The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as 
the cause of chromosome 9-linked frontotemporal dementia and motor neuron 
disease offers the opportunity for greater understanding of the relationship 
between these disorders and other clinical forms of frontotemporal lobar 
degeneration. In this study, we screened a cohort of 398 patients with 
frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or 
mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron 
disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 
mutations, representing 8% of the cohort. The patients' clinical phenotype at 
presentation varied: nine patients had frontotemporal dementia with motor neuron 
disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia 
with frontal features and three had progressive non-fluent aphasia. There was, 
as expected, a significant association between C9ORF72 mutations and presence of 
motor neuron disease. Nevertheless, 46 patients, including 22 familial, had 
motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the 
patients with C9ORF72 mutations presented with psychosis, with a further 28% 
exhibiting paranoid, deluded or irrational thinking, whereas <4% of non-mutation 
bearers presented similarly. The presence of psychosis dramatically increased 
the odds that patients carried the mutation. Mutation bearers showed a low 
incidence of motor stereotypies, and relatively high incidence of complex 
repetitive behaviours, largely linked to patients' delusions. They also showed a 
lower incidence of acquired sweet food preference than patients without C9ORF72 
mutations. Post-mortem pathology in five patients revealed transactive response 
DNA-binding protein 43 pathology, type A in one patient and type B in three. 
However, one patient had corticobasal degeneration pathology. The findings 
indicate that C9ORF72 mutations cause some but not all cases of frontotemporal 
dementia with motor neuron disease. Other mutations remain to be discovered. 
C9ORF72 mutations are associated with variable clinical presentations and 
pathology. Nevertheless, the findings highlight a powerful association between 
C9ORF72 mutations and psychosis and suggest that the behavioural characteristics 
of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the 
C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor 
neuron disease but also of late onset psychosis.