Identification of risk factors associated with onset and progression of amyotrophic lateral sclerosis using systematic review and meta-analysis

Neurotoxicology. 2017 Jul:61:101-130. doi: 10.1016/j.neuro.2016.06.015. Epub 2016 Jul 1.


Although amyotrophic lateral sclerosis (ALS) was identified as a neurological condition 150 years ago, risk factors related to the onset and progression of ALS remain largely unknown. Monogenic mutations in over 30 genes are associated with about 10% of ALS cases. The age at onset of ALS and disease types has been found to influence ALS progression. The present study was designed to identify additional putative risk factors associated with the onset and progression of ALS using systematic review and meta-analysis of observational studies. Risk factors that may be associated with ALS include: 1) genetic mutations, including the intermediate CAG repeat expansion in ATXN2; 2) previous exposure to heavy metals such as lead and mercury; 3) previous exposure to organic chemicals, such as pesticides and solvents; 4) history of electric shock; 5) history of physical trauma/injury (including head trauma/injury); 6) smoking (a weak risk factor for ALS in women); and 6) other risk factors, such as participating in professional sports, lower body mass index, lower educational attainment, or occupations requiring repetitive/strenuous work, military service, exposure to Beta-N-methylamino-l-alanin and viral infections. Risk factors that may be associated with ALS progression rate include: 1) nutritional status, including vitamin D deficiency; 2) comorbidities; 3) ethnicity and genetic factors; 4) lack of supportive care; and 4) smoking. The extent to which these associations may be causal is discussed, with further research recommended to strengthen the evidence on which determinations of causality may be based.

Keywords: Amyotrophic lateral sclerosis; Etiology; Meta-analysis; Onset; Progression; Risk factor; Systematic review.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Age of Onset
  • Amyotrophic Lateral Sclerosis / epidemiology*
  • Amyotrophic Lateral Sclerosis / etiology*
  • Amyotrophic Lateral Sclerosis / genetics
  • Databases, Bibliographic / statistics & numerical data
  • Disease Progression*
  • Environmental Exposure / adverse effects
  • Humans
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Nutritional Status
  • Pesticides / toxicity
  • Risk Factors
  • Vitamin D Deficiency / epidemiology


  • ATXN2L protein, human
  • Nerve Tissue Proteins
  • Pesticides