Published in:Journal of Neurology, Neurosurgery & Psychiatry
Language:
English
DOI:
10.1136/jnnp-2018-319089
ISSN:
0022-3050;
1468-330X
Origination:
Footnote:
Description:
<jats:sec><jats:title>Objective</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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<jats:sup>−5</jats:sup>, 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).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec>