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Amyotrophic lateral sclerosis: a long preclinical period?
  1. Andrew Eisen1,
  2. Matthew Kiernan2,
  3. Hiroshi Mitsumoto3,
  4. Michael Swash4,5
  1. 1Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada
  2. 2Bushell Chair of Neurology, University of Sydney, Australia
  3. 3Wesley J. Howe Professor of Neurology at CUMC, Eleanor and Lou Gehrig MDA/ALS Research Center, The Neurological Institute of New York, Columbia University Medical Center, New York, USA
  4. 4Queen Mary University of London, UK
  5. 5Institute of Neuroscience, University of Lisbon, Portugal
  1. Correspondence to Dr Andrew Eisen, Department of Neurology, University of British Columbia, 2862 Highbury Street, Vancouver, B.C. V6R 3T6, Canada; eisen{at}


The onset of amyotrophic lateral sclerosis (ALS) is conventionally considered as commencing with the recognition of clinical symptoms. We propose that, in common with other neurodegenerations, the pathogenic mechanisms culminating in ALS phenotypes begin much earlier in life. Animal models of genetically determined ALS exhibit pathological abnormalities long predating clinical deficits. The overt clinical ALS phenotype may develop when safety margins are exceeded subsequent to years of mitochondrial dysfunction, neuroinflammation or an imbalanced environment of excitation and inhibition in the neuropil. Somatic mutations, the epigenome and external environmental influences may interact to trigger a metabolic cascade that in the adult eventually exceeds functional threshold. A long preclinical and subsequent presymptomatic period pose a challenge for recognition, since it offers an opportunity for protective and perhaps even preventive therapeutic intervention to rescue dysfunctional neurons. We suggest, by analogy with other neurodegenerations and from SOD1 ALS mouse studies, that vulnerability might be induced in the perinatal period.

  • ALS
  • Neurotoxicology
  • Neuroepidemiology
  • Motor Neuron Disease
  • Molecular Biology

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