Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family

Adam L. Boxer, Ian R. Mackenzie, Bradley F. Boeve, Matthew Baker, William W. Seeley, Richard Crook, Howard Feldman, Ging Yuek R. Hsiung, Nicola Rutherford, Victor Laluz, Jennifer Whitwell, Dean Foti, Eric McDade, Jennifer Molano, Anna Karydas, Aleksandra Wojtas, Jill Goldman, Jacob Mirsky, Pheth Sengdy, Stephen DeArmondBruce L. Miller, Rosa Rademakers

Research output: Contribution to journalArticle

149 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)196-203
Number of pages8
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume82
Issue number2
DOIs
StatePublished - Feb 2011

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology
  • Psychiatry and Mental health

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    Boxer, A. L., Mackenzie, I. R., Boeve, B. F., Baker, M., Seeley, W. W., Crook, R., Feldman, H., Hsiung, G. Y. R., Rutherford, N., Laluz, V., Whitwell, J., Foti, D., McDade, E., Molano, J., Karydas, A., Wojtas, A., Goldman, J., Mirsky, J., Sengdy, P., ... Rademakers, R. (2011). Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. Journal of Neurology, Neurosurgery and Psychiatry, 82(2), 196-203. https://doi.org/10.1136/jnnp.2009.204081