Dementia: Update for the Practitioner

As Dr. Honig discussed in his talk, frontotemporal dementia is an umbrella diagnosis for a very complicated list of diseases. There is a great degree of variability that can occur in families, making it difficult to detect a history. Someone whom you suspect has FTD can have a family history of ALS, psychiatric disease, depression, or alcoholism.

Studies estimate that about 40 percent of FTD is familial, and of that about 10 percent is linked to mutations in the MAPT gene, microtubule-associated protein TAU. The TAU gene is located on chromosome 17. The children of an individual with a mutation in this gene have a 50-percent risk of inheriting that same disease-causing mutation. The penetrance is 100 percent with variable presentation.

Most of the available genetic testing for frontotemporal dementia is research testing; the only clinical testing is available through the University of California at San Francisco (UCSF). UCSF is looking for three common mutations: P301L, A279L, and a splice isoform mutation at position 14 of IVS10. If a family does not have one of those mutations, they will enter into a research study and undergo complete screening for mutations in TAU.


Genetic Testing Used in FTD
% of families	Genetic Mechanism	Test Type	Test Availability
~10%	MAPT gene mutations	DNA sequence analysis	Research
Unknown	3 common mutations: P301L, A279l, splice isoform mutation at position 14 of IVS10	Allele-specific oligonucleotides	Clinical

Most of the available genetic testing for frontotemporal dementia is research testing. Courtesy of Jennifer Williamson-Catania, M.S.

One family that participated in an early research study that helped find the gene for TAU later came to me with questions. A woman said, "My husband and his brothers participated in a research study, and we know that there is a history of frontotemporal dementia, because two of the three brothers had autopsy-confirmed frontotemporal dementia with onset in their forties. I want to know what this means for our children." They wanted to have genetic counseling for the three wives so that they could then talk to their children and see if their children wanted to get more information and perhaps genetic testing, if it was available.


	Frontotemporal Dementia


	Profile of a family with a history of frontotemporal dementia. Courtesy of Jennifer Williamson-Catania, M.S.

This family set me on a course of contacting the people that conducted the research study, and we decided that if the family wanted to know if they had a mutation, we would have to get tissue from the autopsies and confirm that the three known mutations were present. I talked with the family about what it would mean to find a mutation, and the family asked me to present my findings to their children. The family decided not to go any further. The three affected individuals all carry one of the common TAU mutations, but the family does not know it.

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