Two studies recently identified a GGGGCC hexanucleotide repeat expansion in a 
non-coding region of the chromosome 9 open-reading frame 72 gene (C9ORF72) as 
the cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and 
frontotemporal dementia (FTD). In a cohort of 231 probands with ALS, we 
identified the C9ORF72 mutation in 17 familial (27.4%) and six sporadic (3.6%) 
cases. Patients with the mutation presented with typical motor features of ALS, 
although subjects with the C9ORF72 mutation had more frequent bulbar onset, 
compared to those without this mutation. Dementia was significantly more common 
in ALS patients and families with the C9ORF72 mutation and was usually 
early-onset FTD. There was striking clinical heterogeneity among the members of 
individual families with the mutation. The associated neuropathology was a 
combination of ALS with TDP-ir inclusions and FTLD-TDP. In addition to 
TDP-43-immunoreactive pathology, a consistent and specific feature of cases with 
the C9ORF72 mutation was the presence of ubiquitin-positive, TDP-43-negative 
inclusions in a variety of neuroanatomical regions, such as the cerebellar 
cortex. These findings support the C9ORF72 mutation as an important newly 
recognized cause of ALS, provide a more detailed characterization of the 
associated clinical and pathological features and further demonstrate the 
clinical and molecular overlap between ALS and FTD.