Neuropathologic heterogeneity in HDDD1: A familial frontotemporal lobar degeneration with ubiquitin-positive inclusions and progranulin mutation

Maria I. Behrens, Odity Mukherjee, Pang Hsien Tu, Rajka M. Liscic, Lea Tenenholz Grinberg, Deborah Carter, Katherine Paulsmeyer, Lisa Taylor-Reinwald, Michael Gitcho, Joanne B. Norton, Sumi Chakraverty, Alison M. Goate, John C. Morris, Nigel J. Cairns

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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.

Original languageEnglish
Pages (from-to)1-7
Number of pages7
JournalAlzheimer disease and associated disorders
Volume21
Issue number1
DOIs
StatePublished - Jan 2007

Keywords

  • Alzheimer disease
  • FTLD-U
  • Frontotemporal lobar degeneration
  • HDDD1
  • Progranulin mutation

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