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Brain Advance Access originally published online on September 26, 2006
Brain 2006 129(11):3091-3102; doi:10.1093/brain/awl267
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia

J. S. Snowden1,2, S. M. Pickering-Brown3, I. R. Mackenzie4, A. M. T. Richardson2, A. Varma2, D. Neary1,2 and D. M. A. Mann1

1 Clinical Neuroscience Research Group, University of Manchester Salford, Manchester, UK 2 Cerebral Function Unit, Department of Neurology, Greater Manchester Neurosciences Centre, Hope Hospital Salford, Manchester, UK 3 Division of Laboratory and Regenerative Medicine, University of Manchester Salford, Manchester, UK 4 Department of Pathology, Vancouver General Hospital Vancouver, BC, Canada

Correspondence to: Prof. David Neary, Cerebral Function Unit, Greater Manchester Neuroscience Centre, Hope Hospital, Stott Lane, Salford M6 8HD, UK E-mail: david.neary{at}manchester.ac.uk

Frontotemporal lobar degeneration (FTLD) refers to a focal, non-Alzheimer form of cerebral degeneration that encompasses the distinct clinical syndromes of frontotemporal dementia (FTD), progressive non-fluent aphasia (PNFA) and semantic dementia. Some patients show tau-based pathological changes and in familial cases mutations have been identified in the microtubule-associated protein tau gene (MAPT) on chromosome 17q21. However, many cases are tau-negative, showing instead ubiquitin-immunoreactive (UBQ-ir) neuronal cytoplasmic inclusions and neurites, and in some familial cases UBQ-ir neuronal intranuclear inclusions of a lentiform appearance. Very recently, mutations have been identified in familial cases in the progranulin (PGRN) gene, also on chromosome 17q21. Clinical, pathological and molecular diversity within FTLD highlights the importance of careful examination of clinical-pathological-genetic relationships. This paper reports, for the first time, a clinico-pathological investigation of two FTLD families with PGRN mutations, and compares the clinical characteristics with those of patients studied in the department with MAPT mutations. The clinical profile associated with PGRN mutations constituted, in some patients, a prototypical picture of FTD and in others one of PNFA, both profiles occurring within the same family. Patients with PGRN mutations exhibited phonological deficits, whereas in patients with MAPT mutations language abnormalities, when present in addition to the prominent behavioural disorder, take the form of semantic disturbance. The findings provide compelling evidence for the link between FTD and PNFA, while raising the possibility of identifiable clinical differences between FTLD patients with MAPT and PGRN mutations.

Key Words: progranulin; frontotemporal dementia; progressive aphasia; ubiquitin

Abbreviations: FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; MAPT, microtubule-associated protein tau gene; PGRN, progranulin; PNFA, progressive non-fluent aphasia; SD, semantic dementia; UBQ-ir, ubiquitin-immunoreactive

Received July 21, 2006. Revised August 24, 2006. Accepted August 29, 2006.


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