Researchers at UCL Institute of Neurology have found for the first time a double mutation in a family with frontotemporal dementia (FTD), which may further our understanding of the underlying processes involved in these diseases.

FTD is the second most common form of early-onset dementia after Alzheimer’s disease. The disease is caused when nerve cells in the frontal and/or temporal lobes of the brain are affected by abnormal changes and eventually die.

The mutations that have been found to cause FTD include changes in the MAPT gene, progranulin gene and the recently identified repeat expansion in the C9orf72 gene. Until now only one mutation in one gene has been associated with individual cases.

Approximately 150 FTD cases were investigated from the Queen Square Brain Bank archives. Brain tissue was examined using special staining techniques to highlight the unique abnormal structures found in cases carrying the C9orf72 expansion repeat mutation. All FTD cases, regardless of any previously identified genetic abnormality, were screened for the unique pathological structures characteristic of cases with C9orf72 mutation. It was during this screening process that two FTD cases already known to have a progranulin mutation were also shown to contain the unique C9orf72 abnormal structures. These two cases were then checked genetically for the C9orf72 repeat expansion mutation to confirm the observations seen down the microscope.

Lead author Dr Tammaryn Lashley, from UCL’s Queen Square Brain Bank for Neurological Studies who is supported by Alzheimer’s Research UK, explained: "To check the pathological hallmarks were specific to the C9orf72 cases, we screened all the FTD cases that had already been assigned a particular genetic mutation and came across two cases, known to carry a progranulin mutation, that had the unique C9orf72 hallmarks. These cases were then screened for the second mutation in the C9orf72 gene. Cases carrying a C9orf72 mutation are interesting because we are able to identify them easily down the microscope before genetic testing has been carried out"

Further information:

Lashley T, Rohrer JD, Mahoney C, Gordon E, Beck J, Mead S, Warren J, Rossor M, Revesz T. A pathogenic progranulin mutation and C9orf72 repeat expansion in a family with frontotemporal dementia. Neuropathol Appl Neurobiol. 2014 Jun;40(4):502-13. doi: 10.1111/nan.12100.

Image: Pathological structures unique to cases with C9orf72 expansion mutation shown in green in the hippocampus in the top panels and cerebellum in the lower panels.