TY - JOUR
T1 - Younger age of onset in familial amyotrophic lateral sclerosis is a result of pathogenic gene variants, rather than ascertainment bias
AU - Mehta, Puja R.
AU - Jones, Ashley R.
AU - Opie-Martin, Sarah
AU - Shatunov, Aleksey
AU - Iacoangeli, Alfredo
AU - Al Khleifat, Ahmad
AU - Smith, Bradley N.
AU - Topp, Simon
AU - Morrison, Karen E.
AU - Shaw, Pamela J.
AU - Shaw, Christopher E.
AU - Morgan, Sarah
AU - Pittman, Alan
AU - Al-Chalabi, Ammar
PY - 2018/9/30
Y1 - 2018/9/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85054246876&partnerID=8YFLogxK
U2 - 10.1136/jnnp-2018-319089
DO - 10.1136/jnnp-2018-319089
M3 - Article
AN - SCOPUS:85054246876
SN - 0022-3050
JO - Journal of Neurology, Neurosurgery and Psychiatry
JF - Journal of Neurology, Neurosurgery and Psychiatry
ER -