C9ORF72 Mutations in Two Patients with Slowly Progressive bvFTD "Phenocopy" (S54.006)

Objective: To describe two patients with slowly progressive behavioral variant frontotemporal dementia (bvFTD-SP) who harbor the C9ORF72 hexanucleotide repeat expansion. Background Some patients meeting bvFTD diagnostic criteria progress slowly and plateau at a mild symptom severity. Previously, such patients who feature stable longitudinal brain imaging showing mild atrophy not suggestive of typical bvFTD, have been referred to as bvFTD "phenocopies." The few post-mortem studies available on bvFTD-SP patients did not find FTLD neuropathology, suggesting that bvFTD-SP is a clinical syndrome that mimics true FTD. Here we describe two bvFTD-SP cases with FTD/ALS-associated C9ORF72 mutations. Design/Methods: We reviewed clinical data from 82 patients meeting FTDC consensus criteria for possible bvFTD, without motor neuron disease at initial evaluation, who had been screened for the C9ORF72 expansion. Patients were categorized as bvFTD-SP if they subsequently showed minimal progression on neurological, neuropsychological and imaging evaluations, with stable symptoms for at least five years without atrophy characteristic of bvFTD. Results: Four of 82 patients screened were categorized as bvFTD-SP, including 2/15 (13.3%) of C9ORF72 mutation carriers and 2/67 (3.0%) non-carriers. Over a follow-up period ranging from 2-6 years, all four bvFTD-SPs had milder cognitive deficits compared to typical bvFTDs, and all lacked characteristic bvFTD imaging abnormalities. As measured by voxel based morphometry, one C9ORF72-positive patient had predominantly thalamic atrophy and the other displayed a non-specific pattern of cortical atrophy without medial or orbito-insular frontal atrophy characteristic of bvFTD. Both C9ORF72 mutation carriers had a family history of late-life behavioral disorders, whereas neither of the non-carriers had a family history suggestive of neurodegenerative disease. Conclusions: Slowly progressive bvFTD can result from the C9ORF72 hexanucleotide expansion. Clinicians should consider genetic causes when evaluating a patient with slowly progressive bvFTD, especially when faced with a family history of neurodegenerative disease. Supported by: In part by M01-RR0079 General Clinical Research Center; the National Institute on Aging (NIA) grants 5-P01 AG19724 and P50 AG023501; the State of California, Alzheimer9s Disease Research Center of California (ARCC) grant 03-7527; NIH grants R01AG038791 and R01AG031278. Disclosure: Dr. Khan has nothing to disclose. Dr. Rankin has nothing to disclose. Dr. Sha has nothing to disclose. Dr. Takada has nothing to disclose. Dr. Yokoyama has nothing to disclose. Dr. Karydas has nothing to disclose. Dr. Fong has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Coppola has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Rosen has nothing to disclose. Dr. Seeley has received personal compensation for activities with Korea Novartis. Dr. Boxer has received personal compensation for activities with BMS, Plexxikon and Phloronol as a consultant. Dr. Boxer has received research support from Elan, Forest, Genentech, Medivation, BMS, Janssen and Pfizer Pharmaceuticals. Dr. Miller has received personal compensation for activities with Allon Therapeutics, Inc. and TauRx Therapeutics, Ltd. Dr. Miller has received research support from Novartis.