17q-linked frontotemporal dementia-amyotrophic lateral sclerosis without tau mutations with tau and α-synuclein inclusions

Background: Frontotemporal dementia (FTD) is a clinically heterogeneous condition that can be associated with clinical manifestations of an extrapyramidal disorder or motor neuron disease. A range of histologic patterns has been described in patients with FTD. The most common familial form of this condition is caused by mutations in the microtubule-associated protein tau gene (MAPtau) and is associated with neuronal or glial tau inclusions. Objectives: To determine the clinical, anatomic, and pathological features of San Francisco family A and to map the mutation responsible for disease in this family. Design: A systematic clinical, neuropsychologic, neuroimaging, and chromosome segregation analysis of San Francisco family A was performed. A pathological and biochemical assessment of a family member was made. Setting: Family study. Patients: San Francisco family A, with FTD, variable extrapyramidal symptoms, and prominent motor neuron disease. Afflicted family members donot have a MAPtau coding or splice regulatory sequence mutation, and the MAPtau is genetically excluded. Main Outcome Measures: Comparison of clinical, neuropsychologic, neuroimaging, and linkage findings of San Francisco family A with other familial forms of FTD and amyotrophic lateral sclerosis (ALS). Results: The most probable location for the mutation responsible for this condition is on chromosome arm 17q, distal to the MAPtau. All previously identified susceptibility loci for FTD and ALS are excluded. Autopsy findings from an afflicted family member show distinctive tau and a-synuclein inclusions. Another unique feature is that the insoluble tau protein consists predominantly of the 4R/0N isoform. Conclusion: The condition affecting members of San Francisco family A is clinically, pathologically, and genetically distinct from previous familial forms of FTD and ALS.