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Hereditary FTD

Approximately 20-50% of individuals with frontotemporal dementia (FTD) have an affected first-degree-relative. Conversely, 50-80% of individuals appear to be the first person with FTD in the family, also called sporadic or nonfamilial FTD. In these cases, other individuals in the family do not appear to be at increased risk for developing the condition.

Familial FTD is suspected when more than one family member is affected, often in two or more generations. The underlying reason for FTD within the family is not always known. Although there does appear to be an increased chance for other family members to develop FTD, the exact risk is often difficult to assess. In these cases, it can be helpful to meet with a genetic counselor to review the family history and discuss possible implications for other family members.

Among individuals with FTD, approximately 10% have a change in a single gene (also called a mutation). Single gene causes for FTD are inherited in an autosomal dominant manner, meaning each child of an affected parent has a 50% chance of inheriting the change and also developing the condition. Currently, changes in five genes have been associated with autosomal dominant FTD. It is possible additional genes will be identified in the future. Therefore, not finding a change in one of these genes does not reduce the risk for family members to zero. At this time, changes in the following five genes have been identified:

  1. MAPT gene on chromosome 17 that makes the protein tau,
  2. GRN gene, also called the PGRN gene, on chromosome 17 that makes progranulin protein,
  3. TARDBP gene on chromosome 1 that produces trans-active response DNA-binding protein of 43-kDa molecular weight (TDP-43),
  4. VCP gene on chromosome 9 that codes for valosin-containing protein and
  5. CHMP2B gene on chromosome 3 that expresses charged multivesicular body protein 2B (also known as chromatin modifying protein 2B).

Mutations in the MAPT and GRN genes on chromosome 17 are the most common genetic causes of FTD. Clinical genetic testing for MAPT, GRN and VCP is available. Genetic testing is usually coordinated through a genetic counselor or other genetics professional following a genetic counseling appointment and detailed three-generation pedigree.

Mutations in the MAPT gene cause the normal tau protein to clump abnormally in brain cells and the nervous system. Normally, tau helps maintain the structure of neurons and move nutrients move up and down the cell. Tau mutations can reduce the effectiveness of tau or increase the quantity of it, either of which can lead to disease. More than 50 different mutations on the tau gene have been associated with hereditary FTD. Genetic changes in the gene that codes for GSK3B, an enzyme that regulates tau, may explain some of the cases where people have FTD and tau inclusions but no MAPT mutations. MAPT mutations are associated with FTD, Pick's disease and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).

GRN mutations cause reduced progranulin production (haploinsufficiency) and increased neuronal inclusions made of TDP-43 and ubiquitin. Progranulin assists cell growth while ubiquitin helps to clear out cellular waste products and TDP-43 regulates the process of creating proteins from DNA (expression). GRN mutations are associated with bvFTD, PNFA and movement disorders, although people with the GRN mutation rarely develop amyotrophic lateral sclerosis (ALS). GRN mutations are responsible for 5-10% of all cases of FTLD and 13-25% of familial cases.

TARDBP mutations lead to accumulated inclusions consisting of ubiquitin and TDP-43 in cells of the brain and nervous system. TDP-43 is normally only found in the nucleus of a cell, but in its abnormal form is found in the working area of the cell outside the nucleus. TARDBP mutations have been identified in individuals with sporadic and familial ALS. Genetic testing to look for changes in the TARDBP gene is available on a research basis only.

Mutations in the VCP gene cause neuronal inclusions made of ubiquitin but not tau and only rarely TDP-43 or VCP. VCP is a structural protein that has a wide variety of functions, particularly in cleaning up the cell. Scientists think that perhaps the VCP mutation disrupts the pathway that uses ubiquitin to clean up cells. VCP mutations are associated with an autosomal dominant condition called inclusion body myopathy associated with Paget disease of bone (PDB) and/or FTD (IBMPFD). Approximately 80% of individuals have a family history of the condition with 20% appearing to be the first affected individual in the family. Among individuals who meet diagnostic criteria for IBMPFD, nearly 100% have an identified mutation in the VCP gene. No other conditions are known to be associated with changes in the VCP gene.

CHMP2B mutations are a rare cause of familial FTLD and may be specific to a single Danish family. CHMP2B encodes a protein that recycles or destroys old receptors on the cell surface. It is unclear at this point whether the mutation increases or decreases function, but it does lead to inclusions made of ubiquitin but not TDP-43 in brain cells. CHMP2B mutations are associated with FTD, FTD-ALS and ALS. Currently, testing for CHMP2B mutations is available on a research basis only.

Because of the variability in how these diseases present, a careful analysis of family, medical and social history can help clarify whether an affected person has a sporadic or genetic form of FTD. Even when there appears to be an autosomal dominant pattern of FTD within a family, the exact genetic cause may not be known. Genetic counseling and testing is appropriate if you have concerns about your family history.

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