Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family.
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.
Boxer
Adam L
AL
UCSF Memory and Aging Center, University of California-San Francisco, CA 94143, USA. aboxer@memory.ucsf.edu
Mackenzie
Ian R
IR
Boeve
Bradley F
BF
Baker
Matthew
M
Seeley
William W
WW
Crook
Richard
R
Feldman
Howard
H
Hsiung
Ging-Yuek R
GY
Rutherford
Nicola
N
Laluz
Victor
V
Whitwell
Jennifer
J
Foti
Dean
D
McDade
Eric
E
Molano
Jennifer
J
Karydas
Anna
A
Wojtas
Aleksandra
A
Goldman
Jill
J
Mirsky
Jacob
J
Sengdy
Pheth
P
Dearmond
Stephen
S
Miller
Bruce L
BL
Rademakers
Rosa
R
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