HOW COMMON ARE GENETIC FORMS OF FRONTOTEMPORAL DEGENERATION (FTD)?
There is a strong family history of a familial disorder in up to 40% of individuals with Frontotemporal degeneration (FTD). A genetic cause can be identified in up to 20% of Frontotemporal degeneration cases. In these cases, there is a detectable genetic cause that can be seen in the individual’s DNA, or genetic material. It is important to keep in mind that the majority of Frontotemporal degeneration is not genetic, meaning that 60% or more of FTD cases do not have a genetic cause. Research is still ongoing to understand and define the non-genetic causes of FTD.
HOW IS A GENETIC FORM OF FTD DIAGNOSED?
The overall symptom profiles of genetic and non-genetic Frontotemporal degeneration are identical. The biggest clue to a genetic cause is family history. A patient with a family history that includes many relatives with FTD or other neurodegenerative diseases, is more likely to have a genetic cause than a patient with no known family history of neurodegenerative diseases. The Penn Frontotemporal Degeneration Center has a genetic counselor available to help document and interpret family history information, as well as provide further information about the genetic testing options for FTD.
There are several specific genes associated with Frontotemporal degeneration or FTD related disorders. All human beings have these genes, as each gene carries specific instructions that the body needs in order to function correctly. Moreover, we have 2 copies of each gene, as one copy is inherited from the mother and one copy from the father. When there is a change in the gene (this is referred to as a mutation), this changes the instructions and consequently can lead to disease. A genetic testing laboratory can check a gene to see if there are any disease-causing mutations. A genetic test typically involves a small sample of blood, but sometimes the testing can be done on an alternative sample, such as saliva. The University of Pennsylvania has one of a small number of certified laboratories in the US that can test for the most common genes implicated in Frontotemporal degeneration. We also have a research laboratory that can test for genes that have been associated with FTD.
HOW IS A GENETIC FORM OF FTD INHERITED?
The known genetic causes of Frontotemporal degeneration all have autosomal dominant inheritance. “Autosomal” means that FTD can affect both men and women equally. “Dominant” inheritance means that only one copy of a gene has to have a mutation to cause disease. Typically, the copy of the gene with the mutation is inherited from one of the parents, and most individuals with an autosomal dominant condition will have a family history of the disease. A child of a person with a dominant mutation has a 50% chance of inheriting the copy of the gene with the mutation and a 50% chance of inheriting the copy of the gene without the mutation.
WHAT GENES ARE ASSOCIATED WITH FTD?
The majority of Frontotemporal degeneration patients with a genetic cause have a mutation occurring in one of the following genes:
· C9orf72 (often referred to as the chromosome 9 gene): This gene was identified in 2011 and the protein and functions related to the gene are being studied. Mutations in C9orf72 are believed to be the most common genetic form of FTD, accounting for 6% of all sporadic FTD cases an up to 25% of all familial FTD cases.
· Microtubule-associated protein tau (MAPT, often referred to as “tau”): This gene carries the instructions for making the tau protein. Tau is a structural protein that occurs in all neurons, and is essential for normal neuronal shape, functioning and metabolism. Mutations in MAPT account for 5-10% of all FTD cases.
· Progranulin (GRN or PGRN): This gene carries the instructions for making the progranulin protein. Granulins derived from progranulin contribute to mechanisms that protect neurons from various forms of injury such as inflammation, and help augment neuronal repair following an injury. Mutations in GRN account for 5-10% of all FTD cases.
· Valosin-Containing Protein (VCP): VCP mutations are associated with a specific condition called inclusion body myopathy with Paget disease of the bone and FTD (IBMPFD). VCP mutations account for a very small percentage of FTD cases (approximately 1-2%).
For more detailed information about these genes, please see the downloadable booklet “Understanding the Genetics of FTD” .
Three additional genes that have been associated with very rare FTD cases:
· Charged multivesicular body protein 2B (CHMP2B): Extremely rare cause of FTD, only found in a few families world-wide.
· TAR DNA-binding protein (TARDBP): Mutations in TARDBP are very rare. These mutations are more associated with hereditary ALS than FTD.
· Fused in sarcoma (FUS): Mutations in FUS are very rare. These mutations are more associated with hereditary ALS than FTD.
WHAT CAN BE DONE IF MY FAMILY OR I HAVE AN INHERITED FORM OF FTD?
The Penn FTD Center has a full-time genetic counselor who can discuss the inheritance of FTD, including options for genetic testing . Our genetics program has the capacity to detect genetic status of individuals with FTD, as well as in family members when a familial mutation has already been identified. It is the hope that with the future development of treatment trials, asymptomatic carriers of a mutation may be able to delay or even prevent the emergence of symptomatic FTD.
THE PENN FTD CENTER AND GENETIC RESEARCH
Researchers at the Penn FTD Center are studying the mechanisms of disease associated with inherited forms of Frontotemporal degeneration. This is crucial to the development of treatments of FTD. We are also searching for genes causing Frontotemporal degeneration that remain to be discovered.
We are interested in discovering genetic factors that can influence the risk or progression of FTD symptoms, as well as genetic factors that might help to predict an individual’s response to a certain treatments or medications. Genetic factors such as these can be very difficult to find and it can take thousands of DNA samples in order to make these types of discoveries.
A majority of individuals withFrontotemporal degeneration do not have a genetic cause; these individuals have sporadic Frontotemporal degeneration. Studies of genetic mechanisms of disease in FTD can teach us how to improve diagnostic accuracy in sporadic FTD. Moreover, factors related to prognosis and response to treatment interventions in genetic FTD may contribute to prognosis and treatment response in sporadic FTD.