Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72
| Autor: | Chiò, A1, Borghero, G, Restagno, G, Mora, G, Drepper, C, Traynor, Bj, Sendtner, M, Brunetti, M, Ossola, I, Calvo, A, Pugliatti, M, Sotgiu, Ma, Murru, Mr, Marrosu, Mg, Marrosu, F, Marinou, K, Mandrioli, J, Sola, P, Caponnetto, C, Mancardi, G, Mandich, P, La Bella, V, Spataro, R, Conte, A, Monsurrò, Mr, Tedeschi, G, Pisano, F, Bartolomei, I, Salvi, F, Lauria Pinter, G, Simone, I, Logroscino, G, Gambardella, A, Quattrone, A, Lunetta, C, Volanti, P, Zollino, M, Penco, S, Battistini, S, Renton, Ae, Majounie, E, Abramzon, Y, Conforti, Fl, Giannini, F, Corbo, M, Sabatelli, M, Moglia, C, Cammarosano, S, Fuda, G, Canosa, A, Gallo, S, Papetti, L, Luigetti, M, Lattante, S, Marangi, G, Colletti, T, Ricci, C, Origone, P, Floris, G, Cannas, A, Piras, V, Parish, Ld, Solinas, G, Ulgheri, L, Ticca, A, Izzo, F, Laiola, A, Trojsi, F. |
|---|---|
| Přispěvatelé: | Chiò, A, Borghero, G, Restagno, G, Mora, G, Drepper, C, Traynor, Bj, Sendtner, M, Brunetti, M, Ossola, I, Calvo, A, Pugliatti, M, Sotgiu, Ma, Murru, Mr, Marrosu, Mg, Marrosu, F, Marinou, K, Mandrioli, J, Sola, P, Caponnetto, C, Mancardi, G, Mandich, P, La Bella, V, Spataro, R, Conte, A, Monsurro', Maria Rosaria, Tedeschi, Gioacchino, Pisano, F, Bartolomei, I, Salvi, F, Lauria Pinter, G, Simone, I, Logroscino, G, Gambardella, A, Quattrone, A, Lunetta, C, Volanti, P, Zollino, M, Penco, S, Battistini, S, the ITALSGEN consortium: Moglia, Cristina, Cammarosano, Stefania, Fuda, Giuseppe, Canosa, Antonio, Gallo, Sara, Papetti, Laura, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Colletti, Tiziana, Ricci, Claudia, Origone, Paola, Floris, Gianluca, Cannas, Antonino, Piras, Valeria, Parish, Leslie D, Solinas, Giuliana, Ulgheri, Lucia, Ticca, Anna, Izzo, Francesco, Laiola, Anna, Trojsi, Francesca, Renton, Ae, Majounie, E, Abramzon, Y, Conforti, Fl, Giannini, F, Corbo, M, Sabatelli, M., Chiò, A., Borghero, G., Restagno, G., Mora, G., Drepper, C., Traynor, B., Sendtner, M., Brunetti, M., Ossola, I., Calvo, A., Pugliatti, M., Sotgiu, M., Murru, M., Marrosu, G., Marrosu, F., Marinou, K., Mandrioli, J., Sola, P., Caponnetto, C., Mancardi, G., Mandich, P., LA BELLA, V., Spataro, R., Conte, A., Monsurrò, M., Tedeschi, G., Pisano, F., Bartolomei, I., Salvi, F., Lauria, G., Simone, I., Logroscino, G., Gambardella, A., Quattrone, A., Lunetta, C., Volanti, P., Zollino, M., Penco, S., Battistini, S., the ITALSGEN, C., Renton, A., Majounie, E., Abramzon, Y., Conforti, F., Giannini, F., Corbo, M. |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Parents Pathology phenotype-genotype correlation Cohort Studies 0302 clinical medicine C9orf72 amyotrophic lateral sclerosi genetics Amyotrophic lateral sclerosis Age of Onset amyotrophic lateral sclerosis familial als C9Orf72 0303 health sciences Sex Characteristics DNA Repeat Expansion Adult Age of Onset Aged Amyotrophic Lateral Sclerosis genetics/pathology Cohort Studies DNA Repeat Expansion DNA genetics Female Humans Italy Male Middle Aged Mutation genetics Parents Pedigree Phenotype Proteins genetics Sex Characteristics Survival Analysis Middle Aged 3. Good health Pedigree Settore MED/26 - NEUROLOGIA Phenotype Italy Settore MED/26 - Neurologia Female Frontotemporal dementia Adult medicine.medical_specialty SOD1 Biology TARDBP 03 medical and health sciences Internal medicine medicine Humans 030304 developmental biology Aged amyotrophic lateral sclerosis familial ALS C9ORF72 gene phenotype–genotype correlation C9orf72 Protein Amyotrophic Lateral Sclerosis genetics/pathology Proteins Original Articles DNA medicine.disease Survival Analysis Settore BIO/18 - Genetica familial ALS C9ORF72 gene Mutation Neurology (clinical) Age of onset Trinucleotide repeat expansion familial al 030217 neurology & neurosurgery |
| Zdroj: | Brain; Vol 135 |
| Popis: | 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. Keywords |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|