netherlands, Slovakia, and the UK), which was later
expanded to other European and non-European countries such as Australia, Canada,
and Spain. The other one is NeuroCJD initiated in 1998, which includes all the
other European countries and Israel [18, 34, 79]. In 2008, the CJD International
Surveillance Network (formerly EuroCJD) was launched and funded by the European
Center for Disease Prevention and Control (CDC) [94, 95]. The network includes
28 collaborating centers from European Union (EU) Member States, European Free
Trade Association countries, and eight non-EU countries/ regions (Argentina,
Australia, Japan, Canada, Mexico, China, Israel, USA, and China-Taiwan) (see
Fig. 4). The primary objective of the network is to identify all cases of vCJD
in the EU and provide accurate data on the worldwide incidence of vCJD through
collaborations with other non-EU countries.
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 [96]. 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 [18]. In 1997, the National Prion
Disease Pathology Surveillance Center of the US was established at the Case
Western Reserve University [97] and the following year, the Canadian CJD
surveillance system was initiated by the Public Health Agency of Canada [98]. In
1999, the CJD Surveillance Committee was established at the Kanazawa University
of Japan, which started carrying out surveillance of CJD nationwide [16]. The
CJD surveillance program in the Republic of Korea was established in 2001 and it
is supported by the Korean CDCs [18]. In 2006, the China CJD surveillance
program was initiated, which is supported by the Chinese CDC [22].
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.
Conclusion
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.
VPSPR ???
dpCJD 'diagnosis pending creutzfeldt jakob disease' ???
TSS
posted by Terry S. Singeltary Sr. at
3:55 PM
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