TY - JOUR
T1 - Neuropathologic heterogeneity in HDDD1
T2 - A familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation
AU - Behrens, Maria I.
AU - Mukherjee, Odity
AU - Tu, Pang Hsien
AU - Liscic, Rajka M.
AU - Grinberg, Lea Tenenholz
AU - Carter, Deborah
AU - Paulsmeyer, Katherine
AU - Taylor-Reinwald, Lisa
AU - Gitcho, Michael
AU - Norton, Joanne B.
AU - Chakraverty, Sumi
AU - Goate, Alison M.
AU - Morris, John C.
AU - Cairns, Nigel J.
PY - 2007/1
Y1 - 2007/1
N2 - 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.
AB - 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.
KW - Alzheimer disease
KW - FTLD-U
KW - Frontotemporal lobar degeneration
KW - HDDD1
KW - Progranulin mutation
UR - http://www.scopus.com/inward/record.url?scp=33947189591&partnerID=8YFLogxK
U2 - 10.1097/WAD.0b013e31803083f2
DO - 10.1097/WAD.0b013e31803083f2
M3 - Article
C2 - 17334266
AN - SCOPUS:33947189591
SN - 0893-0341
VL - 21
SP - 1
EP - 7
JO - Alzheimer Disease and Associated Disorders
JF - Alzheimer Disease and Associated Disorders
IS - 1
ER -