Diversity of Cognitive Phenotypes Associated with C9ORF72 Hexanucleotide Expansion

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• The C9ORF72 gene mutation is a significant genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
• Understanding the prevalence and clinical spectrum of this mutation is crucial for accurate diagnosis and genetic counseling.

Purpose of the Study:

• To determine the frequency of the C9ORF72 gene expansion in a cohort of patients with frontotemporal dementia (FTD) and related disorders.
• To characterize the clinical manifestations associated with the C9ORF72 mutation in this cohort.

Main Methods:

• Genetic screening for the C9ORF72 gene expansion in 162 patients with FTD.
• Screening in 145 additional patients with frontotemporal features or symptoms overlapping with known C9ORF72 carriers.
• Clinical data collection and analysis of positive cases.

Main Results:

• The C9ORF72 expansion was identified in 10 cases (3.7% of the total screened cohort).
• Seven of these cases (4.3% of FTD cohort) presented with FTD syndromes; three cases (2% of the non-FTD cohort) had different diagnoses.
• Common symptoms included language impairment, behavioral changes, memory deficits, and parkinsonism, with a family history of dementia, psychiatric disease, or ALS.

Conclusions:

• The C9ORF72 mutation is infrequent in the studied dementia series but exhibits diverse clinical presentations.
• The mutation's presence in non-FTD cases highlights the importance of genetic testing in patients with frontotemporal features.
• Family history is a key indicator, though not all families with mixed FTD/ALS phenotypes carried the expansion.