Surveillance for variant CJD: should more children with neurodegenerative diseases have autopsies?

OBJECTIVES: To report investigations performed in children with progressive neurodegenerative diseases reported to this UK study. DESIGN: Since 1997 paediatric surveillance for variant Creutzfeldt-Jakob disease (vCJD) has been performed by identifying children aged less than 16 years with progressive intellectual and neurological deterioration (PIND) and searching for vCJD among them. SETTING: The PIND Study obtains case details from paediatricians who notify via the British Paediatric Surveillance Unit. PARTICIPANTS: Between May 1997 and October 2017, a total of 2050 cases meeting PIND criteria had been notified and investigated. RESULTS: Six children had vCJD. 1819 children had other diagnoses, made in 12 cases by antemortem brain biopsy and in 15 by postmortem investigations. 225 children were undiagnosed: only 3 had antemortem brain biopsies and only 14 of the 108 who died were known to have had autopsies; postmortem neuropathological studies were carried out in just 10% (11/108) and only two had prion protein staining of brain tissue. Of the undiagnosed cases 43% were known to come from Asian British families. CONCLUSIONS: Most of the notified children had a diagnosis other than vCJD to explain their neurological deterioration. None of the undiagnosed cases had the clinical phenotype of vCJD but brain tissue was rarely studied to exclude vCJD. Clinical surveillance via the PIND Study remains the only practical means of searching for vCJD in UK children.

Racial and ethnic differences in individuals with sporadic Creutzfeldt-jakob disease in the United States of America.

BACKGROUND: Little is known about racial and ethnic differences in individuals with sporadic Creutzfeldt-Jakob disease (sCJD). The authors sought to examine potential clinical, diagnostic, genetic, and neuropathological differences in sCJD patients of different races/ethnicities. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective study of 116 definite and probable sCJD cases from Johns Hopkins and the Department of Veterans Affairs Healthcare Systems was conducted that examined differences in demographic, clinical, diagnostic, genetic, and neuropathological characteristics among racial/ethnic groups. Age at disease onset differed among racial/ethnic groups. Non-Hispanic Whites had a significantly older age at disease onset compared to the other groups (65 vs. 60, p = 0.036). Non-Whites were accurately diagnosed more rapidly than Whites (p = 0.008) and non-Hispanic Whites were more likely to have normal appearing basal ganglia on brain magnetic resonance imaging (MRI) compared to minorities (p = 0.02). Whites were also more likely to undergo post-mortem evaluation compared to non-Whites (p = 0.02). CONCLUSIONS/SIGNIFICANCE: Racial/ethnic groups affected by sCJD demonstrated differences in age at disease onset, time to correct diagnosis, clinical presentation, and diagnostic test results. Whites were more likely to undergo autopsy compared to non-Whites. These results have implications in regards to case ascertainment, diagnosis, and surveillance of sCJD and possibly other human prion diseases.

Survival to akinetic mutism state in Japanese cases of MM1-type sporadic Creutzfeldt-Jakob disease is similar to Caucasians.

BACKGROUND: It is not known whether the clinical course of Japanese sporadic Creutzfeldt-Jakob disease (sCJD) cases differs from that of Caucasian sCJD cases. PATIENTS AND METHODS: To investigate the clinical course of Japanese sCJD, clinical findings from 29 patients with Japanese MM1-type sCJD were retrospectively evaluated and compared to Caucasian sCJD findings. RESULTS: Survival of Japanese MM1-type sCJD up to the time of akinetic mutism state is similar to that of Caucasian subjects. However, the total disease duration of Japanese patients was approximately three times longer. CONCLUSIONS: The present observations indicate that Japanese sCJD cases generally show a longer disease duration because of the longer survival period after reaching the akinetic mutism state.

Incidence of Creutzfeldt-Jakob disease in Taiwan: a prospective 10-year surveillance.

This study was performed to estimate the incidence of Creutzfeldt-Jakob Disease (CJD) in Taiwan from 1998 to 2007. Suspected cases of CJD were reported to the Taiwan Creutzfeldt-Jakob Disease Surveillance Unit, a nationwide, hospital-based case report system initiated since 1996 to prospectively conduct a CJD epidemiological study. Consecutive patients who met the diagnostic criteria recommended by the World Health Organization were enrolled. The clinical information of each suspected case was collected and case ascertainment was performed by an expert committee. A total of 123 sporadic CJD were identified without any iatrogenic or new variant CJD cases. The overall annual incidence rate (95% CI) was 0.55 (0.46-0.65) cases per million person-year. There was no statistically significant difference between the calendar year of disease onset (P = 0.97). The incidence rates were not significantly different between women and men (P = 0.63). Age was the main factor for the risk of CJD (P < 0.0001). Age-specific incidence rate increased after the age of 40 years with the peak being in the 70-79 years age group. Our data showed low annual incidence rate and high frequency of methionine homozygous prion protein genotype of sCJD in Taiwan. This report provided important epidemiological data on ethnic Chinese.

Analysis of PRNP gene codon 129 polymorphism in the Greek population.

Creutzfeldt-Jakob disease (CJD) is a fatal transmissible neurodegenerative prion disease with a rapid progression comprising familial, sporadic, iatrogenic and variant forms. A polymorphism at codon 129 of PRNP gene has been implicated in the development of variant CJD. We examined Met/Val allele frequencies and the genotype distribution, with respect to the polymorphic codon 129 of PRNP gene in 348 healthy individuals from the region of Athens, Greece. The following genotype frequencies were observed in the Greek population: Met/Met 50%, Met/Val 39% and Val/Val 11%. The presence of the Methionine allele frequencies in various European populations, according to the published data, increases gradually from northwestern to southeastern countries, implying the presence of a cline. The distribution of genotypes of Met homozygotes displays random declination across the 10 compared populations. The observed higher frequency of Met homozygotes at codon 129 does not necessarily suggest that these populations are at increased risk of developing CJD.

Phenotypic variability in familial prion diseases due to the D178N mutation.

BACKGROUND: Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2,100,000 inhabitants. METHODS: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. RESULTS: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. CONCLUSIONS: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene.

Genotype frequencies at codon 129 of the prion protein gene in Brazil: Implications in susceptibility to variant Creutzfeldt-Jakob disease compared to European and Asian populations.

A polymorphism at codon 129 of the prion protein gene has been shown to confer genetic susceptibility to prion diseases, and to influence the epidemic course of variant Creutzfeldt-Jakob disease. We employed a PCR-endonuclease digestion-based assay to investigate this genetic trait in Brazil, and then compared our results to previously published data from several European and Asian countries.

Polymorphisms of the PRNP gene in Chinese populations and the identification of a novel insertion mutation.

The two common polymorphisms (385A > G: M129V and 655G > A: E219 K) in the human prion gene (PRNP) play important roles in the pathogenesis of Creutzfeldt-Jakob diseases. We screened a total of 626 individuals, who represent three ethnic populations of China, Han, Hui, and Uyghur, for the two polymorphisms. The frequencies of M/M homozygote at residue 129 in these three groups differ significantly. The Han has a much higher frequency (98%) than Hui (85%) and Uyghur (60%). On the other hand, the frequencies of the E/E at residue 219 are higher in Uyghur (98%) and Hui (96%) than in Han (90%). We also investigated two other less common variants of PRNP, a silent substitution at residue 117 (351A > G: A117A), and one octapeptide-repeat deletion (1-OPRD) in the octapeptide-coding region. We found three Uyghur individuals with silent substitution at residue 117. Four Hui (2.0%) and one Han (0.5%) donors were found to be heterozygous for 1-OPRD. A novel three extra-repeat (72 bp) insertion within the octapeptide-coding region was identified in one healthy 11-years-old Hui. Identical mutation was also found in her mother but not her father.

Variations in neurodegenerative disease across the UK: findings from the national study of Progressive Intellectual and Neurological Deterioration (PIND).

AIMS: To identify any UK children with variant Creutzfeldt-Jakob disease (vCJD) and obtain information about the causes of progressive intellectual and neurological deterioration (PIND) and the geographical distribution of cases. METHODS: The PIND Study uses the monthly surveillance card that is sent to all UK paediatricians by the British Paediatric Surveillance Unit. Case details are obtained from the reporting paediatricians by telephone interview, site visit, or self completion of a questionnaire. A paediatric neurology expert group then classifies the anonymised cases. The Communicable Disease Surveillance Centre (CDSC) provides mapping support. RESULTS: After five years and five months of surveillance, 1400 children had been reported. In the UK the majority of PIND cases had a confirmed diagnosis (comprising 99 different conditions); 505 "no cases" and 97 "outstanding" cases were excluded. A total of 798 PIND cases were included as follows: 577 with a confirmed underlying diagnosis; six with definite or probable vCJD, 51 who had undiagnosed PIND but were not thought to have vCJD, and 164 cases who were still under investigation. In some districts there were unexpectedly high numbers of PIND cases with a heterogeneous mixture of underlying diagnoses. In the five districts with the largest numbers of resident cases the majority not only came from a particular ethnic group but also had high reported rates of consanguinity. CONCLUSIONS: In districts with large numbers of PIND cases there are major resource implications. These children and their families have complex problems and they need access to diagnostic facilities and appropriate service provision.

Japanese Creutzfeldt-Jakob disease patients exhibiting high incidence of the E200K PRNP mutation and located in the basin of a river.

Seven cases with Creutzfeldt-Jakob disease (CJD) located in the basin of the Fuji river (Fuji area) in Japan were examined genetically and clinicopathologically. The onset of the disease was between 1989 and 1995. All cases were from different families, although 3 cases were family members of previously reported CJD patients. They had clinical and/or neuropathological features, corresponding to subacute spongiform encephalopathy. Five of the 7 cases, including the 3 familial cases, had the E200K mutation in the gene encoding prion protein (PRNP). It is suggested that there is a small cluster of CJD patients with a founder effect of the E200K mutation in the Fuji area, because the incidence of CJD with the E200K mutation appears to be much higher in this area than other areas in Japan. The disease penetrance of the 5 cases with the E200K mutation seems to be low, and they may have an age-related incidence in the Fuji area. These findings support the hypothesis that the phenotypes of CJD patients with the PRNP mutations are linked to the position of the mutation, but not related to ethnic or environmental factors.

Creutzfeldt-Jakob disease in the United States, 1979-1994: using national mortality data to assess the possible occurrence of variant cases.

After a cluster of Creutzfeldt-Jakob disease (CJD) cases among unusually young patients was reported recently from the United Kingdom, we examined trends and the current incidence of CJD in the United States. We found that the age-adjusted CJD death rate in the United States is similar to published estimates of the crude incidence of CJD worldwide and has continued to be stable from 1979 through 1994. The number of CJD deaths in persons

Is ataxic gait the predominant presenting manifestation of Creutzfeldt-Jakob disease? Experience of 14 Chinese cases from Taiwan.

Creutzfeldt-Jakob disease (CJD) is caused by an unusual prion protein. Rare CJD cases have been reported in Chinese individuals. This report describes the clinical manifestations of 14 Chinese individuals with clinically definite CJD from the National Taiwan University Hospital during the period 1976-1995. It is the largest case series of Chinese CJD up to now. All these patients fulfil the clinical definite diagnosis of CJD proposed by Brown et al. (1986), including rapidly evolving dementia, myoclonus, periodic electroencephalographic (EEG) activity (0.5-2 Hz) and death within 12 months. The clinical characteristics of the present series, including age at onset, sex ratio, duration, initial symptoms, neurological signs, EEG abnormalities, and neuroimaging studies were similar to those reported in other countries. However, there is a high incidence of initial ataxic gait as the presentation in our patients. Eight (57%) out of 14 patients initially had gait ataxia alone or in association with dementia. CJD should be considered in the differential provisional diagnosis of any middle-aged patient with a progressive ataxic syndrome.

The risk of developing Creutzfeldt-Jakob disease in subjects with the PRNP gene codon 200 point mutation.

We determined the penetrance of the PRNP 200Lys mutation in the large cluster of Creutzfeldt-Jakob disease (CJD) cases among Jews of Libyan-Tunisian origin living in Israel, utilizing data from 52 carriers with definite or probable CJD and 34 unaffected mutation carriers. A life table analysis was carried out with development of CJD as the end point. The probability of developing CJD rose with age, fitting a second-order regression curve (R = 0.97, p < 0.001). The cumulative penetrance reached 50% at the age of 60 and 80% at 80 years. Including seven elderly possible CJD patients in the analysis made the penetrance approach 100% by age eighty. The penetrance of the mutation is high, and although age is a predominant influencing factor, other factors, such as gender, may also play a role.

Genetics and biochemistry of Creutzfeldt-Jakob disease in Libyan Jews.

A focus of Creutzfeldt-Jakob disease (CJD) among Jews from Libyan origin was identified in Israel 20 years ago. The incidence of the disease in this ethnic group is about 100 times more than in the worldwide population. The consumption of lightly cooked sheep brain has been invoked to explain the high incidence of CJD in this community. The discovery of mutations in the PrP gene which segregates with other familial prion diseases such as Gerstmann-Straussler syndrome (GSS) lead us to perform a molecular genetic study and compare it to an epidemiological survey among the Libyan community. The epidemiological data suggests a very high familial incidence of CJD in this population and a molecular genetic research elucidated that CJD segregates with a point mutation at codon 200 of the PrP gene resulting in the substitution of Lysine for Glutamate. This mutation was found in some 40 CJD patients of Libyan origin and was not found in one Moroccan Jew suffering from CJD. It was also absent in almost 100 healthy Libyan controls above the age of 60. This result strongly supports a genetic etiology for CJD pathogenesis in the Libyan Jewish community and disregards the previous culinary hypothesis. The disease is vertically transmitted in autosomal dominant inheritance with unknown penetrance. All our patients were heterozygote for the mutation except one homozygote patient. The course of the disease in this patient was identical to the heterozygote patients, strongly arguing that inherited CJD displays complete phenotypic dominance.(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution of prion protein in German patients with Creutzfeldt-Jakob disease is different from that in Japanese patients.

We investigated the distribution of prion protein (PrP) in 14 German patients with sporadic Creutzfeldt-Jakob disease (CJD) and compared it with that observed in Japanese patients. Immunohistochemical study revealed diffuse gray matter stainings including synaptic structures in all cases. In addition, 4 patients showed plaque-type deposition which was very rarely observed among sporadic Japanese patients without known mutation of the PrP gene but with valine at codon 129. A higher incidence of PrP plaques in German sporadic CJD may be related to the racial difference in the PrP gene.

Clinical heterogeneity and unusual presentations of Creutzfeldt-Jakob disease in Jewish patients with the PRNP codon 200 mutation.

The cluster of Creutzfeldt-Jakob disease among Jews of Libyan origin is the largest in the world. It was found that the disease in this ethnic group is linked to a point mutation in codon 200 of the prion protein precursor gene. In this study the clinical data from 14 such patients are described, demonstrating wide phenotypic heterogeneity. The age of onset ranged from 34 to 65 years and the duration of disease from 2 to 66 months. Clinical features included cerebral, basal ganglia, brainstem, cerebellar, and spinal cord dysfunction. Uncommon features included fatal insomnia in one patient, pruritus in another, and demyelinating peripheral neuropathy in two.

Prion encephalopathies of animals and humans.

Studies over the past decade of the infectious prions causing scrapie and other transmissible neurodegenerative diseases support the hypothesis that these pathogens are novel. After convincing evidence was obtained showing that scrapie infectivity depends upon a protein component, the term "prion" was introduced to distinguish these infectious pathogens from others, including viroids and viruses. Enriching fractions from Syrian hamster (SHa) brain for scrapie prion infectivity led to the discovery of the prion protein (PrP). Transgenic (Tg) mice expressing both SHa and mouse (Mo) PrP genes were used to probe the molecular basis of the species barrier and the mechanism of scrapie prion replication. Bioassays of brain extracts from two scrapie-infected Tg lines showed that the prion inoculum dictates which prions are synthesized de novo, even though the cells express both PrP genes. Discovery of mutations in the PrP gene from humans with Gerstmann-Sträussler-Scheinker disease (GSS), familial Creutzfeldt-Jakob disease and fatal familial insomnia established that prion diseases are unique among human illnesses--they are both genetic and infectious. Tg mice expressing MoPrP with the GSS point mutation spontaneously develop neurologic dysfunction, spongiform degeneration and astrocytic gliosis. Inoculation of brain extracts prepared from these Tg(GSSMoPrP) mice into Syrian hamsters and Tg mice expressing wild-type PrP transgenes has produced neurodegeneration in recipient animals after prolonged incubation times. If convincing data on serial passage of prions from the inoculated recipients can be obtained, then these results will argue that prions are devoid of foreign nucleic acid in accord with many other lines of evidence. Although it seems likely that transmissible prions are composed only of PrPSc molecules, a hypothetical second component such as a small polynucleotide remains a formal possibility. The conversion of PrPc into PrPSc is a post-translational process that probably occurs in the endocytic pathway. Studies on the structure of PrPSc and PrPC have been unsuccessful in defining a post-translational chemical modification that distinguishes one PrP isoform from the other. These findings suggest that the difference between PrPSc and PrPc may be conformational. The existence of distinct prion isolates or "strains" with different properties poses a conundrum. Distinct isolates produce the accumulation of PrPSc in particular sets of CNS neurons. Whether different conformers of or Asn-linked CHOs attached to PrPSc are produced in specific neurons and are responsible for the properties of distinct prion isolates is unknown. The study of prion diseases seems to be emerging as a new area of investigation at the interface of such disciplines as genetics, cell biology and virology.