Importance Mutations in the progranulin gene are known to cause diverse clinical syndromes, all attributed to frontotemporal lobar degeneration. We describe 2 patients with progranulin gene mutations and evidence of Alzheimer disease (AD) pathology. We also conducted a literature review.
Observations This study focused on case reports of 2 unrelated patients with progranulin mutations at the University of California, San Francisco, Memory and Aging Center. One patient presented at age 65 years with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 years with logopenic progressive aphasia and, at autopsy, showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD.
Conclusions and Relevance In addition to autosomal-dominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical phenotypes and neuropathology.
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Figure 1. Voxel-based morphometry. Single-subject voxel-based morphometry of case 1 (A) and case 2 (B), uncorrected for multiple comparisons at P < .05, displayed as T map (1 < t < 4) and overlaid on Montreal Neurological Institute template brain. Images are displayed in neurological convention.
Figure 2. Positron emission tomography (PET) imaging of case 1. The PET with fluorodeoxyglucose (FDG) shows bilateral temporoparietal hypometabolism and the Pittsburgh compound B (PiB)–PET image of case 1 shows amyloid tracer binding. DVR indicates distribution volume ratio; SUVR, standardized uptake value ratio.
Figure 3. Pathologic findings for case 2. In the angular gyrus, frequent β-amyloid–positive neuritic plaques (3F4 antibody, hematoxylin counterstain) (A) and sparse to moderate neurofibrillary tangles and neuropil threads are seen (PHF-1 antibody, hematoxylin counterstain) (B). C, Dorsolateral frontal cortex shows frequent TAR DNA-binding protein 43 (TDP-43)–immunoreactive crescentic or compact neuronal cytoplasmic inclusions with surrounding wispy neuropil threads, consistent with frontotemporal lobar degeneration–TDP, type A. Scale bars indicated 500 μM (A), 100 μM (B), and 50 μM (C).
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