Genetic Creutzfeldt-Jakob disease associated with 5-octapeptide repeat insertion in the PRNP gene: case and pedigree report and literature review

Clinical Snapshot

Key Findings

• P Value: Not reported

• Effect Size: 25 patients from 14 families analysed

• Primary Outcome: Clinical phenotype characterisation of 5-OPRI genetic CJD

• Nnt Or Sensitivity: 84% showed frontotemporal dementia-like features; 83.3% carried MM genotype at codon 129

• Confidence Interval: Not applicable (descriptive study)

Clinical Application

Genetic testing for PRNP mutations is available in specialist centres Relevant to Australian neurologists managing rare dementias; genetic counselling services available through state genetics services; no specific PBS implications for this rare condition Patients with suspected genetic prion disease, particularly those with family history or early-onset dementia

Abstract

BACKGROUND: Genetic prion diseases caused by octapeptide repeat insertions in the PRNP gene are rare. 5-octapeptide repeat insertion (5-OPRI) is an uncommon subtype that usually manifests as Creutzfeldt-Jakob disease (CJD) but shows marked variability in clinical phenotype and disease course. DISCUSSION: We report a patient with rapidly progressive gCJD caused by a 5-OPRI mutation. A systematic PubMed review identified genetically confirmed 5-OPRI cases with available clinical data. Demographic characteristics, clinical features, ancillary investigations, disease course, and PRNP codon 129 polymorphisms were analyzed. A total of 25 patients from 14 families were included. Age at onset ranged from 26 to 63 years (mean 44.8 ± 9.9 years). Disease duration ranged from 4 to 192 months. Dementia was present in all patients, and 84% showed frontotemporal dementia-like features. Cerebellar signs, extrapyramidal symptoms, and myoclonus occurred in 68%, 60%, and 44% of patients, respectively. Periodic sharp wave complexes were detected in 29.4% of EEGs, and cerebral atrophy was observed in all patients with neuroimaging. Most patients carried the MM genotype at PRNP codon 129 (83.3%). A short disease course was associated with more frequent akinetic mutism and myoclonus, while MM carriers had a younger age at onset than MV carriers. CONCLUSIONS: 5-OPRI-associated CJD exhibits marked heterogeneity in clinical and disease duration. The PRNP codon 129 polymorphism appears to influence disease onset and progression.

References

1. 1.Geng, Q., Liu, R., Xia, J., Lv, Y., Chen, Z., & Lu, Y. (2024). Genetic Creutzfeldt-Jakob disease associated with 5-octapeptide repeat insertion in the PRNP gene: case and pedigree report and literature review. Neurological Sciences. https://doi.org/10.1007/s00415-023-11968-9