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Familial Creutzfeldt-Jakob disease in Finland: epidemiological, clinical, pathological and molecular genetic studies
M Haltia1, J Kovanen, L G Goldfarb
1Department of Pathology, University of Helsinki, Finland.
Insights
A new genetic mutation in the PRNP gene (codon 178) is linked to familial Creutzfeldt-Jakob disease (CJD) in a Finnish family. This mutation co-segregates with the disease, offering insights into CJD
Area of Science:
- Neuroscience
- Genetics
- Epidemiology
Background:
- Creutzfeldt-Jakob disease (CJD) is a rare, fatal neurodegenerative disorder.
- Familial CJD accounts for a portion of cases, suggesting a genetic component.
- Understanding the genetic basis of CJD is crucial for diagnosis and potential therapies.
Purpose of the Study:
- To investigate the genetic and clinical characteristics of a CJD-affected kindred in Finland.
- To identify potential genetic mutations associated with familial CJD.
- To analyze the inheritance pattern and clinical presentation of CJD within this family.
Main Methods:
- Pedigree analysis to determine inheritance patterns.
- Clinical and neuropathological examination of affected individuals.
- Human Leukocyte Antigen (HLA) typing.
- Molecular genetic analysis of the PRNP gene, including mutation screening and linkage analysis.
Main Results:
- A kindred with 15 affected members across four generations exhibiting autosomal dominant CJD was identified.
- Clinical features included a mean age of onset of 47, absence of periodic EEG activity, and a prolonged disease duration.
- A novel G-to-A mutation at codon 178 of the PRNP gene was found to co-segregate with CJD in the family, with a LOD score of 3.6.
- A significant association was observed with HLA antigen A28.
Conclusions:
- The identified PRNP gene mutation at codon 178 is strongly associated with familial CJD in this kindred.
- The findings contribute to the understanding of genetic CJD subtypes and their molecular basis.
- This discovery may aid in genetic counseling and the development of diagnostic tools for familial CJD.
Abstract:
In 1974-1984 30 patients died with a diagnosis of Creutzfeldt-Jakob disease (CJD) in Finland (annual mortality rate of CJD 0.9 per million population for the years 1979-1984). Six of these patients (20%) were familial, all belonging to the same kindred. The pedigree now includes 15 affected members in four generations, and the occurrence of disease is consistent with an autosomal dominant mode of inheritance. The clinical features of CJD in this family are in most respects typical of the familial disease described elsewhere. However, the mean age at onset is 47, periodic EEG activity has not been observed, and the mean duration of illness of 27.5 months is longer than usual for either familial or sporadic CJD. Neuropathological examination of brain biopsy and autopsy specimens revealed spongiform change without amyloid plaques, and brain tissue from one patient transmitted disease to a capuchin monkey. In an analysis of the histocompatibility antigens of the family, CJD was not linked with a single haplotype, but at least 12 out of 13 CJD patients shared the HLA antigen A28. Molecular genetic studies disclosed a new G-to-A mutation in codon 178 of the PRNP gene (resulting in a substitution of asparagine for aspartic acid) in the DNA of eight family members with CJD but not in any of ten currently healthy first degree relatives of the patients, or 86 controls. The codon 178 mutation thus seems to co-segregate with CJD in this family. Linkage analysis gave a LOD score value of 3.6.