Frontotemporal Disorders: Information for Patients, Families, and Caregivers

Frontotemporal lobar degeneration (FTLD) is not a single brain disease but rather a family of brain diseases that share some common molecular features. Scientists are just beginning to understand the biological and genetic basis for the changes observed in brain cells that lead to FTLD.

Scientists describe FTLD in terms of physical changes in the brain seen in an autopsy after death. These changes include loss of neurons and abnormal amounts or forms of proteins called tau and TDP-43. These proteins occur naturally in the body and help cells function properly. When the proteins don’t work properly, for reasons not yet fully understood, neurons in the frontal and/or temporal lobes are damaged and disease results.

About 20 to 40 percent of people with frontotemporal disorders have a family history of them. About 10 percent of people inherit them directly from a parent. In most cases, the cause is unknown.

Familial and inherited forms of frontotemporal disorders are often related to mutations (permanent changes) in certain genes. Genes are basic units of heredity that tell cells how to make the proteins the body needs to function. Even small changes in a gene may produce an abnormal protein, which can lead to changes in the brain and, eventually, disease.

Scientists have discovered several different genes that, when mutated, can lead to frontotemporal disorders:

• Tau gene (also called the MAPT gene)—A mutation in this gene causes abnormal tau to form, which leads to the destruction of brain cells. Inheriting a mutation in this gene means a person will almost surely develop a frontotemporal disorder, usually bvFTD, but the exact age of onset and symptoms cannot be predicted.
• PGRN gene—A mutation in this gene can lead to lower production of the protein progranulin, which in turn causes TDP-43, a cellular protein, to go awry. The result is familial bvFTD and possibly a higher chance of developing PPA.
• VCP gene and CHMP2B gene—Mutations in these genes lead to very rare familial types of frontotemporal disorders.
• C9ORF72 gene—An unusual mutation in this gene appears to be the most common genetic abnormality in familial frontotemporal disorders. It is also the most common genetic abnormality in familial ALS and occurs in some cases of sporadic ALS.

Scientists are continuing to search for other genes and proteins that may play a role in frontotemporal disorders. For example, some researchers are exploring the FUS gene, which causes a type of familial ALS. Scientists are also trying to understand how mutations in a single gene lead to different frontotemporal disorders in different family members.