Much of what we understand about FTD is based on work defining the genetic basis of disease. However, as this recent work shows, sometimes screening the usual suspects is not enough.
Until recently when a disease was suspected to have a genetic cause, a clinician would assess the patient and a genetic test would be directed to the genes known to be associated with the diagnosis reached. For FTD, several genes are known to be associated, with MAPT, GRN and C9ORF72 being the most common. Although no treatment is yet available for FTD, knowing the exact gene involved helps clinical management and also allows family members to be better informed.
However, some families with FTD do not have a mutation in these genes and in order to provide better clinical assistance it is important to uncover the genetic causes of their disease.
Because of several recent technological advances we are now able to read the whole genetic code of an individual. This allows us to look across all genes instead of only analyzing the genes suggested by the clinical symptoms and signs.
By sequencing the whole exome (the entire coding part of the genome) of several Turkish families with FTD, we have identified mutations in the TREM2 gene as the cause of disease in these families.
The same type of mutations in this gene were originally described as the cause of a rare early-onset dementia called Nasu-Hakola disease (named after the doctors who described it for the first time in the 1970’s) and also known as polycystic lipomembranous osteodysplasia with sclerosing leucoencephalopathy or PLOSL.
This is a rare inherited disease characterized by a progressive young onset dementia in association with recurrent bone fractures. The disease typically starts around the age of 20-30 years with pain in the hands, wrists, ankles, and feet. Patients then start suffering from multiple bone fractures. During the third or fourth decade of life, people present with pronounced personality changes characteristic of FTD. In the later stages people develop a profound dementia, frequently dying by the age of 50 years.
This is the typical clinical picture indicating that a genetic test aimed at the genes known to be associated with Nasu-Hakola disease (TREM2 and TYROBP) should be screened for mutations.
In three of the Turkish families that we studied by exome sequencing we identified TREM2 mutations. However the patients in these families did not present any bony problems and their clinical picture was more typical of FTD. If we had taken a directed approach to the genetic study of these families we would have only screened MAPT, GRN and C9ORF72 and would have never found a genetic defect in these patients.
What does this mean for FTD?
Exome sequencing allowed us to identify the genetic cause of disease in three patients who otherwise would have never been screened for TREM2 because of their non-typical clinical presentation. We expect that the use of this novel genetic technology in the study of other FTD patients will lead to the identification of new genes involved in this disease.
Guerreiro RJ, Lohmann E, Brás JM, Gibbs JR, Rohrer JD, Gurunlian N, Dursun B, Bilgic B, Hanagasi H, Gurvit H, Emre M, Singleton A, Hardy J. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 2013;70(1):78-84.