title: A pathogenic progranulin mutation and C9orf72 repeat expansion in a family with frontotemporal dementia.
abstract: OBJECTIVE
  Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disease and is the second most common form of young onset dementia after Alzheimer's disease (AD). An autosomal dominant pattern of inheritance is present in around 25-50% of FTLD cases indicating a strong genetic component. Major pathogenic mutations of FTLD have been demonstrated independently in the progranulin (GRN) gene and the C9orf72 hexanucleotide expansion repeat. In this study we present a family that have been identified as carrying both a GRN Cys31fs mutation and the C9orf72 hexanucleotide expansion repeat.
  
  
  METHODS
  In the present study we describe the clinical and genetic details of family members and pathological features of two family members that have come to post-mortem.
  
  
  RESULTS
  The mean age at disease onset was 57 years (48-61 years) and mean duration 4 years (2-7 years). The most common presenting syndrome was behavioural variant frontotemporal dementia. Brain imaging from available cases showed a symmetrical pattern of atrophy particularly affecting the frontal and temporal lobes. Pathologically two cases were classified as FTLD-TDP type A with TDP-43 positive inclusions, with additional p62-positive 'star-like' inclusions found in the hippocampal formation and cerebellum.
  
  
  CONCLUSIONS
  The type and distribution of the pathological lesions in these two cases were in keeping with FTLD cases carrying only the C9orf72 hexanucleotide repeat. However the driving force of the pathological process may be either pathogenic mutation or a combination of both converging on a singular mechanism.
authors.affiliation: Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Tammaryn
authors.initials: T
authors.lastname: Lashley
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rohrer
authors.forename: Colin
authors.initials: C
authors.lastname: Mahoney
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gordon
authors.forename: Jon
authors.initials: J
authors.lastname: Beck
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.forename: Jason
authors.initials: J
authors.lastname: Warren
authors.forename: Martin
authors.initials: M
authors.lastname: Rossor
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
mesh_terms: D017668:Age of Onset; D000368:Aged; D001921:Brain / Q000473:pathology*; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D057180:Frontotemporal Dementia / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D000077153:Progranulins; D011506:Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C118585:P62 protein, human; D000077153:Progranulins; D011506:Proteins; D016601:RNA-Binding Proteins
keywords: C9orf72; FTLD; TDP-43; progranulin