Disease progression in C9orf72 mutation carriers

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• The C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• Understanding the clinical progression in C9orf72 mutation carriers is crucial for developing targeted therapies.

Purpose of the Study:

• To evaluate longitudinal changes in the Revised ALS Functional Rating Scale (ALSFRS-R), letter fluency, and Frontal Behavioral Inventory (FBI) in C9orf72 mutation carriers.
• To assess how these clinical measures differentiate between various phenotypic presentations (asymptomatic, ALS, ALS-FTD, FTD) and track disease progression.

Main Methods:

• A prospective natural history study enrolled 34 C9orf72 mutation carriers.
• Participants were categorized into asymptomatic, ALS, ALS-FTD, or behavioral-variant FTD groups.
• ALSFRS-R, letter fluency, and FBI were assessed at baseline and at 6, 12, and 18 months.

Main Results:

• ALSFRS-R scores correlated with motor function, while letter fluency correlated with cognitive tests and FBI.
• Significant differences in ALSFRS-R, letter fluency, and FBI were observed among C9orf72 subgroups at baseline.
• Symptomatic patients showed worsening scores over time, with varying rates across subgroups, impacting survival in ALS and ALS-FTD groups.

Conclusions:

• The ALSFRS-R, letter fluency, and FBI effectively distinguish between different C9orf72-associated neurodegenerative phenotypes.
• Longitudinal changes in these measures reflect disease progression and are consistent with the initial clinical presentation.