Familial semantic dementia with P301L mutation in the Tau gene

Semantic dementia (SD) is a clinical subclassification of frontotemporal lobar degeneration. Patients with 'pure SD' present with semantic memory impairment preceding the frontal symptoms, and there have been no reports of familial cases.

We evaluated the clinical features of, and performed neuropsychological examinations on, the proband and two affected family members. Then we performed neuroimaging and genetic analysis of MAPT and other dementia-related genes in the proband.

All three cases had semantic memory impairment with loss of word meanings as the primary early symptom. We diagnosed all cases as pure SD and identified a P301L mutation in the MAPT gene of the proband.

Although the P301L mutation identified here has been previously described as pathogenic for frontotemporal dementia with parkinsonism-17 (FTDP-17), the proband and his two affected relatives showed different clinical symptoms from those of typical FTDP-17 cases who carry the P301L mutation. Pathologically, pure SD usually shows a TAR DNA-binding protein proteinopathy, but the molecular understanding of SD is not well established. Although our cases were clinically pure SD, the proband has a tau gene mutation, which would lead to tauopathy. These findings suggest that reconsideration of the molecular understanding of SD is warranted.