Analysis of unusual accumulation of Creutzfeldt-Jakob disease cases in Orava and Liptov regions (northern Slovak focus) 1983-2000

While familial cases of Creutzfeldt-Jakob disease are extremely rare all over the world, 3 familial clusters were observed between 1983-2000 in a relatively small area situated in the North of Slovakia. Prevalence of CJD in this area exceeded the overall prevalence in Slovakia more than 8 times. The majority of CJD patients admitted consuming sheep brain. Most patients lived in small secluded villages with rather common familial intermarriage. CJD affected both sexes equally. All patients were prior to the disease mentally normal individuals. Shortly after the onset of CJD their mental status deteriorated remarkably with an average survival rate of 3.6 months.     

Geographic accumulation of Creutzfeldt-Jakob disease in Slovakia--environmental metal imbalance as a possible cofactor

Slovakia is characterised by an unusually high number of patients affected by genetic Creutzfeldt-Jakob disease (CJD) with E200K mutation at the PRNP gene. Penetrance of the mutation is incomplete (59%). Therefore, for the onset of the clinical manifestation, an influence of other endo- or exogenous factors could not be excluded. Experimental data suggest that copper and manganese levels may play an important role in the pathogenesis of prion diseases. The highest number of Slovak genetic CJD patients originates from Orava - the northern region of central Slovakia. Manganese is a dominant pollutant in Orava. The objective of this study was to clarify a possible exogenous influence of environmental Mn/Cu imbalance on the CJD clustering. Mn and Cu levels were analysed in the brain tissue of genetic CJD cases (from Orava and from control regions of Slovakia), as well as of sporadic CJD patients and controls. Analyses demonstrate i) significantly higher Mn level in focally accumulated, "clustering" genetic CJD cases in comparison to all other groups, ii) Cu status differences between compared groups were without statistical significance; decreased concentrations were found in genetic cases from extrafocal genetic CJD areas, iii) Mn/Cu ratios were increased in all CJD groups in comparison to controls. Metal ratios in clustering gCJD cases were significantly higher in comparison to sporadic cases and also to controls, but not to the extrafocal genetic CJD subgroup. These results indicate that more important than increasing Mn level in pathogenesis of CJD appears to be the role of the Mn/Cu imbalance in the CNS. The imbalance observed in the cluster of genetic CJD cases is probably a result of both: the excessive environmental Mn level and the disturbance of Mn/Cu ratios in the Orava region. Presented findings indicate an environmental Mn/Cu imbalance as a possible exogenous CJD risk co-factor which may, in coincidence with endogenous (genetic) CJD risk, contribute to the focal accumulation (cluster) of genetic CJD in Slovakia.     

Creutzfeldt-Jacob disease associated with the PRNP codon 200LYS mutation: An analysis of 45 families

200^Lys mutation in the human PRNP coding region has been identified in 45 of the 55 CJ-Daffected families thus far presented to our NIH laboratory. These codon 200^lys families have a total of 87 patients, and originate from 7 different countries: Slovakia, Poland, Germany, Tunisia, Greece, Libya, and Chile. Forty-seven patients were neuropathologically verified, and brain tissue from 14 patients transmitted disease to experimental primates.The mutation was found by direct sequencing in 4 patients, and it was detected by restriction endonuclease analysis with BsmA 1 and/or the single nucleotide extension reaction in 36 other patients and 45 of 109 first degree relatives (1 parent, 14 siblings, and 30 children).The mutation is associated with all known geographical clusters of CJD (Slovakia, Libyan Jews, Chile) in which the annual mortality rate is tens or hundreds of times higher than the world average of 1 per million. All patients originating from the cluster areas carried the mutation, but it was seen in only 1 of 103 unrelated control individuals from the same areas, and in none of 102 controls from other areas, indicating a strong association between the mutation and disease. The penetrance of the mutation was estimated to be 0.56.Branches of some families migrating from cluster areas to other countries continue to have CJD over several generations, suggesting that CJD in these families is a genetic disorder, in which the 200^Lys mutation is responsible for the disease.     

Creutzfeldt–Jakob Disease in health professionals in Slovakia

Creutzfeldt–Jakob disease (CJD) is the most important human transmissible spongiform encephalopathy (prion disease), recognised in sporadic, genetic but also iatrogenic forms. The identification of 8 health care workers in a group of 114 definitive CJD patients in Slovakia suggested the possibility of professionaly acquired CJD and induced the investigation of potential endo- and exogenous risk factors. In CJD-affected health professionals special attention was paid to a detailed occupational history, including a possible professional contact with CJD patient and to the findings characteristic for iatrogenic CJD: early cerebellar symptomatology, long duration of the disease, absence of typical EEG finding and homozygosity of PRNP gene at codon 129. Analysis of epidemiological, clinical and molecular biological data in investigated group of CJD-affected health professionals gave no evidence of an occupational risk for CJD.     

Familial Creutzfeldt-Jakob disease with temporal and spatial separation of affected members

Familial occurrence of three definitive and two possible cases of Creutzfeldt-Jakob disease (CJD) with temporal and spatial separation in the area of focal CJD accumulation in Slovakia is reported. Incubation period is 51 and 53 years respectively, if spatial and temporal separation of affected siblings is considered, and 51 years when the time interval between the death of the affected mother and the clinical onset in the first affected child is determined.Affected children tend to die at the same time (mean difference 3.3 years) and not at the same age (mean difference 6 years). Due to separation of the affected children, a possible common exposure to CID infection was limited to approximately seven years during their childhood. Potential endo- and exogenous risk factors and a possible mode of CJD transmission in the described family, as well as in the CJD focus, is discussed.     

“Clusters” of CJD in Slovakia: The first laboratory evidence of scrapie

Epidemic-like occurrence of Creutzfeldt-Jakob disease was observed in 1987 in Slovakia (Orava). Search for the cause of CID focus indicated a concidence of genetic and environmental risks in clustering patients. Since Spongiform Encephalopathies might be transmitted orally, (Bovine Spongiform Encephalopathy), the possibility of zoonotic source of CJD cases in Orava was also considered. A deficient knowledge about the occurrence of scrapie in Slovakia stimulated an examination of sheep with signs of CNS disorders in two flocks of Valasky breed in Orava. In one flock, neurohistopathological examination revealed in sheep brains lesions characteristic for scrapie. Frozen brain tissue of these animals were used for the detection of scrapie associated fibrils. They were found in 2 animals from the same flock. This is the first laboratory confirmation of scrapie in Czecho-Slovakia. The possible epidemiological and economical implications are emphasized.Corresponding author.     

A case of Creutzfeldt-Jakob disease related to familial retinitis pigmentosa patients

Similarities between serological alterations and retinal degeneration occurring in natural and experimental CJD and in some forms of human retinal degeneration have recently been reported. In the present paper a family from an areal focal accumulation of CJD in Central Slovakia with 1 histopathologically verified case of Creutzfeldt-Jakob disease and 2 case of retinitis pigmentosa is described. Neuropathological and epidemiological data obtained in investigated patients are discussed from the point of view of a possible relationship between the slow virus infections caused by unconventional agents and degenerative disease affecting the ocular system.     

中国2008年克雅氏病监测病例特征分析

目的 了解中国克雅氏病(CJD)的发病情况及流行病学、临床特征.方法 对2008年中国克雅氏病监测网络获得的可疑CJD病例的临床及流行病学资料进行分析,收集患者脑脊液及血液样品,利用Western blot方法榆测脑脊液中是否含有14-3-3蛋白,提取全血基因组DNA并利用PCR及测序方法对脚基因进行129位多态性及基因突变分析.结果 共发现散发型CJD临床诊断病例31例,疑似诊断病例11例,2例家族性CJD和1例格-斯-斯综合征.病例的地理分布及职业无明显聚集性;临床诊断病例发病平均年龄56.7岁,男女比例8:9;疑似诊断病例发病平均年龄为57.4岁,男女比例5:6.快速进行性痴呆为最常见的首发症状,占全部诊断病例的33.3%.临床诊断病例比疑似诊断病例出现更多的典型临床表现.结论 2008年中国监测到的CJD病例以散发型为主,病例的地理分布、职业、性别比例以及平均年龄均符合散发型CJD的分布特点.     

中国2008年克雅氏病监测病例特征分析

目的 了解中国克雅氏病(CJD)的发病情况及流行病学、临床特征.方法 对2008年中国克雅氏病监测网络获得的可疑CJD病例的临床及流行病学资料进行分析,收集患者脑脊液及血液样品,利用Western blot方法榆测脑脊液中是否含有14-3-3蛋白,提取全血基因组DNA并利用PCR及测序方法对脚基因进行129位多态性及基因突变分析.结果 共发现散发型CJD临床诊断病例31例,疑似诊断病例11例,2例家族性CJD和1例格-斯-斯综合征.病例的地理分布及职业无明显聚集性;临床诊断病例发病平均年龄56.7岁,男女比例8:9;疑似诊断病例发病平均年龄为57.4岁,男女比例5:6.快速进行性痴呆为最常见的首发症状,占全部诊断病例的33.3%.临床诊断病例比疑似诊断病例出现更多的典型临床表现.结论 2008年中国监测到的CJD病例以散发型为主,病例的地理分布、职业、性别比例以及平均年龄均符合散发型CJD的分布特点.