Brain Advance Access originally published online on October 9, 2006
Brain 2006 129(11):3103-3114; doi:10.1093/brain/awl268
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Frontotemporal dementia and parkinsonism associated with the IVS1+1G
A mutation in progranulin: a clinicopathologic study
1 Departments of Neurology, Mayo Clinic Rochester, MN 2 Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN 3 Diagnostic Radiology—Neuroradiology, Mayo Clinic Rochester, MN 4 Psychiatry and Psychology, Mayo Clinic Rochester, MN 5 Neuropathology Laboratory, Mayo Clinic Jacksonville, FL, USA 6 Neurogenetics Laboratory, Mayo Clinic Jacksonville, FL, USA 7 Department of Medicine, University of Toronto Toronto, Ontario, Canada 8 Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation USA
Correspondence to: Bradley F. Boeve, MD, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA E-mail: bboeve{at}mayo.edu
We previously reported a kindred with three cases of dementia, in which the proband exhibited features typical of frontotemporal dementia and parkinsonism (FTDP). An arginine insertion at codon 352 (insR352) in the presenilin-1 (PSEN1) gene was identified in the proband, but analyses in plasma and CSF suggested a mechanism of neurodegeneration not directly related to amyloid pathophysiology. The proband was followed with yearly evaluations of functional, clinical, neuropsychologic, neuropsychiatric and radiologic status, which showed relatively linear change over the initial 4 years of assessment. Upon the proband's death at age 63, neuropathologic examination revealed frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (FTLD-U). We recently identified several kindreds with familial FTDP associated with mutations in the progranulin (PGRN) gene, particularly in those cases with neuronal intranuclear inclusions. Our proband was indeed found to have such inclusions, and PGRN analysis in this proband revealed the G to A mutation in the exon 1 splice donor site (IVS1+1G
A) which is predicted to destroy the 5'-splice site of exon 1 and remove the start methionine codon and hence completely block any PGRN protein from being generated. These findings suggest that the insR352 PSEN1 is not pathogenic, and the IVS1+1GA mutation in PGRN causes FTDP associated with FTLD-U pathology and represents a new class of neurodegenerative disease—the ‘hypoprogranulinopathies’.
Key Words: frontotemporal dementia; progranulin; presenilin; neurodegenerative disease; neurogenetics
Abbreviations: Aß, beta-amyloid; FTD, frontotemporal dementia; NFT, neurofibrillary tangles; SP, senile plaques; VV, ventricular volume; WBV, whole-brain volume
Received July 31, 2005. Revised August 29, 2006. Accepted August 30, 2006.
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