title: Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72.
abstract: Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA. bboeve@mayo.edu
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Mariely
authors.initials: M
authors.lastname: DeJesus-Hernandez
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.forename: Otto
authors.initials: O
authors.lastname: Pedraza
authors.forename: Prashanthi
authors.initials: P
authors.lastname: Vemuri
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.forename: Val
authors.initials: V
authors.lastname: Lowe
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.forename: Beth K
authors.initials: BK
authors.lastname: Rush
authors.forename: Mary M
authors.initials: MM
authors.lastname: Machulda
authors.forename: Julie A
authors.initials: JA
authors.lastname: Fields
authors.forename: Tanis J
authors.initials: TJ
authors.lastname: Ferman
authors.forename: Matthew
authors.initials: M
authors.lastname: Baker
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rutherford
authors.forename: Jennifer
authors.initials: J
authors.lastname: Adamson
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Anahita
authors.initials: A
authors.lastname: Adeli
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Savica
authors.forename: Brendon
authors.initials: B
authors.lastname: Boot
authors.forename: Karen M
authors.initials: KM
authors.lastname: Kuntz
authors.forename: Ralitza
authors.initials: R
authors.lastname: Gavrilova
authors.forename: Andrew
authors.initials: A
authors.lastname: Reeves
authors.forename: Jennifer
authors.initials: J
authors.lastname: Whitwell
authors.forename: Kejal
authors.initials: K
authors.lastname: Kantarci
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.forename: John A
authors.initials: JA
authors.lastname: Lucas
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D017668:Age of Onset; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D018888:Aphasia, Primary Progressive / Q000235:genetics / Q000523:psychology; D000073885:C9orf72 Protein; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D042622:DNA Repeat Expansion / Q000235:genetics; D005260:Female; D005431:Florida / Q000453:epidemiology; D057180:Frontotemporal Dementia / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007091:Image Processing, Computer-Assisted; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008910:Minnesota / Q000453:epidemiology; D009483:Neuropsychological Tests; D010300:Parkinson Disease / Q000235:genetics; D049268:Positron-Emission Tomography; D000077153:Progranulins; D011506:Proteins / Q000235:genetics*; D012042:Registries; D015899:Tomography, Emission-Computed, Single-Photon; D044465:White People; D016875:tau Proteins / Q000235:genetics
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D000077153:Progranulins; D011506:Proteins; D016875:tau Proteins; D004247:DNA