____________________________________________________________________ Frontotemporal Dementia
Should a family wish to have a brain autopsy done when the patient dies, the physician can help identify a pathology service experienced in neurologic disorders and preliminary logistical planning can be done ahead of time. Arrangements may be coordinated with a research center that specializes in brain autopsy for FTD. The autopsy is done as soon as pos- sible after death, often within 6 to 24 hours. The procedure is not disfiguring, so open-casket funerals may be planned if the family so chooses. In addition to answering families’ questions regarding diag- nosis, brain autopsy can also aid researchers in better under- standing the correlation between the clinical signs of FTD and the pathologic changes in the brain. This may benefit future generations by improving diagnosis and advancing research on therapies for FTD. GENETICS AND FTD Understanding of the role of genetics in FTD is still evolving. Presently, it appears that most cases of FTD (approximately 60%) are sporadic, meaning one person in a family has the dis- ease, there is no family history of any relative with the disease, and the disease does not appear to be inherited. However, approximately 40% of those with FTD report a family history of one or more relatives with a neurodegenera- tive disease [6; 9; 11]. This is referred to as familial FTD. In some cases of familial FTD, no specific genetic mutation can be identified as the cause. The risk to family members of a person with familial FTD without an identified genetic muta- tion is increased over the general population, but the specific increased risk is unclear. An estimated 10% to 20% of all FTD cases are caused by an inherited genetic mutation [6; 8]. Patients with a strong family history of multiple relatives with FTD and/or MND are more likely to have an inherited form of FTD caused by a genetic mutation. Genetic mutations causing FTD are inherited in an autosomal dominant inheritance pattern, meaning each child of an affected parent is born with a 50% chance of inheriting the genetic mutation. Several specific genetic mutations have been identified as being implicated in inherited FTD. In 1998, the first gene associated with hereditary FTD—the microtubule-associated protein tau (MAPT) gene on chromosome 17—was discovered [16; 17]. Mutations in this gene cause an abnormal accumulation of tau protein in affected neurons. MAPT mutations are thought to account for 5% to 20% of familial FTD cases [18]. These mutations most commonly cause bvFTD but may also cause svPPA, PSP, and/or CBS. FTD symptoms may vary widely, even within families.
In 2006, mutations in the progranulin (GRN) gene on chro- mosome 17 were discovered to cause FTD [20; 21]. Mutations in the GRN gene cause abnormal accumulations of TDP-43 protein in affected neurons. GRN mutations are thought to represent about 5% to 10% of all inherited FTD cases [19]. They most commonly cause bvFTD, but are also associated with nfvPPA and CBS. GRN mutations appear to have decreased penetrance, meaning that, for unknown reasons, some people with the mutation may not develop symptoms of the disease. In 2011, the genetic mutation C9orf72 was discovered on chro- mosome 9 [22; 23]. Mutations in C9orf72 cause an abnormal accumulation of TDP-43 in affected neurons. To date, C9orf72 mutations are the most common genetic cause of FTD, found in about 25% of familial FTD and 6% of sporadic cases [24]. C9orf72 mutations appear to cause FTD (usually bvFTD or language presentation), MND, and a combination of FTD and MND. Other very rare genetic mutations have also been associated with FTD. Mutations in the gene valosin-containing protein (VCP) on chromosome 9, charged multivesicular body protein 2B (CHMP2B) on chromosome 3, TAR DNA-binding protein (TARDBP), FUS, TBK1, EXT2, and SQSTM1 have been associated with FTD [31]. Clinical genetic testing is available for the MAPT , GRN , and C9orf72 genetic mutations causing hereditary FTD, as well as some of the other very rare genetic mutations. Genetic testing may be ordered after informed consent and clear discussion of the implications with the patient and his/her family. For patients with FTD, identification of a genetic mutation con- firms the diagnosis of FTD and provides information about risk to other family members. Each of the patient’s siblings and each of the patient’s children would be at 50/50 risk for having inherited the genetic mutation causing FTD. If a genetic mutation causing FTD is identified, other at-risk family members may be tested. If a genetic mutation causing FTD is identified in a patient with FTD, unaffected at-risk family members could choose to have pre-symptomatic (predictive) genetic testing done to determine if they have inherited the genetic mutation that would someday cause FTD. Individuals considering pre-symptomatic genetic testing are referred for formal professional genetic counseling to help them make the best decision regarding whether or not to learn their FTD genetic status. MANAGEMENT OF FTD There is presently no treatment to slow the progression of or cure FTD. No medication has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of FTD; however, medications used to treat other disorders may be prescribed off-label for the management of FTD symptoms. Their use may be limited by the potential adverse effects. Anti- depressants, particularly selective serotonin reuptake inhibitors
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MDRI2026
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