title: Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family.
abstract: BACKGROUND
  Frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS.
  
  
  METHODS
  The authors report the clinical, volumetric MRI, neuropathological and genetic features of a new chromosome 9p-linked FTD-ALS family, VSM-20.
  
  
  RESULTS
  Ten members of family VSM-20 displayed heterogeneous clinical phenotypes of isolated behavioural-variant FTD (bvFTD), ALS or a combination of the two. Parkinsonism was common, with one individual presenting with a corticobasal syndrome. Analysis of structural MRI scans from five affected family members revealed grey- and white-matter loss that was most prominent in the frontal lobes, with mild parietal and occipital lobe atrophy, but less temporal lobe atrophy than in 10 severity-matched sporadic bvFTD cases. Autopsy in three family members showed a consistent and unique subtype of FTLD-TDP pathology. Genome-wide linkage analysis conclusively linked family VSM-20 to a 28.3 cM region between D9S1808 and D9S251 on chromosome 9p, reducing the published minimal linked region to a 3.7 Mb interval. Genomic sequencing and expression analysis failed to identify mutations in the 10 known and predicted genes within this candidate region, suggesting that next-generation sequencing may be needed to determine the mutational mechanism associated with chromosome 9p-linked FTD-ALS.
  
  
  CONCLUSIONS
  Family VSM-20 significantly reduces the region linked to FTD-ALS on chromosome 9p. A distinct pattern of brain atrophy and neuropathological findings may help to identify other families with FTD-ALS caused by this genetic abnormality.
authors.affiliation: UCSF Memory and Aging Center, University of California-San Francisco, CA 94143, USA. aboxer@memory.ucsf.edu
authors.forename: Adam L
authors.initials: AL
authors.lastname: Boxer
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: Matthew
authors.initials: M
authors.lastname: Baker
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.forename: Richard
authors.initials: R
authors.lastname: Crook
authors.forename: Howard
authors.initials: H
authors.lastname: Feldman
authors.forename: Ging-Yuek R
authors.initials: GY
authors.lastname: Hsiung
authors.forename: Nicola
authors.initials: N
authors.lastname: Rutherford
authors.forename: Victor
authors.initials: V
authors.lastname: Laluz
authors.forename: Jennifer
authors.initials: J
authors.lastname: Whitwell
authors.forename: Dean
authors.initials: D
authors.lastname: Foti
authors.forename: Eric
authors.initials: E
authors.lastname: McDade
authors.forename: Jennifer
authors.initials: J
authors.lastname: Molano
authors.forename: Anna
authors.initials: A
authors.lastname: Karydas
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wojtas
authors.forename: Jill
authors.initials: J
authors.lastname: Goldman
authors.forename: Jacob
authors.initials: J
authors.lastname: Mirsky
authors.forename: Pheth
authors.initials: P
authors.lastname: Sengdy
authors.forename: Stephen
authors.initials: S
authors.lastname: Dearmond
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D001344:Autopsy; D001921:Brain / Q000473:pathology; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D057180:Frontotemporal Dementia / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D007150:Immunohistochemistry; D008126:Lod Score; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics; D010375:Pedigree