Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q2l-22

Hereditary frontotemporal dementia (FTD) is an autosomal dominant neurodege nerative disorder that is associated with mutations in the tau gene and wit h the pathological accumulation of hyperphosphorylated tau protein in affec ted brain cells in about a quarter of cases. However, most FTD families hav e no demonstrable tau mutations. Here we describe the clinical and neuropat hological features of a large family with hereditary FTD. Genetic analysis showed strong evidence for linkage to chromosome 17q21-22 (maximum lod scor e 3.46, theta = 0 for marker D17S950), but mutations in the tau gene were n ot found. Clinical symptoms, neuropsychological deficits and neuroimaging f indings of affected family members were similar to sporadic and tau-related FTD. The mean age at onset was 61.2 years, with loss of initiative and dec reased spontaneous speech as the most prominent presenting symptoms. Pathol ogical examination of the brains of two affected family members showed nons pecific neuronal degeneration with dense cytoplasmic ubiquitin-positive inc lusions in neurones of the second layer of the frontotemporal cortex and de ntate gyrus of the hippocampus. In a number of neurones these inclusions ap peared to be located inside the nucleus, although due to the small number o f these inclusions this localization could not be confirmed by electron mic roscopy. The inclusions were not stained by tau, alpha -synuclein or polygl utamine antibodies. Biochemical analysis of soluble tau did not reveal abno rmalities in tau isoform distribution and analysis of mRNA showed the prese nce of both three- and four-repeat transcripts. This is the first report of ubiquitin-positive, tau-negative inclusions in an FTD family with signific ant linkage to chromosome 17q21-22. Further characterization of the ubiquit in-positive inclusions may clarify the neurodegenerative pathways involved in this subtype of FTD.