An expanded hexanucleotide repeat in the C9ORF72 gene has recently been 
identified as a major cause of familial frontotemporal lobar degeneration and 
motor neuron disease, including cases previously identified as linked to 
chromosome 9. Here we present a detailed retrospective clinical, neuroimaging 
and histopathological analysis of a C9ORF72 mutation case series in relation to 
other forms of genetically determined frontotemporal lobar degeneration 
ascertained at a specialist centre. Eighteen probands (19 cases in total) were 
identified, representing 35% of frontotemporal lobar degeneration cases with 
identified mutations, 36% of cases with clinical evidence of motor neuron 
disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 
cases had no identified relevant family history. Families showed wide variation 
in clinical onset (43-68 years) and duration (1.7-22 years). The most common 
presenting syndrome (comprising a half of cases) was behavioural variant 
frontotemporal dementia, however, there was substantial clinical heterogeneity 
across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical 
features consistent with motor neuron disease during the period of follow-up. 
Anxiety and agitation and memory impairment were prominent features (between a 
half to two-thirds of cases), and dominant parietal dysfunction was also 
frequent. Affected individuals showed variable magnetic resonance imaging 
findings; however, relative to healthy controls, the group as a whole showed 
extensive thinning of frontal, temporal and parietal cortices, subcortical grey 
matter atrophy including thalamus and cerebellum and involvement of long 
intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile 
of the C9ORF72 expansion was significantly more symmetrical than progranulin 
mutations with significantly less temporal lobe involvement than 
microtubule-associated protein tau mutations. Neuropathological examination in 
six cases with C9ORF72 mutation from the frontotemporal lobar degeneration 
series identified histomorphological features consistent with either type A or B 
TAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR 
DNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus 
and cerebellum were a consistent feature of these cases, in contrast to the 
similar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control 
cases with frontotemporal lobar degeneration-TAR DNA-binding protein. These 
findings corroborate the clinical importance of the C9ORF72 mutation in 
frontotemporal lobar degeneration, delineate phenotypic and neuropathological 
features that could help to guide genetic testing, and suggest hypotheses for 
elucidating the neurobiology of a culprit subcortical network.