Original Communication

Journal of Neurology

, Volume 258, Issue 4, pp 647-655

First online:

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

  • Justin P. PearsonAffiliated withMRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine
  • , Nigel M. WilliamsAffiliated withMRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine
  • , Elisa MajounieAffiliated withMRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine
  • , Adrian WaiteAffiliated withMRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine
  • , Jennifer StottAffiliated withDepartment of Pathology, Cardiff University School of Medicine
  • , Victoria NewswayAffiliated withMRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine
  • , Alex MurrayAffiliated withInstitute of Medical Genetics, University Hospital of Wales
  • , Dena HernandezAffiliated withLaboratory of Neurogenetics, National Institute of Aging, National Institutes of Health
  • , Rita GuerreiroAffiliated withLaboratory of Neurogenetics, National Institute of Aging, National Institutes of Health
    • , Andrew B. SingletonAffiliated withLaboratory of Neurogenetics, National Institute of Aging, National Institutes of Health
    • , James NealAffiliated withDepartment of Pathology, Cardiff University School of Medicine
    • , Huw R. MorrisAffiliated withMRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of MedicineNeurology (C4), University Hospital of WalesDepartment of Neurology, Royal Gwent Hospital, Aneurin Bevan Local Health Board Email author 

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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 dementia Amyotrophic lateral sclerosis Mendelian Chromosome 9