Exome sequencing reveals a novel partial deletion in the progranulin gene causing primary progressive aphasia

In 2005, we reported a case of familial primary progressive aphasia (PPA) in this journal.1 The individual in question had a family history of frontotemporal dementia (FTD), her brother having behavioural variant FTD shown to be due to tau-negative, ubiquitin-positive (FTLD-U) pathology at postmortem. She was followed as part of a research programme from the age of 51 years, first developing symptoms of progressive speech disturbance at the age of 55 years. We were able to demonstrate the emergence of neuropsychometric deficits and brain atrophy prior to symptom onset. Through the use of voxel compression mapping, we showed the emergence of very focal, presymptomatic regional atrophy initially almost entirely confined to the pars opercularis (figure 1A).1 Over time, the atrophy spread through the frontal and temporal lobes to affect the parietal lobe and then the right frontal lobe. Subsequent analysis has shown increase in left and right hemispheric lobar atrophy prior to symptom onset, although the left hemisphere volume loss preceded and remained more prominent than the right throughout the disease course (figure 1B). Figure 1 MRI changes in the proband: (A) sagittal MRI showing focal anterolateral left frontal lobe atrophy, particularly centred around the pars opercularis, using voxel compression mapping between the first and second scans (3.4 …