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Original Investigation |

Frontotemporal Dementia Associated With the C9ORF72 Mutation:  A Unique Clinical Profile

Emma Devenney, MRCP1,2; Michael Hornberger, PhD2,3; Muireann Irish, PhD2,4; Eneida Mioshi, PhD2,3; James Burrell, PhD2,3; Rachel Tan, PhD2,3; Matthew C. Kiernan, FRACP2,5; John R. Hodges, FRCP2,3
[+] Author Affiliations
1Prince of Wales Clinical School, University of New South Wales, Sydney, Australia
2Neuroscience Research Australia, Sydney, Australia
3School of Medical Sciences, University of New South Wales, Sydney, Australia
4School of Psychology, University of New South Wales, Sydney, Australia
5Brain and Mind Research Institute, University of Sydney, Sydney, Australia
JAMA Neurol. 2014;71(3):331-339. doi:10.1001/jamaneurol.2013.6002.
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Importance  While advances have been made in characterizing the C9ORF72 clinical phenotype, the hallmark features that discriminate between carriers and noncarriers remain unclear.

Objectives  To determine the frequency of the C9ORF72 mutation in a frontotemporal dementia (FTD) cohort and to define the clinical, neuropsychological, behavioral, and imaging features of C9ORF72 mutation carriers in comparison with noncarriers in a well-defined behavioral-variant (bv)–FTD cohort.

Design, Setting, and Participants  A prospective cohort study of patients assessed during a 5-year period from January 1, 2008, to December 31, 2012, at an FTD specialist referral center (FRONTIER). A total of 114 consecutive patients with FTD, FTD–amyotrophic lateral sclerosis (ALS), and corticobasal syndrome were assessed at FRONTIER. Patients with bvFTD who carried the C9ORF72 mutation (n = 10) were compared with noncarriers (n = 19) and a healthy control group (n = 35). These were matched for age, sex, and education history. Blood sampling for gene analysis was performed after informed consent was obtained.

Main Outcomes and Measures  Clinical, behavioral, cognitive, and neuropsychological deficits, cortical atrophy on a magnetic resonance imaging visual rating scale, and family history as quantified by the Goldman Scale.

Results  In a cohort of 114 FTD cases, 14 patients expressed the C9ORF72 mutation, representing a frequency rate of 34% in bvFTD and 17% in FTD-ALS. Family histories of ALS (P = .001) and psychiatric disorders (P = .02) were significantly more common in mutation carriers. The C9ORF72 carriers were also more likely to experience psychotic symptoms (P = .03). The degree of brain atrophy was significantly less in the C9ORF72 cohort, and in many the progression was slow. Presenting features of C9ORF72 carriers were compared against International Consensus Diagnostic Criteria for bvFTD, and most cases failed to satisfy criteria for probable bvFTD.

Conclusions and Relevance  The C9ORF72 mutation appears to be a common cause of bvFTD. Many of the C9ORF72 carriers have a family history of ALS or psychiatric illness. Psychotic features emerged as the most discriminating clinical feature between mutation carriers and noncarriers. Progression is often slow and brain atrophy is less pronounced than in nonmutation cases of bvFTD. These findings have clinical relevance for both diagnosis and selection of patients for genetic testing.

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Figure 1.
Frequency of C9ORF72 Mutation Positivity in a Frontotemporal Dementia Cohort

The flowchart demonstrates the frequency of C9ORF72 mutation positivity in a frontotemporal dementia cohort. Patients with frontotemporal dementia are categorized according to subtype, and mutation-positive patients are further categorized by Goldman Scale (GS) score. Twenty-eight additional patients were screened but deemed not suitable for inclusion in the study, so they were excluded. bvFTD indicates behavioral-variant frontotemporal dementia; CBS, corticobasal syndrome; FTD-MND, frontotemporal dementia with motor neuron disease; PPA-nf, nonfluent-variant primary progressive aphasia; and PPA-sv, semantic-variant primary progressive aphasia.

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Figure 2.
Cortical Atrophy Ratings in C9ORF72 Mutation Carriers, Noncarriers, and Controls

Box plots (whiskers indicate minimum and maximum scores) demonstrate atrophy ratings for C9ORF72 mutation carriers, noncarriers, and controls. A magnetic resonance imaging visual rating scale assessed 7 cortical regions: the orbitofrontal cortex (A), anterior cingulate (B), anterior temporal lobe (C), insula (D), basal ganglia (E), precuneus (F), and cerebellum (G). There was a statistical trend for more precuneus atrophy in the C9ORF72 mutation carriers compared with controls (P = .02). For all other regions, no statistical differences were found between C9ORF72 mutation carriers and controls. The horizontal lines represent the median (ie, 50% of the data are greater than this value). The top and bottom lines of the box represent the 75th and 25th percentiles, respectively. In some cases, the median is the same value as the 25th or 75th percentile and therefore is not shown.

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Figure 3.
Variable Patterns of Cortical Atrophy in C9ORF72 Mutation Carriers and Noncarriers

Coronal T1-weighted images are shown at the orbitofrontal cortex (slice 1), the anterior temporal lobe (slice 2), and the precuneus and cerebellum (slice 3). These illustrative examples demonstrate the variability in cortical atrophy between C9ORF72 mutation carriers (A and B) and noncarriers (C and D).

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