Phenotype of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia with ALS (FTD/ALS) Associated with the GGGGCC Repeat Expansion in C9ORF72 (c9FTD/ALS) (IN9-1.004)

Objective: To review the phenotype of patients with ALS and FTD/ALS in c9FTD/ALS. Background A hexanucleotide repeat expansion in C9ORF72 recently reported as a major cause of familial ALS, FTD/ALS and FTD, designated c9FTD/ALS, also was found in sporadic ALS and FTD patients (doi:10.1016/j.neuron.2011.09.010; doi:10.1016/j.neuron.2011.09.011). Few data regarding the c9FTD/ALS phenotype in ALS and FTD/ALS are available. Design/Methods: 231 patients with ALS or FTD/ALS identified at the Mayo Clinic Florida ALS Center were screened for the c9FTD/ALS mutation. Patients completed a standard ALS diagnostic evaluation including EMG, and neuropsychological testing where indicated. Autopsy was performed in 5 mutation carriers. Results: Eighteen patients (15 ALS (9 male); 3 FTD/ALS (1 male; cognitive dysfunction preceded ALS in 2) representing 17 independent pedigrees had a c9FTD/ALS mutation. FTD suspected in 2/15 ALS patients was not confirmed owing to motor impairment. Nine probands reported first/second degree relatives with ALS or FTD/ALS; 5 probands reported relatives with FTD/dementia only and 2 probands reported no family history of ALS or FTD/dementia. One proband was adopted. All patients had El Escorial possible/probable/definite ALS except for a male with suspected ALS. Onset was bulbar in 2 patients (1 ALS; 1 FTD/ALS) and spinal in 16. Median onset age was 56 years (41-72yr). Median survival was 2.3 years (1-6.3yr) in 11 deceased; brain/spinal cord in 5 demonstrated TDP-43 pathology typical of ALS, with extramotor brain pathology in 2 FTD/ALS. Conclusions: The c9FTD/ALS phenotype of our patients was predominantly classical ALS with spinal onset. Frontotemporal cognitive impairment antedated motor signs in 2/3 FTD/ALS. Survival ranged from 1 to >6 years. c9FTD/ALS in 2 sporadic ALS patients may represent incomplete penetrance, incomplete ascertainment or new mutations and requires further study. Occurrence of FTD alone in family members supports consideration of FTD in first or second degree relatives of ALS patients as a potential marker of c9FTD/ALS. Supported by: ALS Association, Mayo Foundation and MCF ALS Center donor funds, NIH R01 NS065782 and R01 AG026251, NIH/NINDS 1RC2NS070276, NS057567, P50NS072187-01S2, Dystonia Medical Research Foundation, and a gift from Carl Edward Bolch, Jr., and Susan Bass Bolch. Disclosure: Dr. Boylan has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Rush has nothing to disclose. Dr. Desaro has nothing to disclose. Dr. Johnston has nothing to disclose. Dr. Kryston has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism and Realted Disorders and European Journal of Neurology. Dr. Dickson has nothing to disclose. Dr. Rademakers has nothing to disclose.