title: Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p.
abstract: Frontotemporal dementia and amyotrophic lateral sclerosis are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with members affected by frontotemporal dementia, amyotrophic lateral sclerosis or both, which show genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). In the present study, we provide detailed analysis of the clinical features and neuropathology for 16 unrelated families with frontotemporal dementia caused by the C9ORF72 mutation. All had an autosomal dominant pattern of inheritance. Eight families had a combination of frontotemporal dementia and amyotrophic lateral sclerosis while the other eight had a pure frontotemporal dementia phenotype. Clinical information was available for 30 affected members of the 16 families. There was wide variation in age of onset (mean = 54.3, range = 34-74 years) and disease duration (mean = 5.3, range = 1-16 years). Early diagnoses included behavioural variant frontotemporal dementia (n = 15), progressive non-fluent aphasia (n = 5), amyotrophic lateral sclerosis (n = 9) and progressive non-fluent aphasia-amyotrophic lateral sclerosis (n = 1). Heterogeneity in clinical presentation was also common within families. However, there was a tendency for the phenotypes to converge with disease progression; seven subjects had final clinical diagnoses of both frontotemporal dementia and amyotrophic lateral sclerosis and all of those with an initial progressive non-fluent aphasia diagnosis subsequently developed significant behavioural abnormalities. Twenty-one affected family members came to autopsy and all were found to have transactive response DNA binding protein with M(r) 43 kD (TDP-43) pathology in a wide neuroanatomical distribution. All had involvement of the extramotor neocortex and hippocampus (frontotemporal lobar degeneration-TDP) and all but one case (clinically pure frontotemporal dementia) had involvement of lower motor neurons, characteristic of amyotrophic lateral sclerosis. In addition, a consistent and relatively specific pathological finding was the presence of neuronal inclusions in the cerebellar cortex that were ubiquitin/p62-positive but TDP-43-negative. Our findings indicate that the C9ORF72 mutation is a major cause of familial frontotemporal dementia with TDP-43 pathology, that likely accounts for the majority of families with combined frontotemporal dementia/amyotrophic lateral sclerosis presentation, and further support the concept that frontotemporal dementia and amyotrophic lateral sclerosis represent a clinicopathological spectrum of disease with overlapping molecular pathogenesis.
authors.affiliation: Division of Neurology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
authors.forename: Ging-Yuek R
authors.initials: GY
authors.lastname: Hsiung
authors.forename: Mariely
authors.initials: M
authors.lastname: DeJesus-Hernandez
authors.forename: Howard H
authors.initials: HH
authors.lastname: Feldman
authors.forename: Pheth
authors.initials: P
authors.lastname: Sengdy
authors.forename: Phoenix
authors.initials: P
authors.lastname: Bouchard-Kerr
authors.forename: Emily
authors.initials: E
authors.lastname: Dwosh
authors.forename: Rachel
authors.initials: R
authors.lastname: Butler
authors.forename: Bonnie
authors.initials: B
authors.lastname: Leung
authors.forename: Alice
authors.initials: A
authors.lastname: Fok
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rutherford
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Ian R A
authors.initials: IR
authors.lastname: Mackenzie
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000523:psychology; D001344:Autopsy; D000073885:C9orf72 Protein; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004247:DNA / Q000235:genetics; D056344:Executive Function; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000523:psychology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D013065:Speech Intelligibility
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D004247:DNA