Abstract

We analysed the epidemiological data and clinical features of patients with prion diseases that had been registered by the Creutzfeldt-Jakob Disease Surveillance Committee, Japan, over the past 10 years, since 1999. We obtained information on 1685 Japanese patients suspected as having prion diseases and judged that 1222 patients had prion diseases, consisting of definite (n = 180, 14.7%) and probable (n = 1029, 84.2%) cases, except for dura mater graft-associated Creutzfeldt–Jakob disease which also included possible cases (n = 13, 1.1%). They were classified into 922 (75.5%) with sporadic Creutzfeldt–Jakob disease, 216 (17.7%) with genetic prion diseases, 81 (6.6%) with acquired prion diseases, including 80 cases of dura mater graft-associated Creutzfeldt–Jakob disease and one case of variant Creutzfeldt–Jakob disease, and three cases of unclassified Creutzfeldt–Jakob disease (0.2%). The annual incidence rate of prion disease ranged from 0.65 in 1999 to 1.10 in 2006, with an average of 0.85, similar to European countries. Although methionine homozygosity at codon 129 polymorphism of the prion protein gene was reported to be very common (93%) in the general Japanese population, sporadic Creutzfeldt–Jakob disease in Japan was significantly associated with codon 129 homozygosity (97.5%), as reported in western countries. In sporadic Creutzfeldt–Jakob disease, MM1 type (Parchi’s classification) is the most common, as in western countries. Among atypical sporadic Creutzfeldt–Jakob disease cases, the MM2 type appeared most common, probably related to the very high proportion of methionine allele in the Japanese population. As for iatrogenic Creutzfeldt–Jakob disease, only dura mater graft-associated Creutzfeldt–Jakob disease cases were reported in Japan and, combined with the data from previous surveillance systems, the total number of dura mater graft-associated Creutzfeldt–Jakob disease was 138, comprising the majority of worldwide dura mater graft-associated Creutzfeldt–Jakob disease patients. Regarding genetic prion diseases, the most common mutation of prion protein gene was V180I (41.2%), followed by P102L (18.1%), E200K (17.1%) and M232R (15.3%), and this distribution was quite different from that in Europe. In particular, V180I and M232R were quite rare mutations worldwide. Patients with V180I or M232R mutations rarely had a family history of prion diseases, indicating that a genetic test for sporadic cases is necessary to distinguish these from sporadic Creutzfeldt–Jakob disease. In conclusion, our prospective 10-year surveillance revealed a frequent occurrence of dura mater graft-associated Creutzfeldt–Jakob disease, and unique phenotypes of sporadic Creutzfeldt–Jakob disease and genetic prion diseases related to the characteristic distribution of prion protein gene mutations and polymorphisms in Japan, compared with those in western countries.

Introduction

Prion diseases are a fatal human transmissible spongiform encephalopathy (Prusiner, 1998) and are classified into sporadic, genetic and acquired forms; the most common being sporadic Creutzfeldt–Jakob disease, which is of unknown aetiology. The overall annual mortality rate of sporadic Creutzfeldt–Jakob disease is ∼1.5 per million worldwide (Ladogana et al., 2005). The genetic form (i.e. genetic prion disease) is defined as a prion disease with causative mutations in the human prion protein (PrP) gene (PrP) and/or a relevant family history, including Gerstmann–Sträussler–Scheinker disease, fatal familial insomnia and genetic Creutzfeldt–Jakob disease (Kovács et al., 2005). The acquired forms are transmitted among humans (i.e. iatrogenic Creutzfeldt–Jakob disease or Kuru) or from animals to humans, particularly bovine to human (i.e. variant Creutzfeldt–Jakob disease). To date, >400 patients with iatrogenic Creutzfeldt–Jakob disease have been reported, including transmission via infectious PrP-contaminated neurosurgical instruments, deep brain electrodes, human pituitary growth hormone, human cadaveric dura mater grafts, corneal transplantation or blood transfusion (Brown et al., 2006). In particular, >50% of patients with cadaveric dura mater graft-associated Creutzfeldt–Jakob disease have occurred in Japan (Brown et al., 2006). Although our previous case-control study revealed that medical procedures before the onset of prion diseases did not influence the onset of sporadic Creutzfeldt–Jakob disease, there was a problem that surgical treatments were performed on some patients with sporadic Creutzfeldt–Jakob disease after the onset of prion diseases (Hamaguchi et al., 2009a, b). Since the first identification of variant Creutzfeldt–Jakob disease in the UK in 1996, 212 patients have been reported worldwide, including in Canada, France, Ireland, Italy, Japan, Portugal, Saudi Arabia, Spain, the Netherlands and the USA as well as the UK [The National Creutzfeldt–Jakob Disease Surveillance Unit (NCJDSU) (http://www.cjd.ed.ac.uk/vcjdworld.htm)].

From the viewpoint of public health, identification of the incidence of human and animal prion diseases is essential to prevent disease transmission. Various Creutzfeldt–Jakob disease surveillance systems have been established since the 1990s in many countries, including Australia, Austria, Belgium, Canada, Catalonia, China, France, Germany, Ireland, Italy, Slovakia, Spain, Switzerland, the Netherlands, the UK, the USA and Japan (Will et al., 1998; Nakamura et al., 1999; Collins et al., 2002; Glatzel et al., 2002; Puopolo et al., 2003; Horan et al., 2004; Pocchiari et al., 2004; Sanchez-Valle et al., 2004; Ladogana et al., 2005; de Pedro-Cuesta et al., 2006; Van Everbroeck et al., 2006; Heinemann et al., 2007; Shi et al., 2008; Klug et al., 2009; Holman et al., 2010).

Although detailed data from the nationwide surveillance of human prion diseases have been published by European countries, Australia and the USA (Ladogana et al., 2005; de Pedro-Cuesta et al., 2006; Heinemann et al., 2007; Klug et al., 2009; Holman et al., 2010), large-scale prospective data, comparable to those from western countries, have never been reported from Asia. In Japan, the current Creutzfeldt–Jakob disease surveillance system was established in 1999 (Noguchi-Shinohara et al., 2007) and prospective nationwide surveillance has been ongoing for >10 years. Here we report the prospective 10-year data of the Japanese Creutzfeldt–Jakob disease surveillance.

Materials and methods

Patients and ethical aspects

In Japan, the prospective surveillance of human prion disease by the Creutzfeldt–Jakob Disease Surveillance Committee started in April 1999. Japan was divided into 10 areas for surveillance. The Creutzfeldt–Jakob Disease Surveillance Committee, with 19 members, included members responsible for surveillance in each area, and for epidemiology, neuroimaging, genetic analysis, CSF tests, western blotting and neuropathology. Information on patients with suspected prion diseases was obtained through (i) the registration of each patient’s family with the Intractable Disease Treatment Research Program, the Ministry of Health, Labour and Welfare, Japan; (ii) notification based on the Infectious Diseases Control Law; or (iii) a request for genetic or CSF analyses by physicians to the members of the Creutzfeldt–Jakob disease Surveillance Committee. Written informed consent to participate in the study was given by all patients’ families. The study protocol was approved by the Medical Ethics Committee of Kanazawa University. We analysed all patients suspected of prion disease who had been registered by the Creutzfeldt–Jakob Disease Surveillance Committee in Japan from April 1999 to September 2009. Each patient suspected of having prion disease was investigated by the members of the Creutzfeldt–Jakob Disease Surveillance Committee in cooperation with Creutzfeldt–Jakob disease specialist(s) in each prefecture using the following surveillance protocol: previous medical history, clinical history, neurological findings, laboratory data including analyses of biomarkers (i.e. 14-3-3 protein) in CSF, MRI or CT, analyses of cerebral blood flow by single photon emission computed tomography, EEG, genetic analyses of PrP, neuropathological examinations and western blot analyses of protease K-resistant PrP. Based on discussions with the Creutzfeldt–Jakob Disease Surveillance Committee using the case definition shown below, we decided whether they had prion diseases.

Case definition

Prion diseases were classified into four categories: (i) sporadic Creutzfeldt–Jakob disease, (ii) acquired prion diseases (iatrogenic Creutzfeldt–Jakob disease or variant Creutzfeldt–Jakob disease), (iii) genetic prion diseases and (iv) unclassified prion diseases. Sporadic Creutzfeldt–Jakob disease was diagnosed according to the classical criteria established by Masters et al. (1979). The World Health Organization (WHO) criteria (WHO, 1998) were not applied because the assay of CSF 14-3-3 protein, which is required by the WHO criteria, was not standardized in Japan until April 2009. Regarding acquired prion diseases, iatrogenic Creutzfeldt–Jakob disease was diagnosed using the criteria for sporadic Creutzfeldt–Jakob disease. Cases of dura mater graft-associated Creutzfeldt–Jakob disease are categorized into two subtypes: the plaque type, which shows plaque-type PrP deposits, and the non-plaque type, which shows synaptic-type PrP deposits without PrP plaques (Noguchi-Shinohara et al., 2007; Yamada et al., 2009). Variant Creutzfeldt–Jakob disease was diagnosed using the WHO (2001) criteria. Genetic prion disease was diagnosed by neuropsychiatric findings compatible with prion disease, a relevant family history and a mutation of PrP. In patients with the M232R mutation, Shiga et al. (2007) reported two different clinical types: a rapidly progressive type that developed to akinetic mutism within 6 months (rapid type) and a slowly progressive type that did not develop to akinetic mutism until 15 months (slow type) (Shiga et al., 2007). Unclassified Creutzfeldt–Jakob disease was defined as cases requiring more information (e.g. history of protease K-resistant PrP-contaminated medical procedure) for classification.

The accuracy of the diagnosis of prion disease was defined as: (i) ‘definite’, i.e. pathologically verified cases; (ii) ‘probable’, i.e. cases with neuropsychiatric manifestations compatible with prion diseases and periodic synchronous wave complexes (PSWCs) on EEG without pathological examinations, or cases of genetic prion disease with mutations of PrP; (iii) ‘possible’, i.e. cases with the same findings as ‘probable’ Creutzfeldt–Jakob disease, but no PSWCs on EEG or genetic prion disease cases with relevant family histories but without analyses of PrP.

The instances that did not satisfy the case definition of prion diseases were classified into three categories: (i) ‘prion diseases definitely denied’, (ii) ‘prion diseases probably denied’, and (iii) ‘diagnosis unclear’. ‘Prion diseases definitely denied’ included patients who could be given a definite diagnosis of other diseases, and ‘prion diseases probably denied’ included patients in whom prion diseases were denied due to an improving, stable disease course or other reasons without a definite diagnosis of other diseases. ‘Diagnosis unclear’ was defined as such.

Clinical analyses and laboratory examinations

We analysed the age at onset of prion disease, sex, clinical duration between onset and akinetic mutism or death (if patients did not develop akinetic mutism), neuropsychiatric symptoms and signs during the clinical course, duration between the onset and appearance of each neuropsychiatric finding, brain MRI findings, PSWCs on EEG, PrP genotypes and CSF 14-3-3 protein. In iatrogenic Creutzfeldt–Jakob disease cases, the following points were investigated: year and age of receiving the medical procedure contaminated with prions, incubation period between receiving the transplanted graft and onset of Creutzfeldt–Jakob disease, source of the medical procedure and the type of surgery. PSWCs on EEG were judged to be ‘typical’ or ‘suggested’ by member(s) of the Creutzfeldt–Jakob Disease Surveillance Committee responsible for each area. The ‘typical’ cases were reported to be ‘positive’. For the ‘suggested’ cases, the findings of the EEG were reviewed and discussed by the committee to decide ‘positive’ or ‘negative’ for PSWCs. High intensities on the following MRI sequences were examined in the cerebral cortices, basal ganglia and thalamus: diffusion-weighted images, fluid-attenuated inversion recovery images, or T2-weighted images. The hyperintensities on MRI were defined as high signals in the basal ganglia and/or cerebral cortices, either in T2-weighted images, fluid-attenuated inversion recovery images or diffusion-weighted images, which were compatible with the radiological findings of prion diseases except for variant Creutzfeldt–Jakob disease; hyperintensity on MRI in variant Creutzfeldt–Jakob disease was defined according to the WHO diagnostic criteria (WHO 2001). As reported earlier, the CSF 14-3-3 protein immunoassay was examined by western blotting of CSF with the polyclonal antibody for the β isoform (Santa Cruz Biotechnology, Santa Cruz, CA, USA) or the polyclonal antibody for the γ isoform (Takahashi et al., 1999; Satoh et al., 2006). PrP was analysed in the open reading frame after extracting DNA from patients’ blood, as described earlier (Kitamoto et al., 1992, 1993).

Neuropathological examinations and western blot analyses of protease K-resistant PrP

Brain sections were stained with routine techniques; immunohistochemistry was performed with mouse monoclonal antibody 3F4 (Senetek, MD Heights, MO, USA) (Kitamoto et al., 1992). Frozen brain tissues were homogenized and western blot analyses of protease K-resistant PrP were performed with 3F4 as described earlier (Shimizu et al., 1999).

Statistical analysis

Differences were assessed among three types of prion diseases (sporadic Creutzfeldt–Jakob disease, dura mater graft-associated Creutzfeldt–Jakob disease and genetic prion diseases), between subtypes of sporadic Creutzfeldt–Jakob disease according to Parchi’s classification (Parchi et al., 1999) and between PrP mutation groups of genetic prion disease with respect to age at onset or clinical duration by using one-factor ANOVA, and by positive findings of laboratory studies using the chi-square test or Fisher’s exact probability test. Statistical significance was defined as P < 0.05. Statistical analyses were performed using StatView® J-7.5 (Abacus Concepts, Berkeley, CA, USA). Crude, age- and sex-specific incidence rates were calculated using denominator population data for 2005 provided by the Statistics Bureau, the Ministry of Internal Affairs and Communications, Japan (http://www.stat.go.jp/english/data/kokusei/2005/poj/mokuji.htm). Age-adjusted incidence rate by sex was calculated by the direct method using population data for 2005. Data on the number of deaths from prion diseases were obtained by Vital Statistics of Japan (Statistics and Information Department, Ministers Secretariat, Ministry of Health, Labour and Welfare, 2009) and the mortality rate was calculated using denominator population data for 2005.

Results

Overall characteristics and classification of prion disease

The Creutzfeldt–Jakob Disease Surveillance Committee obtained information on 1685 patients suspected as having prion disease during the 10 years between April 1999 and September 2009. After the surveillance, 1324 patients were judged to have prion diseases, including definite (n = 180, 13.6%), probable (n = 1029, 77.7%) or possible (n = 115, 8.7%) cases. There were 264 patients with ‘prion disease definitely denied’ or ‘prion disease probably denied’ (Table 1) and 61 patients with ‘diagnosis unclear’.

Table 1

Diagnoses in 264 patients with prion disease definitely or probably denied

Diagnosis Number of cases 
Encephalitisa 32 
Alzheimer’s disease 28 
Psychosis 19 
Epilepsy 18 
Encephalopathy of unknown aetiologyb 17 
Metabolic encephalopathy 13 
Frontotemporal dementia 13 
Other autoimmune encephalopathyc 10 
Spinocerebellar degeneration 10 
Corticobasal degeneration 10 
Hypoxic encephalopathy 
Dementia with Lewy bodies 
Vascular dementia 
Hashimoto’s encephalopathy 
Brain tumour 
Paraneoplastic syndrome 
Mitochondrial encephalomyopathy 
Cerebral infarction 
Normal pressure hydrocephalus 
Spastic paraplegia 
Alcohol encephalopathy 
Central nervous system lupus 
Frontotemporal dementia and motor neuron disease 
Alzheimer’s disease and epilepsy 
Cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy 
Hepatic encephalopathy 
Multiple system atrophy 
Progressive supranuclear palsy 
Subacute sclerosing panencephalitis 
Head trauma 
Adult-onset Alexander disease 
Adult-onset type 2 citrullinemia 
Cervical spondylosis 
Dementia of unknown aetiology 
Huntington's disease 
Hypoglycemic encephalopathy 
Motor neuron disease 
Multiple sclerosis 
Spinocerebellar degeneration and motor neuron disease 
Thyrotoxicosis 
Diagnosis Number of cases 
Encephalitisa 32 
Alzheimer’s disease 28 
Psychosis 19 
Epilepsy 18 
Encephalopathy of unknown aetiologyb 17 
Metabolic encephalopathy 13 
Frontotemporal dementia 13 
Other autoimmune encephalopathyc 10 
Spinocerebellar degeneration 10 
Corticobasal degeneration 10 
Hypoxic encephalopathy 
Dementia with Lewy bodies 
Vascular dementia 
Hashimoto’s encephalopathy 
Brain tumour 
Paraneoplastic syndrome 
Mitochondrial encephalomyopathy 
Cerebral infarction 
Normal pressure hydrocephalus 
Spastic paraplegia 
Alcohol encephalopathy 
Central nervous system lupus 
Frontotemporal dementia and motor neuron disease 
Alzheimer’s disease and epilepsy 
Cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy 
Hepatic encephalopathy 
Multiple system atrophy 
Progressive supranuclear palsy 
Subacute sclerosing panencephalitis 
Head trauma 
Adult-onset Alexander disease 
Adult-onset type 2 citrullinemia 
Cervical spondylosis 
Dementia of unknown aetiology 
Huntington's disease 
Hypoglycemic encephalopathy 
Motor neuron disease 
Multiple sclerosis 
Spinocerebellar degeneration and motor neuron disease 
Thyrotoxicosis 

a Viral (including herpes simplex virus) or parasitic encephalitis.

b Encephalopathy excluding metabolic, alcohol, hepatic, hypoxic, hypoglycemic, autoimmune (CNS, Hashimoto’s encephalopathy and others)-induced encephalopathy.

c Autoimmune-induced encephalopathy excluding Hashimoto’s encephalopathy and CNS lupus.

We analysed the characteristics and laboratory data of only definite and probable cases, except for dura mater graft-associated Creutzfeldt–Jakob disease. As patients with plaque-type dura mater graft-associated Creutzfeldt–Jakob disease show mostly progressive ataxia without PSWCs and do not satisfy the criteria of ‘probable’ (Noguchi-Shinohara et al., 2007; Yamada et al., 2009), possible cases were included in the analysis.

Consequently, 1222 patients were analysed and classified into 922 (75.5%) with sporadic Creutzfeldt–Jakob disease, 216 (17.7%) with genetic prion diseases, 81 (6.6%) with acquired prion diseases, including 80 cases of dura mater graft-associated Creutzfeldt–Jakob disease and 1 case of variant Creutzfeldt–Jakob disease, and 3 cases of unclassified Creutzfeldt–Jakob disease (0.2%) (Table 2). There were no iatrogenic Creutzfeldt–Jakob disease cases other than dura mater graft-associated Creutzfeldt–Jakob disease.

Table 2

Classification of each type of prion disease according to accuracy of diagnosis

 Sporadic Creutzfeldt–Jakob disease Variant Creutzfeldt–Jakob disease Dura mater graft-associated Creutzfeldt–Jakob disease Genetic prion disease Total (%) 
Definite 111 33 35 180 (13.6) 
Probable 811 34 181 1026 (77.7) 
Possible 97 13 114 (8.6) 
Total (%) 1019 (77.2) 1 (0.1) 80 (6.1) 220 (16.7) 1320 
 Sporadic Creutzfeldt–Jakob disease Variant Creutzfeldt–Jakob disease Dura mater graft-associated Creutzfeldt–Jakob disease Genetic prion disease Total (%) 
Definite 111 33 35 180 (13.6) 
Probable 811 34 181 1026 (77.7) 
Possible 97 13 114 (8.6) 
Total (%) 1019 (77.2) 1 (0.1) 80 (6.1) 220 (16.7) 1320 

Annual development of prion diseases was 82–141 cases from 1999 to 2008 (mean ± SD 108.8 ± 20.0). The incidence rate of prion diseases per million population during 1999–2008 varied from 0.64 in 1999 to 1.10 in 2006 (0.85 ± 0.16) (Fig. 1). The incidence pattern per year of sporadic Creutzfeldt–Jakob disease [0.55 in 1999 to 0.87 in 2006 (0.66 ± 0.11)] and genetic prion diseases [0.04 in 1999 to 0.20 in 2005 (0.12 ± 0.07)] resembled that of all prion diseases; however, the incidence rate of dura mater graft-associated Creutzfeldt–Jakob disease gradually decreased (0.41 ± 0.02) (Fig. 1). The annual mortality rate per million population, which was obtained by Vital Statistics of Japan, ranged from 0.88 in 1999 and 2000 to 1.59 in 2008 (1.15 ± 0.23) (Fig. 1).

Figure 1

Based on data from 1999–2008, the crude annual incidence rates per million population of all prion diseases, sporadic Creutzfeldt–Jakob disease (CJD), dura mater graft-associated Creutzfeldt–Jakob disease and genetic prion diseases are shown. Black circles = all prion diseases; black squares = sporadic Creutzfeldt–Jakob disease; black triangles = dura mater graft-associated Creutzfeldt–Jakob disease; dotted white circles = genetic prion diseases. Crude annual mortality rate is demonstrated by white bars. The incidence rate data were obtained from this surveillance and the mortality rate data were obtained from Vital Statistics of Japan.

Figure 1

Based on data from 1999–2008, the crude annual incidence rates per million population of all prion diseases, sporadic Creutzfeldt–Jakob disease (CJD), dura mater graft-associated Creutzfeldt–Jakob disease and genetic prion diseases are shown. Black circles = all prion diseases; black squares = sporadic Creutzfeldt–Jakob disease; black triangles = dura mater graft-associated Creutzfeldt–Jakob disease; dotted white circles = genetic prion diseases. Crude annual mortality rate is demonstrated by white bars. The incidence rate data were obtained from this surveillance and the mortality rate data were obtained from Vital Statistics of Japan.

Patients with prion diseases included 512 males and 710 females, and the female to male ratio of all prion diseases, sporadic Creutzfeldt–Jakob disease, dura mater graft-associated Creutzfeldt–Jakob disease and genetic prion diseases was 1.4, 1.4, 1.6 and 1.2, respectively. The age-adjusted incidence rates per million per year for females were higher than those for males in all prion diseases (male 0.79; female 0.88), sporadic Creutzfeldt–Jakob disease (male 0.62; female 0.71) and dura mater graft-associated Creutzfeldt–Jakob disease (male 0.048; female 0.074), except for genetic prion diseases (male 0.16; female 0.14).

The age at onset in all prion diseases ranged from 15 to 94 (mean ± SD 66.9 ± 11.4 years). The age at onset of dura mater graft-associated Creutzfeldt–Jakob disease was significantly younger than for sporadic Creutzfeldt–Jakob disease and genetic prion diseases (P < 0.001) (Table 3).

Table 3

Characteristics of each type of prion disease

 Sporadic Creutzfeldt–Jakob disease (n = 922) Variant Creutzfeldt–Jakob disease (n = 1) Dura mater graft-associated Creutzfeldt–Jakob disease (n = 80) Genetic prion disease (n = 216) 
Male/female 381/541 1/0 30/50 97/119 
Age at onset (years)a 68.2 ± 9.6 (32–94) 48 56.5 ± 16.0 (15–80) 65.5 ± 13.9 (15–93) 
Durationb 4.6 ± 7.9 (0–168) 23 5.7 ± 4.3 (1–16) 15.5 ± 21.4 (0–120) 
Cerebellar signs (%) 467/911 (51) 1/1 (100) 61/79 (77) 111/212 (52) 
Psychiatric symptoms (%) 565/901 (63) 1/1 (100) 47/75 (63) 115/208 (55) 
Dementia (%) 916/919 (100) 1/1 (100) 78/80 (98) 198/213 (93) 
Visual disturbance (%) 385/907 (42) 0/1 (0) 33/77 (43) 36/205 (18) 
Myoclonus (%) 867/919 (94) 1/1 (100) 69/79 (87) 121/210 (58) 
Extrapyramidal signs (%) 582/906 (64) 0/1 (0) 52/79 (66) 112/210 (53) 
Pyramidal signs (%) 618/909 (68) 1/1 (100) 56/78 (72) 112/212 (53) 
Codon 129 polymorphism MM 552; MV 14; VV 4 MM MM 52; MV 2 MM 168; MV 32 
Codon 219 polymorphism EE 561; EK 3 EE EE 49; EK 2 EE 189; EK 3; KK 1 
PSWCs on EEG (%) 889/920 (97) 1/1 (100) 53/80 (66) 77/212 (36) 
Hyperintensities on MRI (%) 719/874 (82) 1/1 (100) 41/60 (68) 159/201 (79) 
Positive 14-3-3 protein (%) 384/439 (87) 1/1 (100) 24/29 (83) 75/98 (77) 
 Sporadic Creutzfeldt–Jakob disease (n = 922) Variant Creutzfeldt–Jakob disease (n = 1) Dura mater graft-associated Creutzfeldt–Jakob disease (n = 80) Genetic prion disease (n = 216) 
Male/female 381/541 1/0 30/50 97/119 
Age at onset (years)a 68.2 ± 9.6 (32–94) 48 56.5 ± 16.0 (15–80) 65.5 ± 13.9 (15–93) 
Durationb 4.6 ± 7.9 (0–168) 23 5.7 ± 4.3 (1–16) 15.5 ± 21.4 (0–120) 
Cerebellar signs (%) 467/911 (51) 1/1 (100) 61/79 (77) 111/212 (52) 
Psychiatric symptoms (%) 565/901 (63) 1/1 (100) 47/75 (63) 115/208 (55) 
Dementia (%) 916/919 (100) 1/1 (100) 78/80 (98) 198/213 (93) 
Visual disturbance (%) 385/907 (42) 0/1 (0) 33/77 (43) 36/205 (18) 
Myoclonus (%) 867/919 (94) 1/1 (100) 69/79 (87) 121/210 (58) 
Extrapyramidal signs (%) 582/906 (64) 0/1 (0) 52/79 (66) 112/210 (53) 
Pyramidal signs (%) 618/909 (68) 1/1 (100) 56/78 (72) 112/212 (53) 
Codon 129 polymorphism MM 552; MV 14; VV 4 MM MM 52; MV 2 MM 168; MV 32 
Codon 219 polymorphism EE 561; EK 3 EE EE 49; EK 2 EE 189; EK 3; KK 1 
PSWCs on EEG (%) 889/920 (97) 1/1 (100) 53/80 (66) 77/212 (36) 
Hyperintensities on MRI (%) 719/874 (82) 1/1 (100) 41/60 (68) 159/201 (79) 
Positive 14-3-3 protein (%) 384/439 (87) 1/1 (100) 24/29 (83) 75/98 (77) 

a Age at onset is expressed as the mean ± SD (range) years.

b Duration between the onset and akinetic mutism or death without akinetic mutism. Duration is expressed as the mean ± SD (range) months.

EE = glutamic acid homozygosity; EK = glutamic acid/lysine heterozygosity; KK = lysine homozygosity; MM = methionine homozygosity; MV = methionine/valine heterozygosity; VV = valine homozygosity.

As shown in Fig. 2A, the age- and sex-specific incidence rate of all prion diseases increased with age to a peak in the eighth decade (all 3.24; male 2.95; female 3.48) for both sexes, and decreased over the age of 80 years. Sporadic Creutzfeldt–Jakob disease showed similar results, with the highest incidence rate in the eighth decade (all 2.76; male 2.51; female 2.97) (Fig. 2B). The incidence rate of dura mater graft-associated Creutzfeldt–Jakob disease showed two peaks in the fourth and eighth decades (0.03 and 0.10, respectively) (Fig. 2C). The incidence rate of male patients with dura mater graft-associated Creutzfeldt–Jakob disease also showed two peaks in the fourth and sixth decades (0.04 and 0.07, respectively), while the incidence rate of female patients with dura mater graft-associated Creutzfeldt–Jakob disease showed two peaks in the third and eighth decades (0.05 and 0.13, respectively) (Fig. 2C). The peak incidence rate of genetic prion diseases was in the ninth decade for male patients (0.62) and the eighth decade for all and female patients (0.58 and 0.69, respectively) (Fig. 2D).

Figure 2

Based on data from 1999–2008, age- and sex-specific annual incidence per million population of all prion diseases (A), sporadic Creutzfeldt–Jakob disease (B), dura mater graft-associated Creutzfeldt–Jakob disease (C), and genetic prion diseases (D) is shown. Dotted white triangles = all patients; black squares = male patients; dashed white circles = female patients.

Figure 2

Based on data from 1999–2008, age- and sex-specific annual incidence per million population of all prion diseases (A), sporadic Creutzfeldt–Jakob disease (B), dura mater graft-associated Creutzfeldt–Jakob disease (C), and genetic prion diseases (D) is shown. Dotted white triangles = all patients; black squares = male patients; dashed white circles = female patients.

In patients with genetic prion diseases, the duration between onset and akinetic mutism or death was significantly longer than in sporadic Creutzfeldt–Jakob disease and dura mater graft-associated Creutzfeldt–Jakob disease (P < 0.001) (Table 3).

The frequencies of each clinical sign are described in Table 3. The positive rates of PSWCs on EEG, hyperintensities on MRI and 14-3-3 protein in CSF were significantly different between sporadic Creutzfeldt–Jakob disease, dura mater graft-associated Creutzfeldt–Jakob disease and genetic prion diseases (P < 0.001, P = 0.039 and P = 0.010, respectively) (Table 3).

Characteristics of sporadic Creutzfeldt–Jakob disease

Genetic analyses for PrP were performed in 608 cases (69.6%) and the results of polymorphic codon 129 (methionine homozygotes, valine homozygotes and heterozygotes) and codon 219 (glutamic acid homozygotes, lysine homozygotes and heterozygotes) are shown in Table 3.

According to Parchi’s classification based on the genotype of polymorphism at codon 129 of PrP and the physicochemical properties of protease K-resistant PrP, 44 patients with pathologically confirmed sporadic Creutzfeldt–Jakob disease were classified as: 25 with type MM1; 10 with type MM2, including cortical (n = 5), thalamic (n = 4) and MM2-cortical and thalamic (n = 1); four with type MM1+2; three with type MV2; and two with type VV2. MV1 and VV1 types were not identified (Table 4). All types were glutamic acid homozygotes at polymorphic codon 219. Among subtypes of sporadic Creutzfeldt–Jakob disease (MM1, MM2-cortical, MM2-thalamic, MV2 and VV2), age at disease onset of the MM2-thalamic subtype was significantly younger than the MM1 type or MM2-cortical and VV2 subtypes (P = 0.0016). In the MM1 type cases, akinetic mutism or death occurred significantly earlier than in MM2-cortical, MM2-thalamic and MV2 subtypes (P < 0.001). Frequencies of positive PSWCs were lower in MM2-cortical, MM2-thalamic, MV2 and VV2 subtypes compared with the MM1 type. The positive rate of CSF 14-3-3 protein in the MM1 type was higher than in MM2-cortical, MM2-thalamic and MV2 subtypes. Hyperintensities on MRI were identified in all but patients with the MM2-thalamic subtype.

Table 4

Characteristics of each subtype of sporadic Creutzfeldt–Jakob disease

 MM1 (n = 25) MM1+2 (n = 4) MM2-cortical (n = 5) MM2-thalamic (n = 4) MM2-cortical and thalamic (n = 1) MV2 (n = 3) VV2 (n = 2) 
Male/female 11/14 1/3 2/3 3/1 1/0 3/0 1/1 
Age at onseta 67.2 ± 5.5 (57–77) 66.3 ± 4.8 (62–73) 66.8 ± 7.3 (57–74) 52.8 ± 8.3 (43–61) 65 62.0 ± 5.3 (58–68) 72 (69–75) 
Durationb 3.1 ± 2.7 (0–14) 7.5 ± 5.4 (3–14) 24.7 ± 15.1 (10–50) 18.5 ± 6.7 (13–28) 11 26.5 (12–41) 
Codon 219 polymorphism EE 23 EE 3 EE 5 EE 3 EE EE 3 EE 2 
PSWCs on EEG (%) 23/25 (92) 4/4 (100) 2/4 (40) 0/4 (0) 0/1 (0) 0/3 (0) 0/2 (0) 
Hyperintensities on MRI (%) 25/25 (100) 4/4 (100) 5/5 (100) 0/4 (0) 1/1 (100) 3/3 (100) 2/2 (100) 
Positive 14-3-3 protein (%) 15/16 (94) 3/4 (75) 2/5 (40) 1/3 (33) 0/1 (0) 0/1 (0) 2/2 (100) 
 MM1 (n = 25) MM1+2 (n = 4) MM2-cortical (n = 5) MM2-thalamic (n = 4) MM2-cortical and thalamic (n = 1) MV2 (n = 3) VV2 (n = 2) 
Male/female 11/14 1/3 2/3 3/1 1/0 3/0 1/1 
Age at onseta 67.2 ± 5.5 (57–77) 66.3 ± 4.8 (62–73) 66.8 ± 7.3 (57–74) 52.8 ± 8.3 (43–61) 65 62.0 ± 5.3 (58–68) 72 (69–75) 
Durationb 3.1 ± 2.7 (0–14) 7.5 ± 5.4 (3–14) 24.7 ± 15.1 (10–50) 18.5 ± 6.7 (13–28) 11 26.5 (12–41) 
Codon 219 polymorphism EE 23 EE 3 EE 5 EE 3 EE EE 3 EE 2 
PSWCs on EEG (%) 23/25 (92) 4/4 (100) 2/4 (40) 0/4 (0) 0/1 (0) 0/3 (0) 0/2 (0) 
Hyperintensities on MRI (%) 25/25 (100) 4/4 (100) 5/5 (100) 0/4 (0) 1/1 (100) 3/3 (100) 2/2 (100) 
Positive 14-3-3 protein (%) 15/16 (94) 3/4 (75) 2/5 (40) 1/3 (33) 0/1 (0) 0/1 (0) 2/2 (100) 

a Age at onset is expressed as the mean ± SD (range) years.

b Duration between the onset and akinetic mutism or death without akinetic mutism. Duration is expressed as the mean ± SD (range) months.

Characteristics of variant Creutzfeldt–Jakob disease

Only one patient with a history of a short stay in the UK, France and other European countries developed variant Creutzfeldt–Jakob disease; this case has already been reported (Yamada, 2006). Although the clinical features in the early stage were compatible with variant Creutzfeldt–Jakob disease (Will et al., 2004), the patient showed PSWCs on EEG in the late stage, leading to the diagnosis of probable sporadic Creutzfeldt–Jakob disease. At polymorphic codons 129 and 219 the patient was homozygotic for methionine and glutamic acid, respectively. The patient developed akinetic mutism at 23 months and died 42 months after onset; autopsy confirmed the diagnosis of variant Creutzfeldt–Jakob disease (Table 3).

Characteristics of dura mater graft-associated Creutzfeldt–Jakob disease

Besides the 80 patients with dura mater graft-associated Creutzfeldt–Jakob disease identified by this surveillance system, 58 patients with dura mater graft-associated Creutzfeldt–Jakob disease had already been reported by previous surveillance systems (Yamada et al., 2009); therefore, the total number of dura mater graft-associated Creutzfeldt–Jakob disease patients was 138. The source of cadaveric dura mater was Lyodura® (B. Braun, Germany) in all dura mater graft-associated Creutzfeldt–Jakob disease cases in which the brand name could be identified.

The medical conditions for which dura mater grafts were used in neurosurgery included meningioma (21.0%), hemifacial spasm (13.8%) and acoustic neurinoma (12.3%) (Table 5). The proportion of non-life-threatening conditions, such as hemifacial spasm (13.8%) and trigeminal neuralgia (5%), were relatively high (Table 5). Dura mater grafts were implanted during 1975–93, and most patients (112 cases, 81.2%) received them during 1983–87 (Fig. 3A); in May 1987 the procedures for the collection and processing of grafts were revised by the company (Sato et al., 1997). It was reported that one of the patients with dura mater graft-associated Creutzfeldt–Jakob disease, who received dura mater grafts after May 1987, received a graft that had been produced before May 1987. The incubation period (i.e. duration from implantation of dura mater grafts to dura mater graft-associated Creutzfeldt–Jakob disease onset) ranged from 1 to 30 years (mean ± SD 11.8 ± 5.5 years) (Fig. 3B). The year of disease onset ranged from 1985 to 2008, and many patients (83 cases, 60.1%) developed dura mater graft-associated Creutzfeldt–Jakob disease during 1993–2001, with a peak in 1995 (Fig. 3C).

Figure 3

The time when cadaveric dura mater grafts were implanted is shown by year, with black bars indicating patients with dura mater graft-associated Creutzfeldt–Jakob disease (A). The incubation period (i.e. duration from implantation of dura mater grafts to onset of dura mater graft-associated Creutzfeldt–Jakob disease) is shown by year, with black bars indicating patients with dura mater graft-associated Creutzfeldt–Jakob disease (B). The year when dura mater graft-associated Creutzfeldt–Jakob disease developed in patients is shown by black bars indicating patients with dura mater graft-associated Creutzfeldt–Jakob disease (C).

Figure 3

The time when cadaveric dura mater grafts were implanted is shown by year, with black bars indicating patients with dura mater graft-associated Creutzfeldt–Jakob disease (A). The incubation period (i.e. duration from implantation of dura mater grafts to onset of dura mater graft-associated Creutzfeldt–Jakob disease) is shown by year, with black bars indicating patients with dura mater graft-associated Creutzfeldt–Jakob disease (B). The year when dura mater graft-associated Creutzfeldt–Jakob disease developed in patients is shown by black bars indicating patients with dura mater graft-associated Creutzfeldt–Jakob disease (C).

Table 5

Medical conditions leading to use of dura mater grafts

Medical conditions No. of cases 
Meningioma 29 
Hemifacial spasm 19 
Acoustic neurinoma 17 
Subarachonoid haemorrhage 11 
Cerebral/cerebellar haemorrhage 
Arteriovenous malformation 
Trigeminal neuralgia 
Brain aneurysm 
Epidural/subdural haematoma 
Trauma 
Arnold-Chiari malformation 
Ependymoma 
Epidermoid 
Glioma 
Hemangioblastoma 
Spinal cord tumour 
Arachonoid cyst 
Osteoma 
Ossification of the posterior longitudinal ligament 
Pituitary adenoma 
Teratoma 
Brain tumour with unknown details 
Medical conditions No. of cases 
Meningioma 29 
Hemifacial spasm 19 
Acoustic neurinoma 17 
Subarachonoid haemorrhage 11 
Cerebral/cerebellar haemorrhage 
Arteriovenous malformation 
Trigeminal neuralgia 
Brain aneurysm 
Epidural/subdural haematoma 
Trauma 
Arnold-Chiari malformation 
Ependymoma 
Epidermoid 
Glioma 
Hemangioblastoma 
Spinal cord tumour 
Arachonoid cyst 
Osteoma 
Ossification of the posterior longitudinal ligament 
Pituitary adenoma 
Teratoma 
Brain tumour with unknown details 

Genetic analyses for PrP were performed in 58 cases (73.1%). The polymorphic PrP codon 129 included 52 methionine homozygotes (96.3%) and two heterozygotes (3.7%), and for codon 219, 49 glutamic acid homozygotes (96.1%) and two heterozygotes (3.9%) (Table 3).

Among 33 patients with definite dura mater graft-associated Creutzfeldt–Jakob disease, 29 patients had sufficient pathological data to be categorized as either plaque type (n = 14, 48%) or non-plaque type (n = 15, 52%).

Characteristics of genetic prion diseases

The distribution and frequencies of PrP mutations associated with genetic prion diseases in Japan are shown in Table 6. The most common mutation was V180I, followed by P102L, E200K, M232R and P105L. The characteristics associated with the mutations are shown in Table 7. The characteristics of relatively frequent mutations in Japan (P102L, P105L, V180I, E200K and M232R) were as follows: patients with P102L, P105L and E200K showed relatively high penetrance (Table 7), whereas only 2.2% of patients with V180I mutation and no patients with M232R mutation had a positive family history (Table 7).

Table 6

Comparison of the distribution in genetic prion disease between Japan and EUROCJD

 Japan (n = 216) (%) EUROCJDa (n = 425) (%) 
Insertion 3 (1.4) 42 (9.9) 
P102L 39 (18.1) 24 (5.6) 
P105L 5 (2.3) 0 (0) 
A117V-129V 0 (0) 12 (2.8) 
D178N-129M 3 (1.4) 64 (15.1) 
D178N-129V 1 (0.5) 16 (3.8) 
V180I 89 (41.2) 1 (0.2) 
E200K 37 (17.1) 175 (41.2) 
V203I 2 (0.9) 5 (1.2) 
R208H 1 (0.5) 2 (0.5) 
V210I 0 (0) 69 (16.2) 
M232R 33 (15.3) 0 (0) 
V180I+M232R 1 (0.5) 0 (0) 
Other mutations 0 (0) 15 (3.5) 
 Japan (n = 216) (%) EUROCJDa (n = 425) (%) 
Insertion 3 (1.4) 42 (9.9) 
P102L 39 (18.1) 24 (5.6) 
P105L 5 (2.3) 0 (0) 
A117V-129V 0 (0) 12 (2.8) 
D178N-129M 3 (1.4) 64 (15.1) 
D178N-129V 1 (0.5) 16 (3.8) 
V180I 89 (41.2) 1 (0.2) 
E200K 37 (17.1) 175 (41.2) 
V203I 2 (0.9) 5 (1.2) 
R208H 1 (0.5) 2 (0.5) 
V210I 0 (0) 69 (16.2) 
M232R 33 (15.3) 0 (0) 
V180I+M232R 1 (0.5) 0 (0) 
Other mutations 0 (0) 15 (3.5) 

a European Creutzfeldt–Jakob Disease Surveillance Network; Kovacs et al., 2005.

Table 7

Characteristics of genetic prion diseases

 Insertion (n = 3) P102L (n = 39) P105L (n = 5) D178N-129M (n = 3) D178N-129V (n = 1) V180I (n = 89) E200K (n = 37) V203I (n = 2) R208H (n = 1) M232R (n = 33) V180I+M232R (n = 1) 
Male/female 2/1 16/23 4/1 2/1 1/0 35/54 15/22 2/0 0/1 18/15 0/1 
Age at onseta 49.5 ± 21.7 (26–55) 54.0 ± 12.4 (22–75) 41.6 ± 8.0 (31–51) 52.3 ± 5.7 (46–57) 74 76.1 ± 7.4 (44–93) 58.5 ± 9.8 (31–77) 73 74 64.2 ± 12.5 (15–81) 74 
Positive family history (%) 1 (33) 29 (74) 4 (80) None None 2 (2) 17 (46) None None None None 
Durationb 20.0 ± 21.4 (3–44) 36.7 ± 30.1 (3–96) 99.7 ± 23.5 (74–120) 10.7 ± 3.2 (7–13) 24 13.3 ± 10.9 (1–58) 3.9 ± 3.6 (1–14) 5 (4–6) 8.0 ± 8.7 (0–32) 
Codon 129 polymorphism MM 2 MM 29; MV 3 MV 4 MM 3 MV 1 MM 65; MV 22 MM 34 MM 2 MM 1 MM 30; MV 2 MM 1 
Codon 219 polymorphism EE 1; KK 1 EE 31; EK 1 EE 4 EE 3 EE 1 EE 81 EE 33; EK 1 EE 2 EE 1 EE 31; EK 1 EE 1 
PSWCs on EEG (%) 2/3 (67) 7/37 (19) 0/5 (0) 0/3 (0) 0/1 (0) 10/88 (11) 34/37 (92) 2/2 (100) 1/1 (100) 20/32 (63) 1/1 (100) 
Hyperintensities on MRI (%) 1/2 (50) 14/36 (39) 0/5 (0) 0/3 (0) 0/1 (0) 84/84 (100) 31/35 (89) 2/2 (100) 1/1 (100) 26/31 (84) 0/1 (0) 
Positive 14-3-3 protein (%) 0/1 (0) 6/10 (60) 1/2 (50) 1/1 (100) 1/1 (100) 35/45 (78) 11/12 (92) 1/1 (100) 1/1 (100) 18/23 (78) 0/1 (0) 
 Insertion (n = 3) P102L (n = 39) P105L (n = 5) D178N-129M (n = 3) D178N-129V (n = 1) V180I (n = 89) E200K (n = 37) V203I (n = 2) R208H (n = 1) M232R (n = 33) V180I+M232R (n = 1) 
Male/female 2/1 16/23 4/1 2/1 1/0 35/54 15/22 2/0 0/1 18/15 0/1 
Age at onseta 49.5 ± 21.7 (26–55) 54.0 ± 12.4 (22–75) 41.6 ± 8.0 (31–51) 52.3 ± 5.7 (46–57) 74 76.1 ± 7.4 (44–93) 58.5 ± 9.8 (31–77) 73 74 64.2 ± 12.5 (15–81) 74 
Positive family history (%) 1 (33) 29 (74) 4 (80) None None 2 (2) 17 (46) None None None None 
Durationb 20.0 ± 21.4 (3–44) 36.7 ± 30.1 (3–96) 99.7 ± 23.5 (74–120) 10.7 ± 3.2 (7–13) 24 13.3 ± 10.9 (1–58) 3.9 ± 3.6 (1–14) 5 (4–6) 8.0 ± 8.7 (0–32) 
Codon 129 polymorphism MM 2 MM 29; MV 3 MV 4 MM 3 MV 1 MM 65; MV 22 MM 34 MM 2 MM 1 MM 30; MV 2 MM 1 
Codon 219 polymorphism EE 1; KK 1 EE 31; EK 1 EE 4 EE 3 EE 1 EE 81 EE 33; EK 1 EE 2 EE 1 EE 31; EK 1 EE 1 
PSWCs on EEG (%) 2/3 (67) 7/37 (19) 0/5 (0) 0/3 (0) 0/1 (0) 10/88 (11) 34/37 (92) 2/2 (100) 1/1 (100) 20/32 (63) 1/1 (100) 
Hyperintensities on MRI (%) 1/2 (50) 14/36 (39) 0/5 (0) 0/3 (0) 0/1 (0) 84/84 (100) 31/35 (89) 2/2 (100) 1/1 (100) 26/31 (84) 0/1 (0) 
Positive 14-3-3 protein (%) 0/1 (0) 6/10 (60) 1/2 (50) 1/1 (100) 1/1 (100) 35/45 (78) 11/12 (92) 1/1 (100) 1/1 (100) 18/23 (78) 0/1 (0) 

EE = glutamic acid homozygosity; EK = glutamic acid/lysine heterozygosity; KK = lysine homozygosity; MM = methionine homozygosity; MV = methionine/valine heterozygosity; PSWCs = periodic synchronous wave complexes; VV = valine homozygosity.

a Age at onset is expressed as the mean ± SD (range) years.

b Duration between the onset and akinetic mutism or death without akinetic mutism. Duration is expressed as the mean ± SD (range) months.

P102L and P105L cases showed onset at a relatively young age and a Gerstmann–Sträussler–Scheinker disease phenotype with slow progression, while V180I cases presented with onset in old age and with slow progression in spite of the Creutzfeldt–Jakob disease type pathology (Mutsukura et al., 2009) (Table 7). Thirty-one M232R patients with sufficient clinical data were classified into 19 with rapid type and 12 with slow type.

P102L and P105L showed low positive rates in PSWCs on EEG and hyperintensities on MRI. V180I and the slow type of M232R presented with a low positive rate of PSWCs on EEG, but a high positive rate of hyperintensities on MRI.

Discussion

This study revealed the epidemiological and clinical characteristics of prion diseases in Japan over a 10-year period. Nationwide surveillance data of prion diseases have been reported from European countries, Australia and the USA (Horan et al., 2004; Sanchez-Valle et al., 2004; Ladogana et al., 2005; de Pedro-Cuesta et al., 2006; Van Everbroeck et al., 2006; Heinemann et al., 2007; Klug et al., 2009; Holman et al., 2010). Although a study of Chinese patients with prion diseases has been reported (Shi et al., 2008), it did not accurately reflect the incidence rate in China, as the number of patients with prion diseases was quite small compared with that estimated for the population in China. Our study is therefore the largest report of prospective prion disease surveillance from Asia.

Incidence rate of prion diseases

The crude annual mortality rate per million of prion diseases in Japan was 0.89–1.58 (mean 1.18), which was obtained from Vital Statistics of Japan and is similar to that in European countries, Australia, Canada and the USA (1.0–1.5 per million) (Ladogana et al., 2005; Klug et al., 2009; Holman et al., 2010). On the other hand, the annual incidence rate of prion diseases per million population in Japan obtained by our surveillance was 0.65–1.10 (mean 0.85), which was lower than the mortality rate obtained by Vital Statistics of Japan, because our surveillance rate was not 100%. The annual incidence rate of sporadic Creutzfeldt–Jakob disease in Japan was 0.55–0.87 per million (mean 0.66), which was slightly lower than in Germany (0.8–1.6) and in European countries, Australia and Canada (1.39 as overall annual mortality rate) (Ladogana et al., 2005; Heinemann et al., 2007). The reasons for the lower incidence rate of sporadic Creutzfeldt–Jakob disease in Japan may be explained by the lower autopsy rate in Japan compared with other western countries, and the limited sensitivity of the diagnostic criteria by Masters et al. (1979) for probable sporadic Creutzfeldt–Jakob disease. When possible sporadic Creutzfeldt–Jakob disease cases were included in the number of sporadic Creutzfeldt–Jakob disease cases, the annual incidence rate per million increased to 0.57–0.95 (mean 0.73), but it was still lower than those of other western countries.

Interestingly, in Japan, female predominance was identified in age-adjusted incidence rates of prion diseases, sporadic Creutzfeldt–Jakob disease, and dura mater graft-associated Creutzfeldt–Jakob disease, but not for genetic prion diseases. An excess of females has been reported for Creutzfeldt–Jakob disease, sporadic Creutzfeldt–Jakob disease or genetic cases (Collins et al., 2002, 2006; Kovács et al., 2005; Holman et al., 2010); however, the average age-adjusted incidence rate of Creutzfeldt–Jakob disease was reported to be similar for males and females in Australia (Collins et al., 2002) and higher for males than for females in the USA (Holman et al., 2010). Further data corrected by the age distribution of gender in the general population of each country are essential to clarify gender difference.

The age- and sex-specific incidence rate of sporadic Creutzfeldt–Jakob disease in Japan was similar to that of sporadic Creutzfeldt–Jakob disease in European countries, Australia and Canada (Ladogana et al., 2005; Heinemann et al., 2007), showing a decreased incidence rate over the age of 80 years. The reason for this remains unknown and requires further study. The age- and sex-specific incidence rate of patients with dura mater graft-associated Creutzfeldt–Jakob disease showed two peaks, reflecting two peaks in the age at dura mater transplantation (male, second and fifth decade; female, second and sixth decade) (data not shown). The incidence pattern of genetic prion diseases peaked in old age, similar to sporadic Creutzfeldt–Jakob disease, and seemed to be influenced by onset in old age in a high proportion of patients with the V180I mutation.

Types of prion diseases

The proportions of sporadic Creutzfeldt–Jakob disease and genetic prion diseases were almost identical to those in European countries, except for Slovakia, in which the percentage of patients with genetic prion diseases was 70% (Ladogana et al., 2005). The proportion of iatrogenic Creutzfeldt–Jakob disease was relatively high in Japan compared with other European countries because of the large number of patients with dura mater graft-associated Creutzfeldt–Jakob disease. Of the 196 (62.7%) worldwide dura mater graft-associated Creutzfeldt–Jakob disease cases, 123 had been identified in Japan up to 2006 (Brown et al., 2006). In France, the proportion of iatrogenic Creutzfeldt–Jakob disease was also high (8.7%) (de Pedro-Cuesta et al., 2006), but most iatrogenic Creutzfeldt–Jakob disease cases were induced by contaminated human growth hormone (Brown et al., 2006). Worldwide, contaminated human growth hormone-associated Creutzfeldt–Jakob disease was the most common iatrogenic Creutzfeldt–Jakob disease, except for dura mater graft-associated Creutzfeldt–Jakob disease (Brown et al., 2006), although there were no cases of human growth hormone-associated Creutzfeldt–Jakob disease in Japan. Although there was only one case of variant Creutzfeldt–Jakob disease in the past 10 years in Japan, the number of variant Creutzfeldt–Jakob disease cases was 212 cases worldwide, in particular 172 (81.3%) in the UK and 25 (11.8%) in France, up to March 2010 (NCJDSU) (http://www.cjd.ed.ac.uk/vcjdworld.htm).

PrP polymorphisms in prion diseases

The genotype distribution at codon 129 of PrP in sporadic Creutzfeldt–Jakob disease in Japan revealed a higher proportion of methionine homozygotes (96.8%) than in European countries, Australia and Canada (67.2%) (Ladogana et al., 2005), whereas the proportion of methionine homozygotes at codon 129 in sporadic Creutzfeldt–Jakob disease was 100% (150/150) in Korea (Jeong et al., 2005) and 97.0 % (131/135) in China (Shi et al., 2008), similar to Japan.

The general Japanese population also presented with a higher frequency of codon 129 homozygosity (methionine homozygotes: 0.92, heterozygotes: 0.08, valine homozygotes: 0) than European countries (methionine homozygotes: 0.37–0.49, heterozygotes: 0.42–0.49, valine homozygotes: 0.08–0.15) (Collinge et al., 1991; Doh-ura et al., 1991; Zimmermann et al., 1999; Nurmi et al., 2003; Mitrová et al., 2005; Georgsson et al., 2006; Dyrbye et al., 2008). The proportion of methionine homozygotes at codon 129 in the general population was 94.3% (499/529) in Korea (Jeong et al., 2004) and 97.6% (200/205) among Han Chinese (Yu et al., 2004), also similar to Japan.

Genetic predisposition to sporadic Creutzfeldt–Jakob disease in codon 129 homozygosity (methionine homozygotes or valine homozygotes) was revealed in the UK (Palmer et al., 1991), but this predisposition was not previously identified in a small number of Japanese sporadic Creutzfeldt–Jakob disease patients (n = 21; methionine homozygotes or valine homozygotes: 0.95, heterozygotes: 0.05) because of the high frequency of methionine homozygotes at codon 129 in the general Japanese population (Doh-ura et al., 1991). Using data on codon 129 polymorphisms (n = 645; methionine homozygotes: 0.93, heterozygotes: 0.07, valine homozygotes: 0; M allele: 0.97, V allele: 0.03) in the general Japanese population obtained from combining previous data (Doh-ura et al., 1991; Ohkubo et al., 2003) as a control, we assessed whether homozygosity, methionine homozygosity or the M allele at codon 129 was associated with sporadic Creutzfeldt–Jakob disease in Japan, and found a significant association (P < 0.001, P = 0.004 and P = 0.019, respectively). This is the first report showing that codon 129 homozygosity is a risk for sporadic Creutzfeldt–Jakob disease in Asia, as reported in western countries. In addition, methionine homozygosity and the M allele were not associated with sporadic Creutzfeldt–Jakob disease in the UK (Palmer et al., 1991). In dura mater graft-associated Creutzfeldt–Jakob disease, neither homozygosity (methionine homozygotes or valine homozygotes: 0.96), methionine homozygosity (0.96) nor the M allele (0.98) at codon 129 were significantly different from the general Japanese population. Genetic prion diseases had a significantly higher proportion of codon 129 heterozygosity and the V allele than the general population (both P < 0.001). This seemed to be related to the higher proportion of codon 129 heterozygosity in V180I cases (methionine homozygotes: 0.75, heterozygotes: 0.25), which is the most common genetic prion disease in Japan, although the V180I mutation was located on the allele with methionine at codon 129 in all cases investigated.

It was previously reported that heterozygosity at codon 219 was found in the general Japanese population (glutamic acid homozygotes: 0.88, heterozygotes: 0.12), while the K allele was not found in 85 Japanese patients with sporadic Creutzfeldt–Jakob disease (Shibuya et al., 1998). The frequencies of the K allele (0.0027) and heterozygous genotype (heterozygotes: 0.0053) at codon 219 in sporadic Creutzfeldt–Jakob disease patients in this study were significantly lower than in the general Japanese population (n = 566; glutamic acid homozygotes: 0.86, heterozygotes: 0.14, lysine homozygotes: 0; E allele: 0.93, K allele: 0.07) (Kitamoto et al., 1994; Ohkubo et al., 2003) (P < 0.001). The frequencies of the K allele (0.013) and heterozygous genotype (0.016) at codon 219 in genetic prion diseases were also significantly lower than in the general Japanese population (both P < 0.001), while in dura mater graft-associated Creutzfeldt–Jakob disease, the frequencies of the K allele (0.02) and heterozygosity (0.04) were not significantly different from the general population.

Sporadic Creutzfeldt–Jakob disease

The very high frequency of PSWCs in sporadic Creutzfeldt–Jakob disease (97%), compared with the data of western countries (Collins et al., 2006), is related to the application of the diagnostic criteria by Masters et al. (1979) and the low autopsy rate in Japan. Regarding the subtypes according to Parchi’s classification (Parchi et al., 1999), the MM1 type was the most common (25/44, 56.8%), characterized by typical Creutzfeldt–Jakob disease features: rapid clinical course, positive PSWCs and CSF 14-3-3 protein and typical MRI findings (Table 4). Among atypical cases other than the MM1 type, the proportion of the MM2 type was relatively high (10/44, 22.7%) compared with Europe, the USA (12/300, 4.0%) (Parchi et al., 1999) and Germany (12/243, 4.9%) (Heinemann et al., 2007). MM2 type cases included cortical (50%), thalamic (40%) and combined (cortical and thalamic) forms (10%). Our results were influenced by the bias that atypical cases might have been more selectively autopsied to confirm the diagnosis; however, the relatively high proportion of the MM2 type in Japanese patients with sporadic Creutzfeldt–Jakob disease reflected the high proportion of the methionine homozygote genotype in the Japanese population.

Clinical characteristics of each sporadic Creutzfeldt–Jakob disease subtype (MM1, MM2-cortical, MM2-thalamic, MV2 and VV2) were almost the same as in previous reports (Parchi et al., 1999; Collins et al., 2006), except for the higher frequency of extrapyramidal signs (72%) in the MM1 type [7% in a previous report (Parchi et al., 1999)] and the lower frequency of pyramidal signs (0%) in MM2-cortical subtype [83% in previous reports (Parchi et al., 1999; Krasnianski et al., 2006)]. The deficiency of pyramidal or other neurological signs in the MM2-cortical subtype would lead to difficulties in the clinical diagnosis of MM2-type sporadic Creutzfeldt–Jakob disease on the basis of the current sporadic Creutzfeldt–Jakob disease criteria, although cortical hyperintensities on MRI suggest the diagnosis (Hamaguchi et al., 2005). In this study, the age at onset of the MM2-thalamic subtype was younger with a longer duration than the MM1 type, and neither PSWCs on EEG nor hyperintensities on MRI were identified in the MM2-thalamic subtype.

Dura mater graft-associated Creutzfeldt–Jakob disease

Worldwide, the majority of patients with dura mater graft–associated Creutzfeldt–Jakob disease have been reported from Japan (Belay et al., 2005; Brown et al., 2006; Noguchi-Shinohara et al., 2007; Nakamura et al., 2008; Yamada et al., 2009). In Japan, all dura mater graft-associated Creutzfeldt–Jakob disease cases in which the origin of the dural grafts could be identified were recipients of Lyodura®, as previously reported (Yamada et al., 2009). In Japan, the import of Lyodura® was approved in 1973 and then prohibited in 1997. The mean incubation period of dura mater graft-associated Creutzfeldt–Jakob disease (11.8 years) was shorter than human growth hormone-associated Creutzfeldt–Jakob disease (20.5 years) (Belay et al., 2005). The longest incubation period of dura mater graft-associated Creutzfeldt–Jakob disease was 30 years, and the year when the patient received implantation (1975) was also the earliest among previous reports (Nakamura et al., 2008; Yamada et al., 2009). Regarding the medical conditions in which patients received the implantation of cadaveric dura mater grafts, non-life-threatening conditions such as hemifacial spasm and trigeminal pain were relatively common, because recipients with lethal conditions might have died before dura mater graft-associated Creutzfeldt–Jakob disease developed. Clinical duration (from onset to akinetic mutism or death) of dura mater graft-associated Creutzfeldt–Jakob disease was longer than that of sporadic Creutzfeldt–Jakob disease, and positive rates of PSWCs on EEG and hyperintensities on MRI were lower than those of sporadic Creutzfeldt–Jakob disease (Table 3). These findings can be explained by the fact that dura mater graft-associated Creutzfeldt–Jakob disease presented with two distinct clinicopathological subtypes, i.e. ‘plaque’ and ‘non-plaque’ types: in contrast to the non-plaque type with classic Creutzfeldt–Jakob disease features, the plaque type shows relatively slow progression and no or late occurrence of PSWCs on EEG (Noguchi-Shinohara et al., 2007; Yamada et al., 2009). When patients with negative PSWCs and dura mater graft-associated Creutzfeldt–Jakob disease were combined with those with plaque-type dura mater graft-associated Creutzfeldt–Jakob disease, and patients with positive PSWCs and dura mater graft-associated Creutzfeldt–Jakob disease with those with non-plaque type dura mater graft-associated Creutzfeldt–Jakob disease, one-third of patients with dura mater graft-associated Creutzfeldt–Jakob disease could have ‘plaque type’ (data not shown), which was almost the same as in previous reports (Noguchi-Shinohara et al., 2007; Yamada et al., 2009).

Genetic prion diseases

As shown in Table 6, the proportion of PrP mutations was quite different from those of EUROCJD, the European Creutzfeldt–Jakob Disease Surveillance Network (Kovacs et al., 2005). The V180I mutation was the most common in Japan but is very rare in Europe (only one case in France). Conversely, the most common mutation in Europe was E200K, which was the third most common in Japan. Additionally, the V210I mutation was the second most common mutation in Europe but was not identified in Japan.

In China, the following 10 genetic prion diseases cases have been reported; three D178N-129M cases and one case each of S97N, G114V, T188K, F198V, E200K, R208C and M232R (Shi et al., 2008; Zheng et al., 2009); in Korea, three genetic prion disease cases (D178N-129M, E200K and M232R) have been identified (Choi et al., 2009). The V180I mutation was not identified in China or Korea but, conversely, S97N, G114V, T188K, F198V and R208C mutations were not identified in Japan or Korea. Despite the similar ethnic background of East Asia, the distribution of genetic prion diseases in Japan might be different from China and Korea; however, the number of patients reported from China and Korea (Shi et al., 2008; Choi et al., 2009) is too small to reach a conclusion, requiring a larger study in the future.

V180I and M232R mutations were common in Japan but rare in European countries. Interestingly, patients with V180I or M232R mutations had no or rare family histories; therefore, they would have been misdiagnosed with sporadic Creutzfeldt–Jakob disease if genetic analysis had not been performed. Previous reports also showed no family history in cases of V180I or M232R mutations (Bratosiewicz et al., 2001; Jin et al., 2004; Shiga et al., 2007; Zheng et al., 2008; Choi et al., 2009). These findings suggest that V180I and M232R might be polymorphisms, but not pathogenic mutations. Compared with the genotypes of PrP in the general Japanese population (n = 466; isoleucine allele at codon 180:0; arginine at codon 232:0) (Ohkubo et al., 2003), both V180I and M232R mutations had significantly higher proportions of overall prion disease with PrP (n = 881) (both P < 0.001), indicating that V180I and M232R are not simple polymorphisms, but are disease related.

Age at disease onset of patients with the V180I mutation was older than that of sporadic Creutzfeldt–Jakob disease (P < 0.001), and patients with the V180I mutation had a longer clinical duration (P < 0.001) and lower rate of positive PSWCs on EEG (P < 0.001) than those with sporadic Creutzfeldt–Jakob disease (Tables 3 and 7). Similar findings were reported by Jin et al. (2004), who mentioned that MRI findings in V180I revealed characteristic hyperintensities in medial regions, posterior to the parieto-occipital sulci in occipital lobes on T2-weighted, fluid-attenuated inversion recovery, and diffusion weighted images. The following characteristics of V180I cases appeared to be similar to the MM2-cortical type: longer duration, hyperintensities on MRI and a lower rate of PSWCs; therefore, genetic analysis for PrP is necessary for a differential diagnosis.

The M232R mutation was the fourth most common in Japan, but is rare worldwide. Outside Japan, only three cases (Polish, Chinese and Korean) have been identified (Bratosiewicz et al., 2001; Zheng et al., 2008; Choi et al., 2009). As the M232R mutation has been identified mainly in Asian countries, this mutation may be particular to an Asian ethnic background. M232R cases included two clinical subtypes, slow and rapid, as reported previously (Shiga et al., 2007). The proportion of the slow type was higher (39%) than reported earlier (25%) (Shiga et al., 2007). While rapid-type patients with the M232R mutation present with clinical and laboratory findings, similar to MM1 type sporadic Creutzfeldt–Jakob disease, patients with the slow-type M232R mutation have atypical features similar to MM2-cortical type sporadic Creutzfeldt–Jakob disease. Further, M232R cases with a much longer clinical duration may be misdiagnosed as other neurodegenerative diseases if genetic examination of PrP is not performed.

In conclusion, the incidence rate of prion diseases was similar to that of western countries, but dura mater graft-associated Creutzfeldt–Jakob disease was frequent in Japan. Genetic differences, such as codon 129 and 219 polymorphisms and mutations in PrP, show some differences in the phenotypes of prion diseases between Japan and western countries.

Funding

The Creutzfeldt-Jakob Disease Surveillance Committee belongs to the Research Group on Prion Disease and Slow Virus Infection, funded by the Ministry of Health, Labour and Welfare of Japan. This work was supported in part by a Health and Labour Sciences Research Grant for Research on Measures for Intractable Diseases (Prion Disease and Slow Virus Infections) from the Ministry of Health, Labour and Welfare of Japan.

Acknowledgements

The authors thank Creutzfeldt–Jakob disease specialists in the prefectures, doctors-in-chief and Creutzfeldt–Jakob disease patients and families for providing clinical information about patients.

Abbreviations

    Abbreviations
  • PrP 

     prion protein

  • PSWC 

     periodic synchronous wave complex

  • WHO 

     World Health Organization

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