Controversies and priorities in amyotrophic lateral sclerosis
Martin R Turner,Orla Hardiman,Michael Benatar,Benjamin Rix Brooks,Adriano Chiò,Mamede de Carvalho,Paul G. Ince,Cindy S.-Y. Lin,Robert G. Miller,Hiroshi Mitsumoto,Garth A. Nicholson,John Ravits,Pamela J. Shaw,Michael Swash,Michael Swash,Kevin Talbot,Bryan J. Traynor,Leonard H. van den Berg,Jan H. Veldink,Steve Vucic,Matthew C. Kiernan +20 more
TLDR
Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease.Abstract:
Two decades after the discovery that 20% of familial amyotrophic lateral sclerosis (ALS) cases were linked to mutations in the superoxide dismutase-1 (SOD1) gene, a substantial proportion of the remainder of cases of familial ALS have now been traced to an expansion of the intronic hexanucleotide repeat sequence in C9orf72. This breakthrough provides an opportunity to re-evaluate longstanding concepts regarding the cause and natural history of ALS, coming soon after the pathological unification of ALS with frontotemporal dementia through a shared pathological signature of cytoplasmic inclusions of the ubiquitinated protein TDP-43. However, with profound clinical, prognostic, neuropathological, and now genetic heterogeneity, the concept of ALS as one disease appears increasingly untenable. This background calls for the development of a more sophisticated taxonomy, and an appreciation of ALS as the breakdown of a wider network rather than a discrete vulnerable population of specialised motor neurons. Identification of C9orf72 repeat expansions in patients without a family history of ALS challenges the traditional division between familial and sporadic disease. By contrast, the 90% of apparently sporadic cases and incomplete penetrance of several genes linked to familial cases suggest that at least some forms of ALS arise from the interplay of multiple genes, poorly understood developmental, environmental, and age-related factors, as well as stochastic events.read more
Citations
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State of play in amyotrophic lateral sclerosis genetics.
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.
Journal ArticleDOI
Potential roles of gut microbiome and metabolites in modulating ALS in mice
Eran Blacher,Stavros Bashiardes,Hagit Shapiro,Daphna Rothschild,Uria Mor,Mally Dori-Bachash,Christian Kleimeyer,Claudia Moresi,Yotam Harnik,Maya Zur,Michal Zabari,Rotem Ben-Zeev Brik,Denise Kviatcovsky,Niv Zmora,Yotam Cohen,Noam Bar,Izhak Levi,Nira Amar,Tevie Mehlman,Alexander Brandis,Inbal E. Biton,Yael Kuperman,Michael Tsoory,Leenor Alfahel,Alon Harmelin,Michal Schwartz,Adrian Israelson,Liisa Arike,Malin E. V. Johansson,Gunnar C. Hansson,Marc Gotkine,Eran Segal,Eran Elinav +32 more
TL;DR: It is demonstrated that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS, and it is suggested that environmentally driven microbiome–brain interactions may modulate ALS in mice.
Journal ArticleDOI
Large-scale genomics unveils the genetic architecture of psychiatric disorders
TL;DR: The emerging genetic architecture implies a large number of contributing loci (that is, a high genome-wide mutational target) and suggests that genetic risk of psychiatric disorders involves the combined effects of many common variants of small effect, as well as rare and de novo variants of large effect.
Journal ArticleDOI
Genetics of amyotrophic lateral sclerosis: an update.
TL;DR: This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the disease neuropathogenesis.
Journal ArticleDOI
Amyotrophic lateral sclerosis: moving towards a new classification system
Ammar Al-Chalabi,Orla Hardiman,Matthew C. Kiernan,Adriano Chiò,Benjamin Rix-Brooks,Benjamin Rix-Brooks,Leonard H. van den Berg +6 more
TL;DR: A new strategy is needed to combine the benefits of a systematic approach to classification with the rich and varied phenotypic descriptions used in clinical practice to avoid confusion between diagnosis and phenotype.
References
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Journal ArticleDOI
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
Journal ArticleDOI
Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Manuela Neumann,Deepak M. Sampathu,Linda K. Kwong,Adam C. Truax,Matthew Micsenyi,Thomas T. Chou,Jennifer Bruce,Theresa Schuck,Murray Grossman,Christopher M. Clark,Leo McCluskey,Bruce L. Miller,Eliezer Masliah,Ian R. A. Mackenzie,Howard Feldman,Wolfgang Feiden,Hans A. Kretzschmar,John Q. Trojanowski,Virginia M.-Y. Lee +18 more
TL;DR: It is shown that TDP-43 is the major disease protein in both frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis.
Journal ArticleDOI
Correspondence of the brain's functional architecture during activation and rest.
Stephen M. Smith,Peter T. Fox,Karla L. Miller,David C. Glahn,P. Mickle Fox,Clare E. Mackay,Nicola Filippini,Kate E. Watkins,Roberto Toro,Angela R. Laird,Christian F. Beckmann,Christian F. Beckmann +11 more
TL;DR: It is concluded that the full repertoire of functional networks utilized by the brain in action is continuously and dynamically “active” even when at “rest.”
Journal ArticleDOI
El Escorial revisited : revised criteria for the diagnosis of amyotrophic lateral sclerosis
TL;DR: The criteria described below represent the result of a three-day workshop, convened at Airlie Conference Center, Warrenton, Virginia on 2–4 April, 1998 by the World Federation of Neurology Research Committee on Motor Neuron Diseases, and are placed on the WFN ALS website.
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.
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Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
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Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
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