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Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family
  1. Adam L Boxer1,
  2. Ian R Mackenzie2,
  3. Bradley F Boeve3,
  4. Matthew Baker4,
  5. William W Seeley1,
  6. Richard Crook4,
  7. Howard Feldman5,
  8. Ging-Yuek R Hsiung5,
  9. Nicola Rutherford4,
  10. Victor Laluz1,
  11. Jennifer Whitwell6,
  12. Dean Foti5,
  13. Eric McDade3,
  14. Jennifer Molano3,
  15. Anna Karydas1,
  16. Aleksandra Wojtas4,7,
  17. Jill Goldman8,
  18. Jacob Mirsky1,
  19. Pheth Sengdy5,
  20. Stephen DeArmond9,
  21. Bruce L Miller1,
  22. Rosa Rademakers4
  1. 1Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA
  2. 2Department of Pathology and Laboratory Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada
  3. 3Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
  4. 4Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA
  5. 5Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada
  6. 6Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
  7. 7Department of Oncology, University of Silesia, Katowice, Poland
  8. 8Taub Institute, Department of Neurology, Columbia University, New York, USA
  9. 9Department of Pathology and Laboratory Medicine, University of California, San Francisco, California, USA
  1. Correspondence to Dr Adam L Boxer, UCSF Memory and Aging Center, Box 1207, San Francisco, CA 94143, USA; aboxer{at}


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.

  • Frontotemporal dementia
  • amyotrophic lateral sclerosis
  • chromosome 9p
  • TAR-DNA binding protein 43
  • ALS
  • clinical neurology
  • dementia
  • genetics
  • pathology

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  • Funding This work was supported by the National Institutes of Health (K23NS48855 to ALB, R01AG031278 to ALB, P01AG019724 to BLM, P50AG0300601 to BLM, P50AG16574 to BB and RR and R01 NS065782 to RR); the John Douglas French Foundation (ALB); the Hellman Family Foundation (ALB); the L. Hillblom Foundation (BLM); the ALS association (RR); the Canadian Institutes of Health Research (IM, HF); the Pacific Alzheimer Research Foundation (IM, HF and RR); and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation (BB).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the institutional review boards and ethics committees at the Mayo Clinic, University of British Columbia (UBC) and University of California, San Francisco (UCSF).

  • Provenance and peer review Not commissioned; externally peer reviewed.