This hexanucleotide (GGGGCC) repeat expansion in the non-coding region of the C9orf72 gene is responsible for autosomal dominant amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) (Renton et al., 2011, and DeJesus-Hernandez et al., 2011). Alleles up to 25 repeats are generally considered normal and those greater than 60 pathogenic.
Globally, this variant represents the most frequent cause of sporadic and familial ALS (7 and 38% of cases, respectively), the most frequent cause of sporadic FTD (6% of cases), and one of the most frequent 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 diseases. 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 course of the disease. Although there are no definitive clinical features that allow these patients to be distinguished from other ALS or FTD mutation carriers, this variant is usually associated with an earlier age at onset (regardless of initial symptoms), faster clinical course, shorter survival, bulbar onset (in case of ALS), a higher incidence of neurodegenerative diseases in relatives (mainly dementia, in 35% of cases), parkinsonism (mainly of the akinetic-rigid type with focal dystonia and poor response to levodopa), and a greater tendency to develop psychiatric symptoms such as psychosis, early-onset delusions, paranoia, and late-onset hallucinations.