Journal of Neurology

, Volume 258, Issue 4, pp 647–655

Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p

  • Justin P. Pearson
  • Nigel M. Williams
  • Elisa Majounie
  • Adrian Waite
  • Jennifer Stott
  • Victoria Newsway
  • Alex Murray
  • Dena Hernandez
  • Rita Guerreiro
  • Andrew B. Singleton
  • James Neal
  • Huw R. Morris
Original Communication

DOI: 10.1007/s00415-010-5815-x

Cite this article as:
Pearson, J.P., Williams, N.M., Majounie, E. et al. J Neurol (2011) 258: 647. doi:10.1007/s00415-010-5815-x

Abstract

Families with autosomal dominant frontotemporal dementia and amyotrophic lateral sclerosis (FTD/ALS) have previously been linked to a locus on chromosome 9p21. We describe the clinical phenotype and pathology of a large family with autosomal dominant FTD/ALS with nine affected members originating from Gwent in South Wales, UK. We also further refine the locus on chromosome 9p21 using a haplotype sharing approach and assess heterogeneity in 9p21 linked families. Within this family, affected individuals present with either FTD or ALS or both diseases simultaneously. In addition there was marked phenotypic variation including ataxia, Parkinsonism, psychosis and visuo-spatial cognitive deficits. The pathological features of the three cases described were consistent with type 2 FTD pathology, as previously reported in similar families. However, we also report distinctive cerebellar and glial pathology and a significant proportion of TDP-43 negative inclusions. No mutations in known genes for FTD or ALS were found. We identified a large 4.8-megabase haplotype on chromosome 9p21, which was shared by all affected family members. This haplotype overlaps and limits the previously reported FTD/ALS linkage region on chromosome 9p21. Sequencing of this region did not identify any evidence of a pathogenic exonic mutation. This suggests that the pathogenic change affects non-coding DNA and that the disease is caused by variation in gene or protein expression.

Keywords

Frontotemporal dementiaAmyotrophic lateral sclerosisMendelianChromosome 9

Supplementary material

415_2010_5815_MOESM1_ESM.pdf (149 kb)
Online Resource 1: Radiological features, coronal and axial T2 MRI showing parieto-occipital atrophy in case 6 (A–D), frontotemporal atrophy in case 8 (E–H) and normal imaging in case 9 (I–L). (PDF 148 kb)
415_2010_5815_MOESM2_ESM.pdf (50 kb)
Online Resource 2: Case histories (PDF 50 kb)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Justin P. Pearson
    • 1
  • Nigel M. Williams
    • 1
  • Elisa Majounie
    • 1
  • Adrian Waite
    • 1
  • Jennifer Stott
    • 4
  • Victoria Newsway
    • 1
  • Alex Murray
    • 2
  • Dena Hernandez
    • 3
  • Rita Guerreiro
    • 3
  • Andrew B. Singleton
    • 3
  • James Neal
    • 4
  • Huw R. Morris
    • 1
    • 5
    • 6
  1. 1.MRC Centre for Neuropsychiatric Genetics and GenomicsCardiff University School of MedicineCardiffUK
  2. 2.Institute of Medical GeneticsUniversity Hospital of WalesCardiffUK
  3. 3.Laboratory of NeurogeneticsNational Institute of Aging, National Institutes of HealthBethesdaUSA
  4. 4.Department of PathologyCardiff University School of MedicineCardiffUK
  5. 5.Neurology (C4)University Hospital of WalesCardiffUK
  6. 6.Department of NeurologyRoyal Gwent Hospital, Aneurin Bevan Local Health BoardGwentUK