Distinct genetic forms of frontotemporal dementia

Abstract

<b>Background: </b> Frontotemporal dementia (FTD) is the second most common type of presenile dementia and can be distinguished into various clinical variants. The identification of <i>MAPT</i> and <i>GRN</i> defects and the discovery of the TDP-43 protein in FTD have led to the classification of pathologic and genetic subtypes. In addition to these genetic subtypes, there exist familial forms of FTD with unknown genetic defects. <b>Methods: </b> We investigated the frequency, demographic, and clinical data of patients with FTD with a positive family history in our prospective cohort of 364 patients. Genetic analysis of genes associated with FTD was performed on all patients with a positive family history. Immunohistochemical studies were carried out with a panel of antibodies (tau, ubiquitin, TDP-43) in brains collected at autopsy. <b>Results: </b> In the total cohort of 364 patients, 27% had a positive family history suggestive for an autosomal mode of inheritance, including <i>MAPT</i> (11%) and <i>GRN</i> (6%) mutations. We identified a new Gln300X <i>GRN</i> mutation in a patient with a sporadic FTD. The mean age at onset in <i>GRN</i> patients (61.8 ± 9.9 years) was higher than <i>MAPT</i> patients (52.4 ± 5.9 years). In the remaining 10% of patients with suggestive autosomal dominant inheritance, the genetic defect has yet to be identified. Neuropathologically, this group can be distinguished into familial FTLD+MND and familial FTLD-U with hippocampal sclerosis. <b>Conclusion: </b> Future genetic studies need to identify genetic defects in at least two distinct familial forms of frontotemporal dementia (FTD) with unknown genetic defects: frontotemporal lobe degeneration with ubiquitin-positive inclusions with hippocampal sclerosis and frontotemporal lobe degeneration with motor neuron disease. <b>GLOSSARY: </b><b>CA1</b> = cornu ammonis field 1; <b>FTD</b> = frontotemporal dementia; <b>FTD-bv</b> = behavioral variant of FTD; <b>FTD+MND</b> = FTD with motor neuron disease; <b>FTLD</b> = frontotemporal lobe degeneration; <b>FTLD-tau</b> = FTLD with tau-positive pathology; <b>FTLD-U</b> = FTLD with tau-negative, ubiquitin-positive inclusions; <b>HS</b> = hippocampal sclerosis; <b>PNFA</b> = progressive nonfluent aphasia; <b>TDP-43</b> = TAR-DNA binding protein 43.