Prominent phenotypic variability associated with mutations in Progranulin.
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.
Kelley
Brendan J
BJ
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Haidar
Wael
W
Boeve
Bradley F
BF
Baker
Matt
M
Graff-Radford
Neill R
NR
Krefft
Thomas
T
Frank
Andrew R
AR
Jack
Clifford R
CR
Shiung
Maria
M
Knopman
David S
DS
Josephs
Keith A
KA
Parashos
Sotirios A
SA
Rademakers
Rosa
R
Hutton
Mike
M
Pickering-Brown
Stuart
S
Adamson
Jennifer
J
Kuntz
Karen M
KM
Dickson
Dennis W
DW
Parisi
Joseph E
JE
Smith
Glenn E
GE
Ivnik
Robert J
RJ
Petersen
Ronald C
RC
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
C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins