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Exome sequencing reveals a novel partial deletion in the progranulin gene causing primary progressive aphasia
  1. Jonathan D Rohrer1,
  2. Jonathan Beck2,
  3. Vincent Plagnol3,
  4. Elizabeth Gordon1,
  5. Tammaryn Lashley4,
  6. Tamas Revesz4,
  7. John C Janssen5,
  8. Nick C Fox1,
  9. Jason D Warren1,
  10. Martin N Rossor1,
  11. Simon Mead2,
  12. Jonathan M Schott1
  1. 1Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
  2. 2MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
  3. 3Department of Statistics, Institute of Genetics, University College London, UK
  4. 4Queen Square Brain Bank, UCL Institute of Neurology, London, UK
  5. 5Department of Neurology, Chelsea and Westminster Hospital, London, UK
  1. Correspondence to Dr Jonathan M Schott, Institute of Neurology – Dementia Research Centre, Queen Square, London WC1N 3BG, UK; j.schott{at}ucl.ac.uk

https://doi.org/10.1136/jnnp-2013-306116

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    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 …

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    Footnotes

    • Contributors JDR wrote the draft of the manuscript and analysed the imaging data. JB, VP and SM performed the genetic analyses. TL and TR performed the pathological analyses. EG performed imaging analyses. JCJ, JMS, MNR, JDW and NCF performed patient evaluation. All authors reviewed and contributed to the final manuscript.

    • Competing interests None.

    • Ethics approval Ethical approval for the study was obtained from the National Hospital for Neurology and Neurosurgery Local Research Ethics Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.