Abstract Details

Title Clinicopathologic Variability of GRN A9D Mutation, Including Amyotrophic Lateral Sclerosis

Topic Anterior Horn

Presentation(s) P05 - (-)

Poster/Presentation
Number 077

Objective

Background 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 DESIGN/METHODS: Three patients with GRN A9D mutations were evaluated clinically and came to autopsy with subsequent neuropathologic examination.

Results 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 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.

Authors/Disclosures
Shinsuke Fujioka, MD PRESENTER	Dr. Fujioka has received research support from Japan Society for the Promotion of Science.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Tanis J. Ferman, PhD (Mayo Clinic Jacksonville)	Ms. Ferman has nothing to disclose.
	No disclosure on file
Kevin B. Boylan, MD	No disclosure on file
	No disclosure on file
Neill R. Graff-Radford, MD, FAAN (Mayo Clinic Jacksonville)	The institution of Dr. Graff-Radford has received research support from Biogen. The institution of Dr. Graff-Radford has received research support from Lilly. The institution of Dr. Graff-Radford has received research support from Eisai. The institution of Dr. Graff-Radford has received research support from Biogen. Dr. Graff-Radford has received publishing royalties from a publication relating to health care.
Ryan J. Uitti, MD, FAAN (Mayo Clinic of Jacksonville)	Dr. Uitti has nothing to disclose.
Rosa Rademakers, PhD (Mayo Clinic Dept of Neuroscience)	Rosa Rademakers, PhD has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Mayo Clinic. Rosa Rademakers, PhD has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Arkuda Therapeutics. Rosa Rademakers, PhD has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Alzheimer Fondation. Rosa Rademakers, PhD has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Kisick Family Foundation (FTD grant program). The institution of Rosa Rademakers, PhD has received research support from NIH. The institution of Rosa Rademakers, PhD has received research support from DOD. The institution of Rosa Rademakers, PhD has received research support from Flanders Institute for Biotechnology (VIB). The institution of Rosa Rademakers, PhD has received research support from Flanders Funds for Scientific Research.
Zbigniew K. Wszolek, MD, FAAN (Mayo Clinic- Jacksonville)	Dr. Wszolek has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Polish Neurological Society/Via Medica. Dr. Wszolek has received intellectual property interests from a discovery or technology relating to health care.
Dennis W. Dickson, MD (Mayo Clinic)	Dr. Dickson has nothing to disclose.

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