title: Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p.
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.
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Pearson
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Williams
authors.forename: Elisa
authors.initials: E
authors.lastname: Majounie
authors.forename: Adrian
authors.initials: A
authors.lastname: Waite
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stott
authors.forename: Victoria
authors.initials: V
authors.lastname: Newsway
authors.forename: Alex
authors.initials: A
authors.lastname: Murray
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: James
authors.initials: J
authors.lastname: Neal
authors.forename: Huw R
authors.initials: HR
authors.lastname: Morris
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000378:metabolism; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005192:Family Health; D005260:Female; D057180:Frontotemporal Dementia / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D005787:Gene Frequency; D005820:Genetic Testing; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein