caa a22 4500 44580971X CHVBK 20180317145207.0 cr unu---uuuuu 170323e20110401xx s 000 0 eng 10.1007/s00415-010-5815-x doi (NATIONALLICENCE)springer-10.1007/s00415-010-5815-x Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome9p [Elektronische Daten] [Justin Pearson, Nigel Williams, Elisa Majounie, Adrian Waite, Jennifer Stott, Victoria Newsway, Alex Murray, Dena Hernandez, Rita Guerreiro, Andrew Singleton, James Neal, Huw Morris] Families with autosomal dominant frontotemporal dementia and amyotrophic lateral sclerosis (FTD/ALS) have previously been linked to a locus on chromosome9p21. 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 chromosome9p21 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 type2 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 chromosome9p21, which was shared by all affected family members. This haplotype overlaps and limits the previously reported FTD/ALS linkage region on chromosome9p21. 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. Springer-Verlag, 2010 Frontotemporal dementia nationallicence Amyotrophic lateral sclerosis nationallicence Mendelian nationallicence Chromosome9 nationallicence Pearson Justin MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut Williams Nigel MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut Majounie Elisa MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut Waite Adrian MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut Stott Jennifer Department of Pathology, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut Newsway Victoria MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut Murray Alex Institute of Medical Genetics, University Hospital of Wales, CF14 4XN, Cardiff, UK aut Hernandez Dena Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, USA aut Guerreiro Rita Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, USA aut Singleton Andrew Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, USA aut Neal James Department of Pathology, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut Morris Huw MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut Journal of Neurology Springer-Verlag 258/4(2011-04-01), 647-655 0340-5354 258:4<647 2011 258 415 https://doi.org/10.1007/s00415-010-5815-x text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00415-010-5815-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Pearson Justin MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut NATIONALLICENCE 700 1- Williams Nigel MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut NATIONALLICENCE 700 1- Majounie Elisa MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut NATIONALLICENCE 700 1- Waite Adrian MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut NATIONALLICENCE 700 1- Stott Jennifer Department of Pathology, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut NATIONALLICENCE 700 1- Newsway Victoria MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut NATIONALLICENCE 700 1- Murray Alex Institute of Medical Genetics, University Hospital of Wales, CF14 4XN, Cardiff, UK aut NATIONALLICENCE 700 1- Hernandez Dena Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, USA aut NATIONALLICENCE 700 1- Guerreiro Rita Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, USA aut NATIONALLICENCE 700 1- Singleton Andrew Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, USA aut NATIONALLICENCE 700 1- Neal James Department of Pathology, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut NATIONALLICENCE 700 1- Morris Huw MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, CF14 4XN, Cardiff, UK aut NATIONALLICENCE 773 0- Journal of Neurology Springer-Verlag 258/4(2011-04-01), 647-655 0340-5354 258:4<647 2011 258 415 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer