title: Controversies and priorities in amyotrophic lateral sclerosis.
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.
authors: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors: Martin R
authors: MR
authors: Turner
authors: Orla
authors: O
authors: Hardiman
authors: Michael
authors: M
authors: Benatar
authors: Benjamin R
authors: BR
authors: Brooks
authors: Adriano
authors: A
authors: Chio
authors: Mamede
authors: M
authors: de Carvalho
authors: Paul G
authors: PG
authors: Ince
authors: Cindy
authors: C
authors: Lin
authors: Robert G
authors: RG
authors: Miller
authors: Hiroshi
authors: H
authors: Mitsumoto
authors: Garth
authors: G
authors: Nicholson
authors: John
authors: J
authors: Ravits
authors: Pamela J
authors: PJ
authors: Shaw
authors: Michael
authors: M
authors: Swash
authors: Kevin
authors: K
authors: Talbot
authors: Bryan J
authors: BJ
authors: Traynor
authors: Leonard H
authors: LH
authors: Van den Berg
authors: Jan H
authors: JH
authors: Veldink
authors: Steve
authors: S
authors: Vucic
authors: Matthew C
authors: MC
authors: Kiernan
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D006801:Humans