Chapter

Genetics of frontotemporal dementia<sup>1</sup>

Bryan J. Traynor and Stuart Pickering-Brown

in Amyotrophic Lateral Sclerosis and the Frontotemporal Dementias

Published on behalf of Oxford University Press

Published in print October 2012 | ISBN: 9780199590674
Published online November 2012 | e-ISBN: 9780191753466 | DOI: http://dx.doi.org/10.1093/med/9780199590674.003.0020
Genetics of frontotemporal dementia1

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Frontotemporal dementia (FTD) is the second or third most common cause of dementia, accounting for approximately 10% of all cases and an even higher proportion of cases under the age of 65 years. In contrast to Alzheimer's disease, which increases in prevalence after the age of 65, the median age of onset of FTD is 52.8 years of age, albeit with a relatively wide range. Clinically, the disease is characterized by abnormalities in personality, behaviour, and language with relatively preserved memory. About 10% of FTD cases manifest motor neurone dysfunction at some stage during the course of disease. Median survival is typically 7 years, though it tends to be significantly less in the presence of concomitant motor neurone disease. Importantly from the perspective of genetics, a significant portion of FTD has a family history; as high as 40% in some studies.

To date, mutations in six genes have been described as causes of familial FTD, namely MAPT, PRGN, CHMP2B, VCP, TYROBP, and TREM2. In addition, a 120 kb locus on chromosome 9p21 appears to account for a significant proportion of familial FTD and FTD/amyotrophic lateral sclerosis (ALS), though the precise genetic defect underlying this locus has not yet been determined. Cumulatively, these genes account for well less than half of all familial cases suggesting that additional pathogenic genes remain to be found. Regardless of the absolute number of cases caused by mutations in each gene, each one has provided fundamental insights into the biology of the disease. Indeed many of the molecular biology work, including animal models, biomarker studies, and therapeutic development, that is ongoing in the field at present is driven by identification of one of these genes.

Most of the genes known for FTD were discovered by linkage analysis of large families followed by positional cloning of the genes in the linked region. More recently, genomic techniques (i.e. testing the entire genome agnostic of biological function) have been applied to FTD with interesting results (see below). In addition to detection of the previously identified chromosome 9p21 region, genetic variation on chromosome 7p21 was associated with altered risk for developing this fatal neurodegenerative disease.

In this review, we will describe each of these six genes in terms of their initial discovery, the phenotype associated with them, and proposed mechanisms of action. We will then describe the results of genome-wide association studies (GWAS) that have been performed in this fatal neurodegenerative disease. We will conclude with a discussion about what future of FTD genetics holds in store.

Chapter.  5347 words. 

Subjects: Neurology ; Clinical Genetics

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