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January 2007

Progranulin and Tau Gene Mutations Both as Cause for Dementia: 17q21 Finally Defined

Arch Neurol. 2007;64(1):18-19. doi:10.1001/archneur.64.1.18

Frontotemporal dementia (FTD) is the second most common form of dementia, second to Alzheimer disease, in persons under 65 years of age. It manifests as a clinically progressive disorder with language impairment, affecting expression and comprehension; behavioral and personality changes; perseveration; apathy; irritability; and disinhibition; progressing to general cognitive impairment.1,2 It is associated with significant atrophy with neuronal degeneration in the frontal and/or temporal lobes. Frontotemporal dementia has been described with the presence of ubiquitin-immunoreactive neuronal inclusions without tau pathology and is referred to as FTD with ubiquitin inclusions (FTDU).3,4 The composition of the neuronal cytoplasmic inclusions, other than being ubiquinated, is not known.3,4 Mutations in the gene encoding the microtubule-associated protein tau gene (MAPT) linked to chromosome 17q21 have been known to produce familial FTD associated with parkinsonism, amyotrophy, disinhibition, and dementia (FTDP-17).5 The MAPT mutations are associated with cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau.5 Of note, in multiple FTD families with linkage to the same region on chromosome 17q21, MAPT mutations have not been identified and the neuropathologic findings do not include tau-immunoreactive inclusion pathology.3,4 Rather, these families have ubiquitin-immunoreactive neuronal cytoplasmic inclusions with associated lentiform ubiquitin-immunoreactive neuronal intranuclear inclusions.3,4,6,7 Thus 2 inherited forms of FTD with similar phenotypes have been mapped to 17q21, one linked to MAPT mutations with tau inclusions and the other not linked to MAPT with ubiquitin inclusions.