Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72

被引：167

作者：

Chio, Adriano ^{[1
,2
]}

Borghero, Giuseppe ^{[3
,4
]}

Restagno, Gabriella ^{[5
]}

Mora, Gabriele ^{[12
]}

Drepper, Carsten ^{[6
]}

Traynor, Bryan J. ^{[7
]}

Sendtner, Michael ^{[6
]}

Brunetti, Maura ^{[5
]}

Ossola, Irene ^{[5
]}

Calvo, Andrea ^{[1
,2
]}

Pugliatti, Maura ^{[8
]}

Sotgiu, Maria Alessandra ^{[9
]}

Murru, Maria Rita ^{[10
]}

Marrosu, Maria Giovanna ^{[10
]}

Marrosu, Francesco ^{[3
]}

Marinou, Kalliopi ^{[12
]}

Mandrioli, Jessica ^{[11
]}

Sola, Patrizia ^{[11
]}

Caponnetto, Claudia ^{[13
]}

Mancardi, Gianluigi ^{[13
]}

Mandich, Paola ^{[13
]}

La Bella, Vincenzo ^{[14
]}

Spataro, Rossella ^{[14
]}

Conte, Amelia ^{[15
,16
]}

Monsurro, Maria Rosaria ^{[17
]}

Tedeschi, Gioacchino ^{[17
]}

Pisano, Fabrizio ^{[18
]}

Bartolomei, Ilaria ^{[19
]}

Salvi, Fabrizio ^{[19
]}

Pinter, Giuseppe Lauria ^{[20
]}

Simone, Isabella ^{[21
]}

Logroscino, Giancarlo ^{[21
]}

Gambardella, Antonio ^{[22
]}

Quattrone, Aldo ^{[22
]}

Lunetta, Christian ^{[23
]}

Volanti, Paolo ^{[24
]}

Zollino, Marcella ^{[25
]}

Penco, Silvana ^{[26
]}

Battistini, Stefania ^{[27
]}

Renton, Alan E. ^{[7
]}

Majounie, Elisa ^{[28
]}

Abramzon, Yevgeniya ^{[7
]}

Conforti, Francesca Luisa ^{[22
]}

Giannini, Fabio ^{[27
]}

Corbo, Massimo ^{[23
]}

Sabatelli, Mario ^{[15
,16
]}

机构：

[1] Univ Turin, Dept Neurosci, I-10126 Turin, Italy

[2] Azienda Osped Univ San Giovanni Battista Turin, I-10126 Turin, Italy

[3] Azienda Univ Osped Cagliari, I-09100 Cagliari, Italy

[4] Univ Cagliari, I-09100 Cagliari, Italy

[5] ASO OIRM St Anna, Mol Genet Unit, Dept Clin Pathol, I-10126 Turin, Italy

[6] Univ Wurzburg, Inst Clin Neurobiol, D-97018 Wurzburg, Germany

[7] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20894 USA

[8] Univ Sassari, Dept Neurosci, I-07100 Sassari, Italy

[9] Univ Sassari, Dept Biomed Sci, I-07100 Sassari, Italy

[10] Univ Cagliari, Ctr Sclerosi Multipla, Osped Binaghi, I-09100 Cagliari, Italy

[11] Univ Modena, St Agostino Estense Hosp, Dept Neurosci, I-41126 Modena, Italy

[12] Salvatore Maugeri Fdn IRCSS, Sci Inst Milan, I-20138 Milan, Italy

[13] Univ Genoa, Dept Neurosci Ophthalmol & Genet, I-16132 Genoa, Italy

[14] Univ Palermo, Dept Neurosci, ALS Clin Res Ctr, Bio Ne C, I-90100 Palermo, Italy

[15] Catholic Univ, Neurol Inst, I-00168 Rome, Italy

[16] I CO MM Assoc ALS Res, I-00168 Rome, Italy

[17] Univ Naples 2, Dept Neurol Sci, I-80138 Naples, Italy

[18] Salvatore Maugeri Fdn IRCSS, Sci Inst Veruno, I-28010 Veruno, NO, Italy

[19] Bellaria Hosp, Dept Neurol, Ctr Diag & Cure Rare Dis, I-40139 Bologna, Italy

[20] Natl Neurol Inst Besta, Dept Neurol, I-20133 Milan, Italy

[21] Univ Bari, Dept Neurosci, I-70100 Bari, Italy

[22] CNR, Inst Neurol Sci, I-87050 Cosenza, Italy

[23] Serena Fdn, Neuromuscular OnmiCtr, I-20162 Milan, Italy

[24] Salvatore Maugeri Fdn IRCSS, Sci Inst Mistretta, I-98073 Mistretta, ME, Italy

[25] Catholic Univ, Dept Lab Med, Mol Genet Lab, I-00168 Rome, Italy

[26] Osped Niguarda Ca Granda, Dept Lab Med, I-20162 Milan, Italy

[27] Univ Siena, Neurol Sect, Dept Neurosci, I-53100 Siena, Italy

[28] NIA, Neurogenet Lab, Mol Genet Unit, Bethesda, MD 20892 USA

来源：

BRAIN | 2012年 / 135卷

基金：

美国国家卫生研究院;

关键词：

amyotrophic lateral sclerosis; familial ALS; C9ORF72; gene; phenotype-genotype correlation; TARDBP MUTATIONS; ALS; POPULATION; DISEASE; DEMENTIA; FTD;

D O I：

10.1093/brain/awr366

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 similar to 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 similar to 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.

引用

页码：784 / 793

页数：10

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