title: Variability of the clinical phenotype in an Italian family with dementia associated with an intronic deletion in the GRN gene.
abstract: Mutations in the progranulin gene (GRN) were recently identified as an important cause of familial frontotemporal dementia (FTD). More than 60 pathogenic mutations have been reported up to now and prominent phenotypic variability within and among affected kindreds has been described. We have studied an Italian family with clinical evidence of dementia, and here we report detailed clinical records, imaging, sequential neurological examinations, cognitive assessments, and genetic analysis of three affected members of the same generation. Genetic analysis revealed the presence of the null mutation IVS6 + 5_8delGTGA in GRN, leading to haploinsufficiency, as documented by mRNA analysis. The mutation is associated with wide variation of the clinical phenotype, ranging from FTD to Alzheimer's disease and to a rapidly-progressive dementia. In summary, the patients of this kindred showed highly variable clinical features that do not have a close correspondence with the pattern of the cerebral atrophy. Our data extend the phenotypic spectrum and the complexity of neurodegenerative diseases linked to GRN mutations.
authors.affiliation: Division of Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy DISM, University of Udine, Udine, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marcon
authors.forename: Giacomina
authors.initials: G
authors.lastname: Rossi
authors.forename: Giorgio
authors.initials: G
authors.lastname: Giaccone
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Giovagnoli
authors.forename: Elena
authors.initials: E
authors.lastname: Piccoli
authors.forename: Sergio
authors.initials: S
authors.lastname: Zanini
authors.forename: Onelio
authors.initials: O
authors.lastname: Geatti
authors.forename: Vito
authors.initials: V
authors.lastname: Toso
authors.forename: Marina
authors.initials: M
authors.lastname: Grisoli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Tagliavini
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000523:psychology*; D000647:Amnesia / Q000209:etiology / Q000523:psychology; D001519:Behavior / Q000502:physiology; D001921:Brain / Q000473:pathology; D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology / Q000523:psychology*; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000235:genetics*; D007558:Italy; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010551:Personality / Q000502:physiology; D010641:Phenotype; D000077153:Progranulins; D012313:RNA / Q000032:analysis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013064:Speech Disorders / Q000209:etiology
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D012313:RNA; D004247:DNA