Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder that primarily affects the frontal and temporal lobes of the brain. These regions control important functions like behavior, personality, and language, and their deterioration leads to profound changes in a person’s life. As this condition often appears in individuals younger than those with Alzheimer’s disease, a common question for affected families is whether the disorder is passed down through generations.
Sporadic Versus Inherited FTD
When considering the genetics of FTD, it is important to distinguish between sporadic and inherited cases. The majority of FTD diagnoses (60 to 70%) are categorized as sporadic, meaning the condition occurs without any known family history or identifiable genetic cause. This suggests that environmental or other unknown factors play a significant role in their development.
Conversely, a significant minority of cases are familial or inherited, appearing to run in the family and often affecting multiple generations. About 30 to 40% of people with FTD report having at least one other relative with a neurodegenerative disorder. Of all FTD cases, a single, identifiable gene mutation is responsible for the disease in roughly 10 to 20%.
Major Genes Linked to Familial FTD
The vast majority of FTD cases caused by a single gene mutation are linked to variants in three specific genes: C9orf72, MAPT, and GRN. These genes provide instructions for proteins essential to brain cell function. A mutation disrupts this process, leading to the accumulation of toxic proteins and providing insight into the specific protein pathology driving the disease.
C9orf72
The C9orf72 gene is the most common genetic cause of FTD. A mutation involves an abnormal expansion of a section of DNA (a hexanucleotide repeat), which causes the gene to produce toxic proteins. This variant is notable because it can cause FTD, amyotrophic lateral sclerosis (ALS), or a combination of both conditions in the same family.
MAPT
The MAPT gene (Microtubule-Associated Protein Tau) is linked to a different disease pathway. When mutated, it leads to the accumulation of abnormal tau protein inside brain cells, a pathology known as tauopathy. Tau protein normally helps stabilize the internal structure of neurons, but the mutated version clumps together, disrupting cell function.
GRN
The third major gene is GRN, which codes for progranulin. Progranulin is a growth factor that plays a role in cell survival and inflammation in the brain. Mutations in GRN lead to a deficiency of this protein. This deficiency subsequently causes the buildup of TAR DNA-binding protein 43, a pathology referred to as TDP-43 proteinopathy.
Understanding Inheritance Patterns and Risk
The inherited forms of FTD caused by mutations in C9orf72, MAPT, or GRN typically follow Autosomal Dominant inheritance. This means the gene is located on a non-sex chromosome, and a person only needs to inherit one copy of the mutated gene from a single parent to be at risk of developing the disorder.
A person carrying one of these pathogenic variants has a 50% chance of passing the mutated copy to any child. Conversely, there is a 50% chance the child will inherit the healthy copy, meaning they will not develop the genetic form of FTD. This inheritance pattern is a primary consideration when family members assess their personal risk.
If a first-degree relative has a known FTD-causing mutation, their children and siblings are considered at-risk. Even with the same mutation, the age of symptom onset can vary significantly, sometimes by a decade or more between relatives. While the lifetime risk is very high for these single-gene forms, not everyone who inherits the mutation will necessarily develop the disease.
The Role of Genetic Testing and Counseling
For individuals concerned about a potential genetic link to FTD, genetic counseling is the recommended first step. A genetic counselor assesses and communicates genetic risk, providing guidance on testing options. The consultation includes a thorough review of the family’s medical history to determine the likelihood of a single-gene mutation being the cause.
Genetic testing for FTD serves two main purposes: diagnostic and predictive.
Diagnostic Testing
Diagnostic testing is performed on individuals already showing symptoms. Its purpose is to confirm if their FTD is due to a known genetic mutation, which helps classify the disease.
Predictive Testing
Predictive testing is offered to asymptomatic adults who have a known FTD mutation in their family and wish to know their own risk status. The decision to undergo this testing is deeply personal and involves complex ethical and psychological considerations.
Genetic counseling provides informed consent, ensuring the individual understands what a positive or negative result means for their future, including potential impacts on employment, insurance, and family planning. Counselors also provide psychological support before and after testing, acknowledging the anxiety associated with learning one’s genetic risk for a progressive condition.
A positive test confirms the mutation and the high likelihood of developing FTD, but it cannot predict the exact age of onset or specific symptoms. This knowledge is useful for making proactive life decisions, financial planning, and determining eligibility for clinical trials targeting specific genetic mutations. A negative result indicates the person’s risk is no greater than that of the general population.