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Clinicopathologic correlation in PGRN mutations

From the Department of Pathology (S.D., E.H.B.), Cognitive Neurology and Alzheimer Disease Center (N.J., S.W., M.-M.M., A.E., M.M., E.H.B.), and Department of Neurology (M.-M.M.), Northwestern University Feinberg School of Medicine, Chicago, IL; and Neurogenetics Laboratory, Mayo Clinic Jacksonville (M.B., J.A., M.H., R.R.), FL.

Address correspondence and reprint requests to Dr. Eileen H. Bigio, Northwestern University, Feinberg School of Medicine, Department of Pathology, 710 N. Fairbanks Ct., Olson 2-459, Chicago, IL 60611 e-bigio{at}northwestern.edu

Background: Frontotemporal dementia (FTD) has been linked to the microtubule associated protein tau (MAPT) gene region of chromosome 17. However, many chromosome-17 linked FTLDs do not have MAPT mutations or tau protein deposits, but have ubiquitin positive, tau and alpha-synuclein negative inclusions. Mutations in the progranulin (PGRN) gene, located 1.7 Mb from MAPT at 17q21.31, were recently discovered in some of these individuals. The pathologic phenotype in all cases has thus far included ubiquitinated neuronal intranuclear inclusions (NIIs) and neuronal cytoplasmic inclusions (NCIs).

Methods: PGRN mutation analysis was performed in 12 individuals. Informed consent was obtained from next of kin under an IRB-approved protocol. We compared clinical and pathologic findings in those cases with and without PGRN mutations.

Results: PGRN mutations were found in four patients, two with clinical FTD and a positive family history, and two with clinical primary progressive aphasia (PPA), one with and one without a family history. All four cases with, and five of eight cases without, PGRN mutations had ubiquitinated NCIs and NIIs. Brains of individuals with PGRN mutations are associated with more frequent frontal NCIs and dystrophic neurites, less frequent dentate gyrus NCIs, and more frequent striatal NIIs than FTLD-U cases without PGRN mutations.

Conclusion: PGRN mutations at 17q21 may occur in apparently sporadic frontotemporal lobar dementia with ubiquitinated inclusions cases and in cases presenting with either primary progressive aphasia or the behavioral variant of frontotemporal dementia. Some cases without PGRN mutations also have ubiquitinated neuronal intranuclear inclusions. Clinicopathologic differences are observed among individuals with and without PGRN mutations.

e-Pub ahead of print on May 23, 2007, at www.neurology.org.

Supported in part by NIH grants AG13854 (S.W., M.-M.M., and E.H.B.), NIA program grant PO1 AG17216 (M.H.), and support from the Mayo foundation. R.R. is a postdoctoral fellow of the Fund for Scientific Research Flanders (FWO-F).

Disclosure: The authors report no conflicts of interest.

Received August 25, 2006. Accepted in final form April 9, 2007.

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