C9orf72 repeat length might influence clinical sub-phenotypes in dementia patients

Area of Science:

• Neurogenetics
• Neurology
• Molecular Biology

Background:

• C9orf72 repeat expansions are implicated in various neurodegenerative disorders.
• Current methods for sizing C9orf72 alleles are often semi-quantitative, obscuring the distinction between normal and pathogenic alleles.
• Intermediate C9orf72 alleles may play a role in disease prevalence and phenotype, similar to other repeat expansion disorders.

Purpose of the Study:

• To determine the prevalence of small, intermediate, and expanded C9orf72 alleles.
• To investigate the influence of C9orf72 alleles on disease phenotype in neurodegenerative disorders.

Main Methods:

• DNA samples from 1804 patients and 643 healthy individuals were analyzed.
• Genotyping was performed using a two-step PCR assay followed by Southern blotting.

Main Results:

• Pathological C9orf72 repeat expansions were found in 3.4% of frontotemporal dementia (FTD) and 0.8% of Alzheimer's disease (AD) cases.
• Expansion carriers exhibited significantly earlier disease onset in both FTD and AD cohorts compared to non-carriers.
• C9orf72 intermediate alleles were associated with cerebellar symptoms and sensory deficits in the dementia cohort.

Conclusions:

• C9orf72 repeat expansion carriers experience an earlier onset of FTD and AD.
• Intermediate C9orf72 repeats may modify the phenotypic presentation of dementia.