GGGGCC hexanucleotide repeat expansion in the non-coding sequence of the C9orf72 gene is associated with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) (Renton et al., 2011; DeJesus-Hernandez et al., 2011), of autosomal dominant inheritance. Generally, alleles with less than 25 repeats are considered normal and those with more than 60 are pathogenic.
Globally, this variant represents the most common cause of sporadic and familial ALS (7% and 38% of cases, respectively), the most common cause of sporadic FTD (6% of cases), and one of the most common causes of familial FTD (25% of cases) (Majounie et al., 2012).
In Spain, this variant is responsible for 27% of familial ALS, 3% of sporadic ALS, 30% of familial FTD, and 22.58% of sporadic FTD (García-Redondo et al., 2013; van der Zee et al., 2013).
Carriers of this expansion are typically diagnosed with ALS, FTD, or both. Some carriers never develop the disease, which is consistent with incomplete penetrance.
The initial manifestations can be pure ALS or FTD, and the appearance of other symptoms is normal throughout the disease. Although there are no definitive clinical characteristics that would allow distinguishing these patients from carriers of ALS- or FTD-related mutations in other genes, this variant is usually associated with:
- Earlier age of onset (regardless of initial symptoms)
- Faster clinical course
- Shorter survival
- Bulbar onset (in the case of ALS)
- Higher incidence of relatives with neurodegenerative diseases (especially dementia, in 35% of cases)
- Parkinsonism (mainly rigid-akinetic type with focal dystonia and poor levodopa response)
- Increased susceptibility to psychiatric symptoms, such as psychosis, early-onset delusions, paranoia, and late-onset hallucinations.
