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The real onset of amyotrophic lateral sclerosis
  1. Andrew Eisen
  1. Correspondence to Professor A Eisen, University of British Columbia, 2862 Highbury Street, Vancouver, BC, Canada, USA; eisen{at}

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A biomarker that has generated considerable interest is digit ratio, the ratio of the second (index) finger to the fourth (ring) finger, 2D:4D. Men have a longer fourth digit relative to the second digit than do women, and the ratio is lower in boys and men than in girls and women.1 A reduced 2D:4D ratio is assumed to indicate reduced prenatal androgen exposure or sensitivity and high prenatal testosterone levels.

Vivekananda and colleagues2 describe how they used 2D:4D as a surrogate for prenatal testosterone levels, hypothesising that reduced exposure is a risk factor for amyotrophic lateral sclerosis (ALS) in later life (see page 635). Nevertheless, there remains a compelling need for additional evidence directly examining the link between prenatal androgen exposure and digit ratio.1

ALS is regarded as a neurodegeneration of the ageing nervous system with symptom onset in mid to later life.3 The intriguing aspect raised by Vivekananda et al is that ALS is subject to prenatal risk factors. In other words, the seeds for ALS are sewn decades before symptoms develop.

It is well established that there is a lengthy preclinical period in both Alzheimer's and Parkinson's diseases, amounting to years or decades. In contrast, little attention has been given to presymptomatic ALS or when ALS really begins, and it is generally assumed that ALS onset is coincident with, or starts shortly before, clinical onset. Support of this is the frequently quoted loss of motor unit number estimates preceding clinical deficits, by only a few weeks, in asymptomatic heterozygotes with superoxide dismutase mutations.4 However, loss of motor units determined by motor unit number estimates or EMG abnormalities gives no information on cellular dysfunction at a molecular level, insufficient to cause clinical features, but potentially present for years or decades prior to disease onset. Furthermore, these studies give no information about of the influence of descending motor pathways.

It has also been suggested that ALS results from early life developmental somatic mutations.5 A continuum of risk is predicted. Those who inherit a predisposing mutation have the highest risk and earliest disease onset and those with very few mutations have such low risk as to escape the disease. Epigenetics may constitute the missing link in the interplay between genes and environment, although the understanding of how epigenetic modulation occurs during the neurodegenerative process is still in the early stages.6

Rethinking the onset of ALS would have major therapeutic implications. A lengthy presymptomatic period in ALS opens a window of opportunity to rescue dysfunctional cells not yet dead. This will of course require identification of good biomarkers.


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  • Linked article 237412.

  • Competing interests None.

  • Provenance and peer review Commissioned; not externally peer reviewed.

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