What is the genetic distribution of frontotemporal dementia (FTD)?

Updated: Jun 14, 2018
  • Author: Howard S Kirshner, MD; Chief Editor: Jasvinder Chawla, MD, MBA  more...
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The cause of frontotemporal lobe dementia (FTD) is unknown, but, as discussed earlier, significant evidence supports a genetic component to these syndromes.

As many as 40-50% of patients with FTD have an affected family member. In a Dutch study, 38% of the index cases of FTD had a first-degree relative with similar symptoms at an early age of onset. A review by Seelaar and colleagues found that 27% of cases had autosomal-dominant inheritance. [42]

The molecular genetics of FTD has become much more complex in recent years. As mentioned above, the first genetic link in FTD was to markers on band 17q21-22, the gene locus for the tau protein.

The tau gene marker has linked cases of FTD in several Dutch families, cases of hereditary dysphasic dementia reported in the United States, and a variety of other clinical syndromes called tauopathies, including familial parkinsonism with dementia, corticobasal degeneration, Pick disease without Pick bodies, and progressive supranuclear palsy (PSP). Overlap cases with these other tauopathies have been reported. The pathophysiology involves abnormal tau proteins, leading to the designation of FTD as one of a series of tauopathies.

In the words of an editorial by Wilhelmsen, the linkage of FTD with this gene site has put frontotemporal lobe dementia "on the map" (ie, gene map). [43] Many cases of familial FTD with specific tau mutations have now been reported. On the other hand, apolipoprotein E4 (APOE-4), which increases the risk for late-onset, sporadic Alzheimer disease, does not appear to have increased frequency in patients with FTD or primary progressive aphasia (PPA). [44, 45]

In the published series by Seelaar et al of 364 patients with FTD, 27% had positive family histories, which suggests autosomal dominant inheritance. Of these, 11% had tauopathies secondary to mutations of the MAPT gene on chromosome 17, whereas 6% had progranulin mutations. [46] These authors also reported that 10% had autosomal dominant inheritance patterns without a specific, demonstrated molecular genetic abnormality, adding up to 27% with autosomal dominantly inherited disorders. The other 73% of cases in their series were not clearly hereditary, and the molecular genetic basis of these disorders is not yet understood. [46]

In a National Institutes of Health study of 1425 FTD patients, the C9ORF72 mutation, with a pathogenic hexanucleotide repeat expansion, was associated with a large proportion of both sporadic and familial FTD cases. Specifically, the mutation was carried by 6% of white Europeans with sporadic FTD and 24.8% of white Europeans with familial FTD. The mutation was not found in Asian patients with sporadic FTD. [47]

Formerly, patients with all of these pathologies were lumped together under the term dementia lacking specific histological features, or nonspecific dementia. [18] Currently, most cases with autopsy study can be placed either in the tauopathy or the ubiquitin categories, so only rare cases are truly nonspecific. [48]

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