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Molecular Genetics of Frontotemporal Dementia

  1. Raffaele Ferrari,
  2. Avinash Thumma,
  3. Parastoo Momeni

Published Online: 15 MAY 2013

DOI: 10.1002/9780470015902.a0024457

eLS

eLS

How to Cite

Ferrari, R., Thumma, A. and Momeni, P. 2013. Molecular Genetics of Frontotemporal Dementia. eLS. .

Author Information

  1. Texas Tech University, Lubbock, Texas, USA

Publication History

  1. Published Online: 15 MAY 2013

Abstract

Frontotemporal dementia (FTD) is a nonAlzheimer's form of dementia. Onset age lies in the mid-to-late 50s. FTD affects the frontal and/or the temporal lobes and is clinically divided into two main categories: behavioural variant (bvFTD) and language variant. FTD is characterised by heterogeneous pathology defined by pathogenic protein inclusions: microtubule-associated protein tau (MAPT), ubiquitin/transactive responses (TAR) deoxyribonucleic acid (DNA)-binding protein 43 (TDP)-43, fused in sarcoma (FUS) and p62. MAPT, progranulin (PGRN) and, recently, C9orf72 genes represent the three main genetic markers associated with FTD. In addition, genetic variability in TDP-43, charged multivesicular body protein 2B (CHMP2B), valosin-containing protein (VCP), FUS and TMEM106B genes contribute to ⩽5% of cases. Research tools such as genome-wide association studies and exome and genome sequencing hold promise to further uncover the genetic underpinnings of this complex disorder.

Key Concepts:

  • Frontotemporal dementia (FTD) is a nonAlzheimer's form of dementia; it affects behaviour, cognition and language, while memory (in the early phases).

  • The anatomical areas of the brain that are affected by atrophy are the frontal and the temporal lobes; based on this fact FTD is considered part of the spectrum called frontotemporal lobar degeneration (FTLD).

  • FTD is a complex disease with insidious onset; no therapeutic measures are available as yet.

  • Behavioural variant FTD (bvFTD) is the most common syndrome of FTD, which is associated with gradual deterioration of behaviour and cognition.

  • Different protein inclusions in the brain are used to classify the pathology associated with FTLD.

  • TDP-43 and tau pathology represent the most common (∼90%) types of pathological signatures associated with FTLD.

  • MAPT, PGRN and C9orf72 are the major (∼95%) genetic markers associated with familial FTD.

  • TMEM106B regulates granulin protein levels.

  • Genome-wide association studies (GWASs) and next-generation sequencing technologies whole exome sequencing (WES) and whole genome sequencing (WGS) hold promise for dissecting the genetic aetiology of complex diseases; in molecular genetics these technologies help in screening a wide range of genetic variabilities from SNPs to CNVs in large cohorts across different populations.

Keywords:

  • frontotemporal dementia;
  • frontotemporal lobar degeneration;
  • bvFTD;
  • PPA;
  • MAPT;
  • PGRN;
  • C9orf72;
  • TMEM106B;
  • tau pathology;
  • TDP-43 pathology