Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72.
Adriano Chiò,Giuseppe Borghero,Gabriella Restagno,Gabriele Mora,Carsten Drepper,Bryan J. Traynor,Michael Sendtner,Maura Brunetti,Irene Ossola,Andrea Calvo,Maura Pugliatti,Maria Alessandra Sotgiu,Maria Rita Murru,Maria Giovanna Marrosu,Francesco Marrosu,Kalliopi Marinou,Jessica Mandrioli,Patrizia Sola,Claudia Caponnetto,Gianluigi Mancardi,Paola Mandich,Vincenzo La Bella,Rossella Spataro,Amelia Conte,Maria Rosaria Monsurrò,Gioacchino Tedeschi,Fabrizio Pisano,Ilaria Bartolomei,Fabrizio Salvi,Giuseppe Lauria Pinter,Isabella Laura Simone,Giancarlo Logroscino,Antonio Gambardella,Aldo Quattrone,Christian Lunetta,Paolo Volanti,Marcella Zollino,Silvana Penco,Stefania Battistini,Alan E. Renton,Elisa Majounie,Yevgeniya Abramzon,Francesca Luisa Conforti,Fabio Giannini,Massimo Corbo,Mario Sabatelli +45 more
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TLDR
The phenotype of amyotrophic lateral sclerosis cases carrying C9ORF72 hexanucleotide repeat expansions was described 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 amyotroph lateral sclerosis.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.read more
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Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis.
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TL;DR: Current literature of the major genes underlying ALS, SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72 and PFN1 are summarized and how each new genetic discovery is broadening the phenotype associated with the clinical entity the authors know as ALS is outlined.
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TL;DR: Recent advances in understanding the molecular aspects of FTD are highlighted, which will provide the basis for improved patient care through the development of more-targeted diagnostic tests and therapies.
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A Pan‐European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats
Julie van der Zee,Ilse Gijselinck,Lubina Dillen,Tim Van Langenhove,Jessie Theuns,Sebastiaan Engelborghs,Stéphanie Philtjens,Mathieu Vandenbulcke,Kristel Sleegers,Anne Sieben,Anne Sieben,Veerle Bäumer,Githa Maes,Ellen Corsmit,Barbara Borroni,Alessandro Padovani,Silvana Archetti,Robert Perneczky,Janine Diehl-Schmid,Alexandre de Mendonça,Gabriel Miltenberger-Miltenyi,Sónia Pereira,José Pimentel,Benedetta Nacmias,Silvia Bagnoli,Sandro Sorbi,Caroline Graff,Caroline Graff,Huei-Hsin Chiang,Marie Westerlund,Raquel Sánchez-Valle,Albert Lladó,Ellen Gelpi,Isabel Santana,Maria Rosário Almeida,Beatriz Santiago,Giovanni B. Frisoni,Orazio Zanetti,Cristian Bonvicini,Matthis Synofzik,Walter Maetzler,Jennifer Müller vom Hagen,Ludger Schöls,Michael T. Heneka,Michael T. Heneka,Frank Jessen,Frank Jessen,Radoslav Matej,Eva Parobkova,Gabor G. Kovacs,Thomas Ströbel,Stayko Sarafov,Ivailo Tournev,Ivailo Tournev,Albena Jordanova,Adrian Danek,Thomas Arzberger,Gian Maria Fabrizi,Silvia Testi,Eric Salmon,Patrick Santens,Jean-Jacques Martin,Patrick Cras,Rik Vandenberghe,Peter Paul De Deyn,Marc Cruts,Christine Van Broeckhoven,Peter Paul De Deyn,Alfredo Ramirez,Delia Kurzwelly,Carmen Sachtleben,Wolfgang Mairer,Clara Firmo,Anna Antonell,José Luis Molinuevo,Anne Kinhult Ståhlbom,Håkan Thonberg,Inger Nennesmo,Anne Börjesson-Hanson,Valentina Bessi,Irene Piaceri,Maria Helena Ribeiro,Catarina R. Oliveira,João Massano,Carolina Garret,Paula Pires,Adrian Danel,Sergio Ferrari,Tiziana Cavallaro +88 more
TL;DR: In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss‐of‐function disease mechanism.
References
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Journal ArticleDOI
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
Mariely DeJesus-Hernandez,Ian R. A. Mackenzie,Bradley F. Boeve,Adam L. Boxer,Matt Baker,Nicola J. Rutherford,Alexandra M. Nicholson,Ni Cole A. Finch,Heather C. Flynn,Jennifer Adamson,Naomi Kouri,Aleksandra Wojtas,Pheth Sengdy,Ging-Yuek Robin Hsiung,Anna Karydas,William W. Seeley,Keith A. Josephs,Giovanni Coppola,Daniel H. Geschwind,Zbigniew K. Wszolek,Howard Feldman,Howard Feldman,David S. Knopman,Ronald C. Petersen,Bruce L. Miller,Dennis W. Dickson,Kevin B. Boylan,Neill R. Graff-Radford,Rosa Rademakers +28 more
TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
Journal ArticleDOI
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Alan E. Renton,Elisa Majounie,Adrian James Waite,Javier Simón-Sánchez,Javier Simón-Sánchez,Sara Rollinson,J. Raphael Gibbs,J. Raphael Gibbs,Jennifer C. Schymick,Hannu Laaksovirta,John C. van Swieten,John C. van Swieten,Liisa Myllykangas,Hannu Kalimo,Anders Paetau,Yevgeniya Abramzon,Anne M. Remes,Alice Kaganovich,Sonja W. Scholz,Sonja W. Scholz,Sonja W. Scholz,Jamie Duckworth,Jinhui Ding,Daniel W. Harmer,Dena G. Hernandez,Dena G. Hernandez,Janel O. Johnson,Janel O. Johnson,Kin Y. Mok,Mina Ryten,Danyah Trabzuni,Rita Guerreiro,Richard W. Orrell,James Neal,Alexandra Murray,J. P. Pearson,Iris E. Jansen,David Sondervan,Harro Seelaar,Derek J. Blake,Kate Young,Nicola Halliwell,Janis Bennion Callister,Greg Toulson,Anna Richardson,Alexander Gerhard,Julie S. Snowden,David M. A. Mann,David Neary,Mike A. Nalls,Terhi Peuralinna,Lilja Jansson,Veli-Matti Isoviita,Anna-Lotta Kaivorinne,Maarit Hölttä-Vuori,Elina Ikonen,Raimo Sulkava,Michael Benatar,Joanne Wuu,Adriano Chiò,Gabriella Restagno,Giuseppe Borghero,Mario Sabatelli,David Heckerman,Ekaterina Rogaeva,Lorne Zinman,Jeffrey D. Rothstein,Michael Sendtner,Carsten Drepper,Evan E. Eichler,Can Alkan,Ziedulla Abdullaev,Svetlana Pack,Amalia Dutra,Evgenia Pak,John Hardy,Andrew B. Singleton,Nigel Williams,Peter Heutink,Stuart Pickering-Brown,Huw R. Morris,Huw R. Morris,Huw R. Morris,Pentti J. Tienari,Bryan J. Traynor,Bryan J. Traynor +85 more
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
Journal ArticleDOI
SeminarAmyotrophic lateral sclerosis
Matthew C Kiernan,Steve Vucic,Benjamin C. Cheah,Martin R Turner,Andrew Eisen,Orla Hardiman,James R. Burrell,Margaret C. Zoing +7 more
TL;DR: This paper summarized current concepts about the origin of the disease, what predisposes patients to develop the disorder, and discuss why all cases of ALS are not the same, focusing on the small steps of extending longevity, improving therapies, undertaking clinical trials, and compiling population registries to the overarching goals of establishing the measures that guard against onset and finding the triggers for this neurodegenerative disorder.
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John D. Lee,Nur A. Kamaruzaman,Jenny Nt Fung,Stephen Maxwell Taylor,Bradley J. Turner,Julie D. Atkin,Trent M. Woodruff,Peter G. Noakes +7 more
TL;DR: This Seminar summarises current concepts about the origin of the disease, what predisposes patients to develop the disorder, and why all cases of ALS are not the same.
Journal ArticleDOI
Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS
Janel O. Johnson,Jessica Mandrioli,Michael Benatar,Yevgeniya Abramzon,Vivianna M. Van Deerlin,John Q. Trojanowski,J. Raphael Gibbs,J. Raphael Gibbs,Maura Brunetti,Susan Gronka,Joanne Wuu,Jinhui Ding,Leo McCluskey,Maria Martinez-Lage,Dana Falcone,Dena G. Hernandez,Dena G. Hernandez,Sampath Arepalli,Sean Chong,Jennifer C. Schymick,Jeffrey D. Rothstein,Francesco Landi,Yong Dong Wang,Andrea Calvo,Gabriele Mora,Mario Sabatelli,Maria Rosaria Monsurrò,Stefania Battistini,Fabrizio Salvi,Rossella Spataro,Patrizia Sola,Giuseppe Borghero,Giuliana Galassi,Sonja W. Scholz,Sonja W. Scholz,J. Paul Taylor,Gabriella Restagno,Adriano Chiò,Bryan J. Traynor,Bryan J. Traynor +39 more
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