TY - JOUR T1 - Clinicopathologic Variability of GRN A9D Mutation, Including Amyotrophic Lateral Sclerosis (P05.077) JF - Neurology JO - Neurology SP - P05.077 LP - P05.077 VL - 80 IS - 7 Supplement AU - Shinsuke Fujioka AU - Cannon Ashley AU - Sharleen Traynor AU - Nicola Rutherford AU - Tanis Ferman AU - Daniel Broderick AU - Kevin Boylan AU - Neill Graff-Radford AU - Ryan Uitti AU - Rosa Rademakers AU - Zbigniew Wszolek AU - Dennis Dickson Y1 - 2013/02/12 UR - //www.ez-admanager.com/content/80/7_Supplement/P05.077.abstract N2 - OBJECTIVE: We examined the clinical and pathologic phenotype of GRN mutation carriers with the pathogenic A9D (g.26C>A) missense mutation.BACKGROUND: GRN gene mutations are common causes of frontotemporal lobar degeneration (FTLD). Behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia are the most frequent clinical presentations. GRN mutations are rarely associated with FTLD with motor neuron disease, but there have been no reports of amyotrophic lateral sclerosis (ALS) due to pathogenic GRN mutations. Pathologically, most GRN mutation carriers have Type A TDP-43 pathology. The majority of GRN mutations promote premature termination of the coding sequence, which results in haploinsufficiency due to nonsense-mediated RNA decay. An exception is the A9D (g.26C>A) missense mutation, which results in haploinsufficiency due to loss of GRN secretion.DESIGN/METHODS: Three patients with GRN A9D mutations were evaluated clinically and came to autopsy with subsequent neuropathologic examination.RESULTS: The clinical diagnoses of patients with GRN A9D mutations were ALS, atypical extrapyramidal disorder, and bvFTD. TDP-43 pathology was variable in morphology and distribution, with notable involvement of motor neurons in the spinal cord of the patient presenting with ALS. TDP-43 morphology was consistent with Type A in all but the ALS case, which was Type B.CONCLUSIONS: The clinical presentation of the GRN A9D missense mutation is highly variable and only occasionally presents with bvFTD, which is typical for other pathogenic GRN mutations. Importantly, we report for the first time that a GRN mutation can be associated with clinical and pathologic features ALS.Supported by: ZKW, RJU, and DWD are partially supported by the NIH/NINDS Morris K. Udall center awarded to the Mayo Clinic Jacksonville, P50 NS072187-01S2.Disclosure: Dr. Fujioka has nothing to disclose. Dr. Ashley has nothing to disclose. Dr. Traynor has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Ferman has nothing to disclose. Dr. Broderick has nothing to disclose. Dr. Boylan has received research support from Biogen Idec, Cytokinetics, Inc., and Neuraltus Pharmaceuticals, Inc. Dr. Graff-Radford has received personal compensation for activities with Codman. Dr. Graff-Radford has received personal compensation in an editorial capacity for the Neurologist. Dr. Graff-Radford has received research support from Janssen, Pfizer Pharmaceuticals, Medivation, Forrest, and Allon. Dr. Uitti has received personal compensation in an editorial capacity for Neurology. Dr. Uitti has received research support from NINDS, Mayo Clinic, and St. Jude Medical. Dr. Rademakers has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial cqapacity for Parkinsonism and Related Disorders and the European Journal of Neurology. Dr. Wszolek has received research support from the NIH/NINDS, Mayo Clinical Florida Research Committee CR Program, and Dystonia Medical Research Foundation. Dr. Dickson has received personal compensation for activities with Neotope, Inc. as a consultant.Wednesday, March 20 2013, 2:00 pm-7:00 pm ER -