title: Prominent phenotypic variability associated with mutations in Progranulin.
abstract: Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer's disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateralized topography of degeneration across all affected individuals.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Kelley
authors.forename: Wael
authors.initials: W
authors.lastname: Haidar
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Thomas
authors.initials: T
authors.lastname: Krefft
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Frank
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.forename: Maria
authors.initials: M
authors.lastname: Shiung
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.forename: Sotirios A
authors.initials: SA
authors.lastname: Parashos
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Mike
authors.initials: M
authors.lastname: Hutton
authors.forename: Stuart
authors.initials: S
authors.lastname: Pickering-Brown
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adamson
authors.forename: Karen M
authors.initials: KM
authors.lastname: Kuntz
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Smith
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ivnik
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D018888:Aphasia, Primary Progressive / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D003704:Dementia / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D007839:Functional Laterality / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D000077153:Progranulins
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins