Frontotemporal dementia (FTD) is a progressive neurological disorder affecting the frontal and temporal lobes of the brain, causing a gradual decline in behavior, personality, and language abilities. FTD typically manifests at an earlier age than other dementias, often between 45 and 64 years old. While FTD is less common than Alzheimer’s disease, it is a distinct type of dementia. This article explores the nature of FTD and the genetic mechanisms that contribute to its occurrence.
Understanding Frontotemporal Dementia
FTD is characterized by the degeneration and cell loss within the frontal and temporal lobes, which govern executive functions, social conduct, and language processing. The specific pattern of brain atrophy determines the clinical presentation, which falls into two types. The behavioral variant FTD (bvFTD) is the most common presentation, involving marked changes in personality, social behavior, and conduct.
Individuals with bvFTD may exhibit a lack of inhibition, apathy, poor judgment, or compulsive behaviors. Memory often remains relatively intact in the early stages of bvFTD. The second major category is primary progressive aphasia (PPA), which primarily affects language ability. PPA causes a progressive loss of the capacity to speak, understand speech, read, or write.
These changes arise from the accumulation of abnormal proteins within the damaged brain cells, causing them to malfunction and die. The underlying protein pathology is diverse, but clinical symptoms result directly from damage to the frontal and temporal lobes. Because initial symptoms are often behavioral, FTD can sometimes be misdiagnosed as a psychiatric disorder before the progressive neurodegeneration is clear.
The Role of Inheritance in FTD
The majority of FTD cases occur spontaneously, without a clear family history of the disorder; this is referred to as sporadic FTD. Sporadic FTD accounts for approximately 60% of all diagnoses, meaning a genetic cause is not identified in most instances. These cases are thought to arise from a combination of unknown risk factors, rather than a single inherited gene mutation.
The remaining cases are classified as familial FTD, where there is a history of the disorder in at least one other close relative. About 40% of individuals diagnosed with FTD report a family history of dementia. Within this familial group, a definite genetic cause, traceable to a single gene mutation, can be identified in approximately 15% to 40% of all FTD cases.
The presence of a family history suggests a genetic component, although not all familial cases have an identifiable mutation with current testing methods. Identifying an inherited gene mutation is important for understanding disease risk and progression within a family.
Key Genes and Inheritance Patterns
For families with a clear genetic cause, the inheritance pattern is typically Autosomal Dominant. This means a person needs to inherit only one copy of the mutated gene from either parent to have a high likelihood of developing FTD. A child of a parent with a dominant FTD-causing mutation has a 50% chance of inheriting the mutated gene.
The majority of genetic FTD is caused by mutations in one of three genes: C9orf72, MAPT, and GRN. The C9orf72 gene is the most common genetic cause, often accounting for FTD, amyotrophic lateral sclerosis (ALS), or a combination of both. This gene contains a hexanucleotide repeat expansion, an abnormally long section of repeating DNA that disrupts normal gene function.
Mutations in the MAPT gene (Microtubule-Associated Protein Tau) cause the buildup of abnormal Tau protein tangles inside brain cells. The Tau protein normally helps stabilize the internal structure of neurons; its dysfunction leads to the loss of nerve cells. The GRN gene (Progranulin) mutation results in a deficiency of progranulin protein, which is important for lysosomal function and neuronal survival.
Both C9orf72 and GRN mutations are associated with the accumulation of the protein TDP-43, leading to a condition called TDP-43 proteinopathy. The specific gene mutation often dictates the type of protein aggregation, providing insight into the biological mechanism driving neurodegeneration.
Genetic Testing and Counseling
For individuals with a family history of FTD, genetic testing can be offered to confirm a diagnosis or determine risk. Testing is typically offered to an affected relative first to identify the specific mutation in the family. If a mutation is found, unaffected, at-risk relatives may then pursue predictive testing.
Genetic testing is a complex decision, particularly for predictive testing of an adult-onset disorder. Genetic counseling is a mandatory part of this process, providing individuals with pre-test education on the implications of the results. A genetic counselor assesses the family history, explains the inheritance patterns, and discusses the range of possible outcomes.
Post-test counseling provides psychological support, regardless of whether the result is positive or negative for the familial mutation. Ethical considerations are significant, and predictive testing for FTD is only offered within a comprehensive counseling protocol. This ensures individuals are fully prepared for the emotional and social impact of the results.