Identifying Environmental Risk Factors in ALS: Take Two?

Watch Your Six. The number of molecular events needed to trigger the onset of ALS is reduced in inherited forms of ALS compared to sporadic disease suggesting that the ALS develops through a multi-stage process that is both genetic and epigenetic in nature (Chiò et al, 2018). [Courtesy of Eisen et al., 2014, Journal of Neurology, Neurosurgery and Psychiatry. Reproduced with permission.]

A new approach may help identify risk factors for ALS according to a new study. The report, led by University of Torino’s Adriano Chiò in Italy, proposed that key environmental exposures and/or life choices that contribute to the onset of ALS may be easier to pinpoint by studying people with inherited forms of the disease.

The analysis, which evaluated the relationship between ALS incidence and age on the log scale, suggests that ALS develops in a 6-step process (see Armitage and Doll, 1954). And, inherited ALS-linked mutations explain at least some of these molecular events that lead to the disease. What’s more, only two additional steps may be needed to trigger the onset of SOD1 ALS suggesting that changes in the gene encoding this enzyme could account for most of the etiology underlying the disease.

Together, the results suggest that by focusing on people with specific inherited forms of ALS such as SOD1 ALS, scientists may be able to zero in on key environmental factors that contribute to the onset of the disease.

The study appeared on July 25 in Neurology.

The strategy is in contrast with existing approaches, which often explore the role of the environment and/or lifestyle in sporadic ALS. The approach builds on a previous analysis, led by Ammar Al-Chalabi at King’s College London in England, which suggests that ALS occurs due to a multi-stage process similar to many types of cancer (Al-Chalabi et al., 2014; see also Vogelstein and Kinzler, 1993).


Chiò A, Mazzini L, D’Alfonso S, Corrado L, Canosa A, Moglia C, Manera U, Bersano E, Brunetti M, Barberis M, Veldink JH, van den Berg LH, Pearce N, Sproviero W, McLaughlin R, Vajda A, Hardiman O, Rooney J, Mora G, Calvo A, Al-Chalabi A. The multistep hypothesis of ALS revisited: The role of genetic mutations. Neurology. 2018 Jul 25. pii: 10.1212/WNL.0000000000005996 [PubMed].

Al-Chalabi A, Calvo A, Chio A, Colville S, Ellis CM, Hardiman O, Heverin M, Howard RS, Huisman MHB, Keren N, Leigh PN, Mazzini L, Mora G, Orrell RW, Rooney J, Scott KM, Scotton WJ, Seelen M, Shaw CE, Sidle KS, Swingler R, Tsuda M, Veldink JH, Visser AE, van den Berg LH, Pearce N. Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. Lancet Neurol. 2014 Nov;13(11):1108-1113. [PubMed].

Armitage P, Doll R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer. 1954 Mar;8(1):1-12. [PubMed].

Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet. 1993 Apr;9(4):138-41. [PubMed].

Further Reading

Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol. 2013 Nov;9(11):617-28. [PubMed].

Eisen A, Kiernan M, Mitsumoto H, Swash M. Amyotrophic lateral sclerosis: a long preclinical period? J Neurol Neurosurg Psychiatry. 2014 Nov;85(11):1232-8. [PubMed].

Frank SA. Somatic evolutionary genomics: mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration. Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1725-30. [PubMed].



c9orf72 disease-als environment environmental factor SOD1 tdp-43 topic-genetics topic-riskfactors
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