Document Detail


Controversies and priorities in amyotrophic lateral sclerosis.
MedLine Citation:
PMID:  23415570     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Martin R Turner; Orla Hardiman; Michael Benatar; Benjamin R Brooks; Adriano Chio; Mamede de Carvalho; Paul G Ince; Cindy Lin; Robert G Miller; Hiroshi Mitsumoto; Garth Nicholson; John Ravits; Pamela J Shaw; Michael Swash; Kevin Talbot; Bryan J Traynor; Leonard H Van den Berg; Jan H Veldink; Steve Vucic; Matthew C Kiernan
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Lancet neurology     Volume:  12     ISSN:  1474-4465     ISO Abbreviation:  Lancet Neurol     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-18     Completed Date:  2013-04-18     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  101139309     Medline TA:  Lancet Neurol     Country:  England    
Other Details:
Languages:  eng     Pagination:  310-22     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Elsevier Ltd. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Amyotrophic Lateral Sclerosis* / etiology,  genetics,  physiopathology
Animals
Humans
Grant Support
ID/Acronym/Agency:
G0701923//Medical Research Council; Z01-AG000949-02/AG/NIA NIH HHS; //Medical Research Council

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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