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Inherited prion disease with 5-OPRI: phenotype modification by repeat length and codon 129
S Mead1, T E F Webb, T A Campbell
1MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London, UK.
Neurology
|August 22, 2007
Summary
Inherited prion diseases show varied symptoms. This study examines 5-octapeptide repeat insertions (5-OPRI) in the prion protein gene (PRNP), revealing a wider phenotypic range and later age of onset compared to 6-OPRI.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Human prion diseases encompass sporadic, acquired, and inherited forms.
- These diseases exhibit significant phenotypic heterogeneity.
- Studying inherited prion diseases with identical mutations clarifies clinicopathologic variability.
Purpose of the Study:
- To investigate the phenotypic spectrum of 5-octapeptide repeat insertion (5-OPRI) mutations in the prion protein gene (PRNP).
- To analyze determinants of clinicopathologic heterogeneity in inherited prion diseases.
- To compare 5-OPRI with other octapeptide repeat mutations.
Main Methods:
- Clinical and pathological data collection from three families with distinct 5-OPRI mutations.
- Review of existing world literature on octapeptide repeat insertion mutations.
- Analysis of PRNP codon 129 genotypes and their correlation with disease onset.
Main Results:
- A South African family presented with rapidly progressive dementia and atypical kuru-like plaques, linked to a novel precursor allele.
- An English family showed a 30-year variation in clinical onset between father and daughter, potentially due to PRNP codon 129 genotype.
- A Northern Irish patient with sporadic Creutzfeldt-Jakob disease phenotype was found to have a 5-OPRI mutation.
Conclusions:
- The mean age of onset for 5-OPRI mutations is later than for 6-OPRI mutations.
- Both 5-OPRI and 6-OPRI mutations demonstrate a significant disease-modifying effect influenced by the PRNP codon 129 genotype.
- PRNP codon 129 polymorphism plays a crucial role in modifying prion disease phenotypes.
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