Frontotemporal Dementia (FTD) is a group of progressive brain disorders caused by the degeneration and loss of nerve cells in the frontal and temporal lobes. Since these areas govern personality, behavior, and language, FTD causes a progressive decline in these functions. Common symptoms include significant changes in personal behavior, such as disinhibition or apathy, and difficulties with expressive or receptive language. While FTD can be a directly inherited condition, the majority of cases occur without a clear genetic cause, which is an important distinction for patients and families to understand.
Understanding Familial Versus Sporadic FTD
FTD cases are broadly categorized based on the presence or absence of a family history, which helps determine the likelihood of a genetic cause.
Sporadic FTD describes cases diagnosed without any known family history of FTD or a related neurodegenerative disorder. Approximately 60 to 80% of all FTD diagnoses are sporadic, meaning the disorder appears to occur randomly with no identifiable genetic variant. The underlying cause for these cases is often unknown, though environmental or subtle genetic risk factors may be involved, making research into these cases challenging.
Familial FTD accounts for about 20 to 40% of all cases and is defined by a clear pattern of inheritance within a family. In a portion of these familial cases, a specific gene mutation can be identified as the cause. When a patient has a first-degree relative, such as a parent or sibling, with FTD or a related condition like amyotrophic lateral sclerosis (ALS), the likelihood of finding a genetic cause increases substantially. Identifying whether a case is sporadic or familial is an initial step in understanding the risk for other family members.
Identifying the Major FTD-Related Genes
Inherited FTD is primarily caused by mutations in a few specific genes that dictate the type of abnormal protein accumulation damaging the nerve cells. The three most commonly implicated genes are C9orf72, MAPT, and GRN, which together account for the vast majority of genetic FTD cases.
C9orf72
The C9orf72 gene is the most frequent cause of genetic FTD. It contains a segment of DNA that is abnormally repeated many times in affected individuals. This mutation is strongly associated with a spectrum of disorders, including FTD and ALS, leading to the accumulation of the TDP-43 protein within affected neurons. The mutation disrupts cellular processes, ultimately causing cell death and neurodegeneration.
MAPT
The MAPT gene provides instructions for creating the tau protein, which normally helps stabilize the internal structure of brain cells. Mutations in MAPT lead to the production of abnormal or excessive tau protein that clumps together. These clumps form neurofibrillary tangles that disrupt the neuron’s function and cause neurodegeneration. This accumulation is directly responsible for the FTD cases linked to this gene.
GRN
The GRN gene codes for progranulin, a protein involved in cell survival and waste management. Mutations in GRN typically reduce the amount of progranulin produced, impairing the cell’s ability to maintain its health. Similar to C9orf72 mutations, this cellular dysfunction is associated with the abnormal accumulation of the TDP-43 protein in the brain.
How FTD is Inherited
The major FTD-causing genes follow an Autosomal Dominant inheritance model. This means a person needs to inherit only one copy of the mutated gene to be at risk for developing the disorder. Since humans inherit chromosomes from both parents, a person with genetic FTD has a 50% chance of passing the mutated gene copy to any child. This 50% probability applies independently to each pregnancy.
The likelihood that a person with a specific FTD gene mutation will develop the disease is referred to as penetrance. Some FTD-related genes are nearly 100% penetrant, meaning the disease is highly likely to develop if the mutation is present. Others, particularly the C9orf72 mutation, have reduced penetrance, meaning some carriers may not develop symptoms during their lifetime. The age at which symptoms begin can also vary widely, even among individuals who carry the same gene mutation.
Genetic Testing and Family Planning
Genetic counseling is the first step for families with a history of FTD, providing risk assessment and emotional support before testing. A genetic counselor reviews the family history to determine the most likely gene involved and discusses the implications of test results. Genetic testing is typically offered to individuals already diagnosed with FTD, especially those with a strong family history, to confirm a genetic cause.
For healthy individuals with a family history, presymptomatic or predictive testing is available to determine if they carry the mutation. Pursuing this testing is a personal choice, as a positive result can have significant emotional and financial consequences, including impacts on long-term care planning or insurance eligibility. Knowledge of a specific gene mutation can also inform family planning decisions. Options include preimplantation genetic diagnosis, which allows for the selection of embryos without the known mutation through in vitro fertilization.