Controversies and priorities in amyotrophic lateral sclerosis

Martin R. Turner, Orla Hardiman, Michael G 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

Research output: Contribution to journalArticle

293 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)310-322
Number of pages13
JournalThe Lancet Neurology
Volume12
Issue number3
DOIs
StatePublished - Mar 1 2013

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Amyotrophic Lateral Sclerosis
Genetic Phenomena
Ubiquitinated Proteins
Genes
Genetic Heterogeneity
Penetrance
Age Factors
Inclusion Bodies
Motor Neurons
Vulnerable Populations
Mutation

ASJC Scopus subject areas

  • Clinical Neurology
  • Medicine(all)

Cite this

Turner, M. R., Hardiman, O., Benatar, M. G., Brooks, B. R., Chio, A., De Carvalho, M., ... Kiernan, M. C. (2013). Controversies and priorities in amyotrophic lateral sclerosis. The Lancet Neurology, 12(3), 310-322. https://doi.org/10.1016/S1474-4422(13)70036-X

Controversies and priorities in amyotrophic lateral sclerosis. / Turner, Martin R.; Hardiman, Orla; Benatar, Michael G; Brooks, Benjamin R.; Chio, Adriano; De Carvalho, Mamede; Ince, Paul G.; Lin, Cindy; Miller, Robert G.; Mitsumoto, Hiroshi; Nicholson, Garth; Ravits, John; Shaw, Pamela J.; Swash, Michael; Talbot, Kevin; Traynor, Bryan J.; Van Den Berg, Leonard H.; Veldink, Jan H.; Vucic, Steve; Kiernan, Matthew C.

In: The Lancet Neurology, Vol. 12, No. 3, 01.03.2013, p. 310-322.

Research output: Contribution to journalArticle

Turner, MR, Hardiman, O, Benatar, MG, Brooks, BR, Chio, A, De Carvalho, M, Ince, PG, Lin, C, Miller, RG, Mitsumoto, H, Nicholson, G, Ravits, J, Shaw, PJ, Swash, M, Talbot, K, Traynor, BJ, Van Den Berg, LH, Veldink, JH, Vucic, S & Kiernan, MC 2013, 'Controversies and priorities in amyotrophic lateral sclerosis', The Lancet Neurology, vol. 12, no. 3, pp. 310-322. https://doi.org/10.1016/S1474-4422(13)70036-X
Turner MR, Hardiman O, Benatar MG, Brooks BR, Chio A, De Carvalho M et al. Controversies and priorities in amyotrophic lateral sclerosis. The Lancet Neurology. 2013 Mar 1;12(3):310-322. https://doi.org/10.1016/S1474-4422(13)70036-X
Turner, Martin R. ; Hardiman, Orla ; Benatar, Michael G ; Brooks, Benjamin R. ; Chio, Adriano ; De Carvalho, Mamede ; Ince, Paul G. ; Lin, Cindy ; Miller, Robert G. ; Mitsumoto, Hiroshi ; Nicholson, Garth ; Ravits, John ; Shaw, Pamela J. ; Swash, Michael ; Talbot, Kevin ; Traynor, Bryan J. ; Van Den Berg, Leonard H. ; Veldink, Jan H. ; Vucic, Steve ; Kiernan, Matthew C. / Controversies and priorities in amyotrophic lateral sclerosis. In: The Lancet Neurology. 2013 ; Vol. 12, No. 3. pp. 310-322.
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