RT Journal Article
SR Electronic
T1 Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family
JF Journal of Neurology, Neurosurgery & Psychiatry
JO J Neurol Neurosurg Psychiatry
FD BMJ Publishing Group Ltd
SP 196
OP 203
DO 10.1136/jnnp.2009.204081
VO 82
IS 2
A1 Adam L Boxer
A1 Ian R Mackenzie
A1 Bradley F Boeve
A1 Matthew Baker
A1 William W Seeley
A1 Richard Crook
A1 Howard Feldman
A1 Ging-Yuek R Hsiung
A1 Nicola Rutherford
A1 Victor Laluz
A1 Jennifer Whitwell
A1 Dean Foti
A1 Eric McDade
A1 Jennifer Molano
A1 Anna Karydas
A1 Aleksandra Wojtas
A1 Jill Goldman
A1 Jacob Mirsky
A1 Pheth Sengdy
A1 Stephen DeArmond
A1 Bruce L Miller
A1 Rosa Rademakers
YR 2011
UL http://jnnp.bmj.com/content/82/2/196.abstract
AB 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.