title: Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72.
abstract: A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ~40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for ~60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.
authors.affiliation: Department of Neuroscience, University of Turin and Azienda Ospedale Università San Giovanni Battista of Turin, I-10126 Turin, Italy. achio@usa.net
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Borghero
authors.forename: Gabriella
authors.initials: G
authors.lastname: Restagno
authors.forename: Gabriele
authors.initials: G
authors.lastname: Mora
authors.forename: Carsten
authors.initials: C
authors.lastname: Drepper
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.forename: Michael
authors.initials: M
authors.lastname: Sendtner
authors.forename: Maura
authors.initials: M
authors.lastname: Brunetti
authors.forename: Irene
authors.initials: I
authors.lastname: Ossola
authors.forename: Andrea
authors.initials: A
authors.lastname: Calvo
authors.forename: Maura
authors.initials: M
authors.lastname: Pugliatti
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Sotgiu
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Murru
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Marrosu
authors.forename: Francesco
authors.initials: F
authors.lastname: Marrosu
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Marinou
authors.forename: Jessica
authors.initials: J
authors.lastname: Mandrioli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sola
authors.forename: Claudia
authors.initials: C
authors.lastname: Caponnetto
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Mancardi
authors.forename: Paola
authors.initials: P
authors.lastname: Mandich
authors.forename: Vincenzo
authors.initials: V
authors.lastname: La Bella
authors.forename: Rossella
authors.initials: R
authors.lastname: Spataro
authors.forename: Amelia
authors.initials: A
authors.lastname: Conte
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Monsurrò
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Tedeschi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pisano
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bartolomei
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Salvi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lauria Pinter
authors.forename: Isabella
authors.initials: I
authors.lastname: Simone
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Logroscino
authors.forename: Antonio
authors.initials: A
authors.lastname: Gambardella
authors.forename: Aldo
authors.initials: A
authors.lastname: Quattrone
authors.forename: Christian
authors.initials: C
authors.lastname: Lunetta
authors.forename: Paolo
authors.initials: P
authors.lastname: Volanti
authors.forename: Marcella
authors.initials: M
authors.lastname: Zollino
authors.forename: Silvana
authors.initials: S
authors.lastname: Penco
authors.forename: Stefania
authors.initials: S
authors.lastname: Battistini
authors.forename: Alan E
authors.initials: AE
authors.lastname: Renton
authors.forename: Elisa
authors.initials: E
authors.lastname: Majounie
authors.forename: Yevgeniya
authors.initials: Y
authors.lastname: Abramzon
authors.forename: Francesca Luisa
authors.initials: FL
authors.lastname: Conforti
authors.forename: Fabio
authors.initials: F
authors.lastname: Giannini
authors.forename: Massimo
authors.initials: M
authors.lastname: Corbo
authors.forename: Mario
authors.initials: M
authors.lastname: Sabatelli
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D000073885:C9orf72 Protein; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D042622:DNA Repeat Expansion; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010290:Parents; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D012727:Sex Characteristics; D016019:Survival Analysis
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D004247:DNA