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Updated: Oct 18, 2025
Protein Misfolding Cyclic Amplification of Prions
Published on: November 7, 2012
Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion
Nicholas Brennecke1, Ignazio Cali2,3, Tze How Mok4
1Department of Neurology, Case Western Reserve University & University Hospitals Cleveland Medical, Cleveland, OH 44106, USA.
Abstract:
Genetic prion disease accounts for 10-15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt-Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt-Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt-Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt-Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk.
Insights
The 2-octapeptide repeat insertion is a low-risk genetic variant for prion disease, with cases resembling sporadic Creutzfeldt-Jakob disease. Genetic testing for relatives is not recommended due to its low penetrance.
Area of Science:
- Neurology
- Genetics
- Molecular Biology
Background:
- Genetic prion diseases represent 10-15% of all prion diseases.
- The pathogenicity of shorter octapeptide repeat insertions, like the 2-octapeptide repeat variant, remains unclear.
- Understanding the clinical and genetic implications of these variants is crucial for accurate diagnosis and risk assessment.
Purpose of the Study:
- To characterize the 2-octapeptide repeat insertion genetic variant in prion disease.
- To assess the risk of developing Creutzfeldt-Jakob disease in asymptomatic carriers of this variant.
- To evaluate the clinical presentation and prion protein characteristics associated with the 2-octapeptide repeat insertion.
Main Methods:
- Case series analysis of patients with 2-octapeptide repeat insertion prion disease from international registries.
- Querying large-scale population genetic databases to determine the allele frequency of the 2-octapeptide repeat insertion.
- Western blot analysis of prion protein profiles in affected individuals.
Main Results:
- Eight cases of 2-octapeptide repeat insertion prion disease were identified.
- Clinical presentation of these cases was indistinguishable from sporadic Creutzfeldt-Jakob disease (sCJD) of the same molecular subtype.
- Western blot analysis revealed distinct prion protein profiles for 2-octapeptide repeat insertion and sCJD.
- Population data indicated a very low penetrance for the 2-octapeptide repeat insertion variant.
Conclusions:
- The 2-octapeptide repeat insertion is associated with prion disease but appears to be a low-risk genetic variant.
- Asymptomatic carriers have a low risk of developing Creutzfeldt-Jakob disease.
- Predictive genetic testing for asymptomatic relatives is generally not justified due to the low penetrance.
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