Frontotemporal dementia (FTD) is a group of progressive neurological disorders characterized by the gradual loss of nerve cells primarily in the frontal and temporal lobes of the brain. This neurodegeneration causes significant changes in a person’s personality, behavior, language, and executive function. FTD often begins earlier in life, typically between the ages of 45 and 65, making it the most common cause of early-onset dementia. While the exact trigger for nerve cell death remains unknown, a substantial portion of FTD diagnoses are directly linked to genetic factors. Determining whether a case is inherited has profound implications for diagnosis, prognosis, and family planning.
Sporadic Versus Familial Frontotemporal Dementia
Frontotemporal dementia cases are broadly categorized into two groups based on family history: sporadic and familial. Sporadic FTD occurs when a person develops the disorder without any known family history of FTD or a related neurodegenerative disease. The majority of FTD diagnoses, between 50% and 70% of all cases, fall into this sporadic category. These cases are thought to arise from a combination of unknown genetic susceptibility factors and environmental influences rather than a single inherited mutation.
Familial FTD refers to cases where the disorder affects multiple relatives across generations. Approximately 30% to 40% of individuals diagnosed with FTD report having at least one other family member affected by dementia or a related condition. Within this group, 10% to 25% of all FTD cases can be definitively traced to a single, identifiable gene mutation. These single-gene causes typically follow a dominant inheritance pattern.
Major Genes Associated with FTD
Genetic FTD is predominantly caused by mutations in three specific genes: C9orf72, MAPT, and GRN. These genes account for the vast majority of inherited FTD, and the type of mutation determines the specific protein pathology seen in the affected neurons. Identifying the mutated gene helps classify the underlying molecular mechanism driving the disease.
The C9orf72 gene is currently recognized as the most frequent genetic cause of FTD, accounting for up to 20% of familial FTD cases and a smaller percentage of sporadic cases. The mutation involves a pathological expansion of a six-nucleotide DNA sequence. This excessive expansion reduces the normal C9orf72 protein (loss of function) and simultaneously produces toxic proteins and RNA molecules that aggregate in the nerve cells. These toxic aggregates are primarily composed of the protein TDP-43. This C9orf72 mutation is also a common genetic cause of amyotrophic lateral sclerosis (ALS), often leading to a combined FTD-ALS spectrum disorder.
The MAPT gene provides instructions for making the microtubule-associated protein tau. In healthy neurons, tau stabilizes microtubules, which are essential for transporting nutrients and other molecules throughout the cell. Mutations in MAPT cause the tau protein to become unstable, leading it to detach and clump together inside the neurons. These characteristic protein aggregates are known as neurofibrillary tangles or tauopathy. MAPT mutations typically account for 5% to 10% of all FTD cases.
The GRN gene codes for the protein progranulin and is the third common cause of inherited FTD. Mutations in GRN lead to TDP-43 protein pathology, similar to C9orf72. Progranulin is involved in regulating inflammation and maintaining lysosomes, which act as the cell’s waste disposal system. A GRN mutation usually results in one copy of the gene being silenced, causing a significant deficiency in the amount of progranulin produced. This shortage impairs the neuron’s ability to recycle waste and manage inflammation.
Genetic Counseling and Testing for FTD
Nearly all genetic forms of FTD follow an autosomal dominant inheritance pattern, meaning only one copy of the mutated gene is necessary to cause the disorder. An individual who has inherited a mutation has a 50% chance of passing that copy to each of their children. This high risk for first-degree relatives makes genetic counseling a necessary step for families considering testing.
Genetic counseling provides a framework for families to understand their risk, review their family health history, and explore the implications of genetic testing. Testing for FTD mutations takes two primary forms. Diagnostic testing confirms a known mutation in an already affected individual, while pre-symptomatic or predictive testing is offered to unaffected relatives at risk of carrying the mutation.
The decision to pursue predictive testing is a highly personal one, as FTD is currently incurable; a positive result offers certainty without immediate medical intervention. Due to potential psychological and emotional consequences, including the impact on career and insurance, predictive testing is only performed after extensive pre-test counseling. Uptake for predictive testing remains low, reflecting the serious ethical and emotional considerations inherent in testing for untreatable conditions.