AI Article Synopsis
- C9orf72 repeat expansions are linked to neurodegenerative disorders, with unclear thresholds distinguishing normal from pathogenic variants.
- In a study of 1804 patients and 643 healthy individuals in Austria, the presence of C9orf72 repeat expansions was found in 3.4% of frontotemporal dementia and 0.8% of Alzheimer's disease cases, with carriers experiencing earlier disease onset.
- Intermediate C9orf72 alleles were associated with specific symptoms, like cerebellar issues and sensory deficits, suggesting they may influence the clinical presentation of dementia.
Article Abstract
Background: C9orf72 repeat expansions have been observed in a wide variety of neurodegenerative disorders. The cut-off between normal and pathogenic alleles is not well established as repeat sizing methods are often semi-quantitative. However, intermediate alleles might influence disease prevalence and phenotype, as seen for other repeat expansion disorders. We aimed to further delineate the prevalence of small, intermediate and expanded C9orf72 alleles and elucidate their potential influence on the disease phenotype.
Methods: DNA derived from patients (n = 1804) and healthy individuals (n = 643) was obtained from multiple collectives in Austria. Genotyping was performed using a two-step PCR assay followed by Southern blotting.
Results: 3.4% of clinically diagnosed frontotemporal dementia (FTD; n = 5/147) cases and 0.8% of clinically diagnosed Alzheimer's disease (AD; n = 5/602) cases were carriers of a pathological C9orf72 repeat expansion. A significantly earlier disease onset was detected in expansion carriers compared to non-carriers in the FTD and AD cohorts (median 50 years, range 39-64 vs. median 64 years, range 36-92, p = 0.018 and median 63 years, range 54-71 vs. median 74 years, range 45-92, p = 0.006, respectively). C9orf72 intermediate alleles were significantly associated with cerebellar symptoms (p = 0.0004) and sensory deficits in the dementia cohort (p = 0.01).
Conclusions: C9orf72 repeat expansion carriers showed earlier disease onset compared to non-carriers with clinical diagnosis of FTD and AD. Furthermore, C9orf72 intermediate repeats might modify the phenotypic expression in dementia.
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| http://dx.doi.org/10.1016/j.nbd.2022.105927 | DOI Listing |
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