What is the role of genetic mutations in the pathogenesis of frontotemporal dementia (FTD)?

Updated: Jun 14, 2018
  • Author: Howard S Kirshner, MD; Chief Editor: Jasvinder Chawla, MD, MBA  more...
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Until the past few years, more than 50% of cases of FTD, even the familial ones, were not associated with tau pathology, although many of these cases were also linked to chromosome 17. Most such cases have been noted to have ubiquitin immunoreactive inclusions in the cytoplasm or nucleus or ubiquitin immunoreactive neurites. This group has been designated frontotemporal lobar degeneration-ubiquitin (FTLD-U), [24] though as we shall see, this term is being replaced by reference to specific mutations.

In 2006, 2 teams of investigators reported mutations in the progranulin gene on chromosome 17 as the cause of this syndrome. [25, 26] Many such cases have now been reported, with mutations resulting in a premature termination codon, causing haploinsufficiency. The progranulin mutations result in a loss of protein, whereas the tau mutations result in a toxic gain of function. The TAR ̶ deoxyribonucleic acid (DNA) binding protein (TDP-43) is a major component of the ubiquitinated inclusions in most of these cases. Progranulin mutations and the TDP-43 positive inclusions have been found in cases of FTD, PPA, and corticobasal degeneration. [27, 28]

Other mutations

Tau and progranulin mutations appear to account for the most cases of FTD, and at least in familial cases, true examples of dementia lacking distinctive histologic features have become much less common. Moreover, other gene loci have been implicated in this family of disorders. Cases of inclusion body myopathy with Paget disease of the bone associated with FTD have been reported and have been associated with mutations involving chromosome 9, the valosin-containing protein (VCP) gene. [29, 30] In some of these cases, TDP-43 protein accumulation has been reported.

Other mutations on chromosome 9 have been associated with FTD-ALS. [31] The most common of these is the C9ORF72 gene, in which hexanucleotide repeat expansions have been reported. This mutation can be seen in patients with FTD, usually the behavioral variant, or familial ALS, or both. [32, 33, 34, 35] Finally, mutations of the chromatin-modifying protein 2B (CHMP2B) gene on chromosome 3 have also been reported in a Danish family. These mutations have generally not been associated with TDP-43 protein accumulation. [36]

Finally, there are a few FTD cases with ubiquitin deposition, but no TDP-43 accumulation, in whom both tau and progranulin mutations are absent. Rather, an accumulation of “fused in sarcoma” (FUS) proteins have been found. Reported cases have included both FTD and ALS. [37, 38]

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