The Genetics of Frontotemporal Lobar Degeneration

There is a growing awareness that dementia may be related to a variety of conditions other than Alzheimer’s disease (AD). It is also apparent now that the pathways leading to some of these disorders may be related. Frontotemporal dementia (FTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA) are all due to the progressive loss of neurons in the frontal and/or temporal lobes of the brain. This group of disorders is often referred to as frontotemporal lobar degeneration (FTLD).

Several genes have been associated with FTLD. However, to understand the genetics of FTLD, it is first necessary to understand the basics of genetics. Most cells of the body have 46 chromosomes, grouped into 23 pairs. One member of each chromosome pair is inherited from each parent. Each chromosome is composed of deoxyribonucleic acid (DNA), the genetic material that provides instructions for how the body grows and functions (See Figure 1). Genes are segments of DNA found on each of our chromosomes. Each gene provides the instructions for a specific protein with a specific function. Certain variations within the genes may lead to differences in individual traits (such as hair or eye color). Other variations in gene sequence may be disease-causing. When a gene variant causes disease, it is often referred to as a mutation.

Figure 1. DNA, chromosomes, and genes.

Many studies have been performed in order to identify gene variants associated with FTLD. Up to 40% of patients with FTLD have a family history of the condition. To date, mutations causing familial FTLD have been found in the microtubule associated protein tau (MAPT), progranulin (GRN), C9orf72, valosin-containing protein (VCP), and charged multivesicular body protein 2B (CHMP2B) genes. The most commonly involved genes are MAPT, GRN, and C9orf72, which are estimated to account for more than 80% of familial FTLD cases. * Mutations in these genes are inherited in an autosomal dominant manner; only 1 copy of the causative gene needs to have a mutation in order to develop FTLD. A person who carries 1 copy of an FTLD-related mutation in one of these genes has a 50% chance of passing it on to each of their children. A person who inherits a mutation in one of these genes will develop FTLD. Individuals who do not inherit the mutation would not be expected to develop FTLD.

Figure 2. Autosomal dominant inheritance of MAPT, GRN, C9orf72, VCP, and CHMP2B gene mutations.

While many cases of familial FTLD are caused by mutations in the MAPT, GRN, C9orf72, VCP, and CHMP2B genes, others may be the result of changes in genes not yet identified. Studies using samples collected and distributed by the National Cell Repository for Alzheimer's Disease will help scientists identify the other important genes contributing to non-AD dementia.