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From the Indiana Alzheimer Disease Center (S.S., J.R.M., M.A.B., A.G.B., R.V., B.G.), Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis; Cognitive Neuroscience Section (E.D.H., E.M.W., P.P., J.G.) and Brain Stimulation Unit (E.M.W.), National Institute of Neurological Disorders and Stroke, NIH, Bethesda; Department of Pathology (J.C.T.), Johns Hopkins University School of Medicine, Baltimore, MD; and Laboratory of Clinical Biochemistry and Molecular Biology (P.P.), University of Pisa, Italy.
Address correspondence and reprint requests to Dr. B. Ghetti, Indiana Alzheimer Disease Center, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Medical Science Bldg. A138, 635 Barnhill Dr., Indianapolis, IN 46202; e-mail: bghetti{at}iupui.edu
Background: Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII).
Objective: To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1).
Methods: Patients underwent a single clinical assessment, MRI, and [18F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out.
Results: Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A
G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2AG may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation.
Conclusions: We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents to the March 13 issue to find the title link for this article.
Commentary, see page 801
This article was previously published in electronic format as an Expedited E-Pub on January 3, 2007, at www.neurology.org.
*These authors contributed equally to this publication.
Supported by PHS P30AG10133 (S.S., J.R.M., R.V., B.G.), PHS P50AG05146 (J.C.T.), Intramural Research Programs of the NIH (National Institute of Neurological Disorders and Stroke; E.D.H., E.M.W., P.P., J.G.), and IIRG-05-14220 award from the Alzheimer's Association (M.A.B, A.G.B., R.V.). S.S. is in part supported by and is a PhD student of the Department of Neurological and Behavioral Sciences, University of Siena, Siena, Italy.
Disclosure: The authors report no conflicts of interest.
Received August 31, 2006. Accepted in final form November 13, 2006.
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