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BACKGROUND: The aetiology of apparently sporadic amyotrophic lateral sclerosis (ALS) is unknown, but prenatal factors are known to influence disease development. In both men and women, motor neurons require testosterone for survival and axonal regeneration after injury, and androgen insensitivity leads to a form of motor neuron degeneration in men. Reduction in the ratio of index to ring finger length (2D:4D ratio) is considered a surrogate marker for high prenatal testosterone levels in both men and women. The authors therefore tested the hypothesis that prenatal testosterone irrespective of gender is an independent risk factor for the development of ALS later in life, and that this would be reflected in a lower 2D:4D ratio in both men and women with ALS. METHODS: Patients and unrelated control individuals attending a specialist tertiary referral centre for ALS were studied. A digital camera was used to photograph hands. Finger lengths were measured by four independent scorers blind to case–control status, and the mean 2D:4D ratio derived. Analysis was by linear regression and receiver-operator-curve analysis. RESULTS: Controlling for differences in sex ratio between groups, the 2D:4D ratio was lower for people with ALS (n=47) than for controls (n=63) (r=–0.25, two-tailed p=0.009). CONCLUSIONS: Patients with ALS have a lower 2D:4D ratio, consistent with higher prenatal circulating levels of testosterone, and possibly a prenatal influence of testosterone on motor-neuron vulnerability in later life. [ABSTRACT FROM AUTHOR]