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. 2019 Mar;90(3):268-271.
doi: 10.1136/jnnp-2018-319089. Epub 2018 Sep 30.

Younger age of onset in familial amyotrophic lateral sclerosis is a result of pathogenic gene variants, rather than ascertainment bias

Puja R Mehta  1   2 , Ashley R Jones  1 , Sarah Opie-Martin  1 , Aleksey Shatunov  1 , Alfredo Iacoangeli  1   3 , Ahmad Al Khleifat  1 , Bradley N Smith  1 , Simon Topp  1 , Karen E Morrison  4 , Pamela J Shaw  5 , Christopher E Shaw  2   6 , Sarah Morgan  7 , Alan Pittman  7 , Ammar Al-Chalabi  8   2
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Younger age of onset in familial amyotrophic lateral sclerosis is a result of pathogenic gene variants, rather than ascertainment bias

Puja R Mehta et al. J Neurol Neurosurg Psychiatry. 2019 Mar.

Abstract

Objective: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease of motor neurons with a median survival of 2 years. Familial ALS has a younger age of onset than apparently sporadic ALS. We sought to determine whether this younger age of onset is a result of ascertainment bias or has a genetic basis.

Methods: Samples from people with ALS were sequenced for 13 ALS genes. To determine the effect of genetic variation, age of onset was compared in people with sporadic ALS carrying a pathogenic gene variant and those who do not; to determine the effect of family history, we compared those with genetic sporadic ALS and familial ALS.

Results: There were 941 people with a diagnosis of ALS, 100 with familial ALS. Of 841 with apparently sporadic ALS, 95 carried a pathogenic gene variant. The mean age of onset in familial ALS was 5.3 years younger than for apparently sporadic ALS (p=6.0×10-5, 95% CI 2.8 to 7.8 years). The mean age of onset of genetic sporadic ALS was 2.9 years younger than non-genetic sporadic ALS (p=0.011, 95% CI 0.7 to 5.2 years). There was no difference between the mean age of onset in genetic sporadic ALS and familial ALS (p=0.097).

Conclusions: People with familial ALS have an age of onset about 5 years younger than those with apparently sporadic ALS, and we have shown that this is a result of Mendelian gene variants lowering the age of onset, rather than ascertainment bias.

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Conflict of interest statement

Competing interests: AA-C reports consultancies from Mitsubishi Tanabe Pharma, Chronos Therapeutics, Orion Pharma and Cytokinetics. AA-C was chief trial investigator for Orion Pharma (NCT02487407) and Cytokinetics (NCT02496767). All other authors declare no conflicts of interest.

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