Original ArticlesNeuropathologic Heterogeneity in HDDD1: A Familial Frontotemporal Lobar Degeneration With Ubiquitin-positive Inclusions and Progranulin MutationBehrens, Maria I. MD, PhD* †; Mukherjee, Odity PhD* ‡; Tu, Pang-hsien MD, PhD* §; Liscic, Rajka M. MD, PhD* ∥; Grinberg, Lea Tenenholz MD* § ¶; Carter, Deborah HT* §; Paulsmeyer, Katherine BS* §; Taylor-Reinwald, Lisa BA* §; Gitcho, Michael PhD* ♯; Norton, Joanne B. MSN, CS* ‡; Chakraverty, Sumi MS* ‡; Goate, Alison M. DPhil* ‡; Morris, John C. MD* § ♯; Cairns, Nigel J. PhD, MRCPath* §Author Information *Alzheimer's Disease Research Center Departments of §Pathology and Immunology ‡Psychiatry ♯Neurology, Washington University School of Medicine, St Louis, MO †Departamento de Neurología y Neurocirugía, Hospital Clínico Universidad de Chile and Clínica Alemana, Santiago, Chile ∥Institute for Medical Research and Occupational Health, Zagreb, Croatia ¶Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, Brazil Support by grants from the National Institute on Aging of the National Institutes of Health (P01 AG-03991 and P50 AG-05681). Odity Mukherjee is a Fogarty International Postdoctoral fellow (Grant No. TW 0511-05). Rajka M. Liscic was supported by a J. William Fulbright Foreign Scholarship (Grant No. 68428174). Reprints: Nigel J. Cairns, PhD, MRCPath, Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St Louis, Missouri 63110 (e-mail: email@example.com). Received for publication May 10, 2006; accepted November 2, 2006 Alzheimer Disease & Associated Disorders: January-March 2007 - Volume 21 - Issue 1 - p 1-7 doi: 10.1097/WAD.0b013e31803083f2 Buy Metrics Abstract Hereditary dysphasic disinhibition dementia (HDDD) describes a familial disorder characterized by personality changes, and language and memory deficits. The neuropathology includes frontotemporal lobar atrophy, neuronal loss and gliosis and, in most cases, abundant Aβ plaques and neurofibrillary tangles (NFTs). A Pick/Alzheimer's spectrum was proposed for the original family (HDDD1). Here we report the clinicopathologic case of an HDDD1 individual using modern immunohistochemical methods, contemporary neuropathologic diagnostic criteria to distinguish different frontotemporal lobar degenerations (FTLDs), and progranulin (PRGN) mutation analysis. Clinical onset was at age 62 years with personality changes and disinhibition, followed by nonfluent dysphasia, and memory loss that progressed to muteness and total dependence with death at age 84 years. There was severe generalized brain atrophy (weight=570 g). Histopathology showed superficial microvacuolation, marked neuronal loss, gliosis, and ubiquitin-positive, tau-negative cytoplasmic and intranuclear neuronal inclusions in frontal, temporal, and parietal cortices. There were also frequent neuritic plaques and NFTs in parietal and occipital cortices. The case met neuropathologic criteria for both FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and Alzheimer disease (Braak NFT stage V). We discovered a novel pathogenic PGRN mutation c.5913 A>G (IVS6-2 A>G) segregating with FTLD-U in this kindred. In conclusion, HDDD1 is an FTLD-U caused by a PGRN mutation and is neuropathologically heterogeneous with Alzheimer disease as a common comorbidity. © 2007 Lippincott Williams & Wilkins, Inc.