Background  Frontotemporal dementia (FTD) is an important cause of neurodegenerative dementia, particularly in younger patients. TAU has been identified as the gene responsible for FTD linked to chromosome 17, but it is likely that there is pathological and genetic heterogeneity among families with FTD.

Objective  To explore the genetic and pathological basis of familial FTD.

Design  Clinical case series with genetic analysis of each family, and pathological confirmation of diagnosis where possible.

Setting  Specialist dementia research group, particularly recruiting patients with young-onset dementia.

Patients  Twenty-two families with an index member with FTD, meeting Lund-Manchester criteria, and a family history of other affected members with dementia were ascertained.

Results  Half of the families had mutations in the TAU gene (TAU exon 10 +14, +16, and P301S), and pathological diagnoses were available in 17 of 22 families. Three main pathological diagnoses were made: FTD with neuronal and glial tau deposition, FTD with ubiquitin inclusions, and FTD with neuronal loss and spongiosis but without intracellular inclusions. No cases of familial Pick disease were identified. With the use of the pathological diagnoses, each family with FTD with neuronal and glial tau deposition had a TAU mutation, whereas TAU mutations were not identified in families in the other 2 diagnostic groups.