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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.
* To whom correspondence should be addressed. E-mail: bghetti{at}iupui.edu.
Abstract-- 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: IVS7-2AHG (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS7-2AHG 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.
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