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

Mehta, PR; Jones, AR; Opie-Martin, S; Shatunov, A; Iacoangeli, A; Al Khleifat, A; Smith, BN; Topp, S; Morrison, KE; Shaw, PJ; et al. Mehta, PR; Jones, AR; Opie-Martin, S; Shatunov, A; Iacoangeli, A; Al Khleifat, A; Smith, BN; Topp, S; Morrison, KE; Shaw, PJ; Shaw, CE; Morgan, S; Pittman, A; Al-Chalabi, A (2019) Younger age of onset in familial amyotrophic lateral sclerosis is a result of pathogenic gene variants, rather than ascertainment bias. J Neurol Neurosurg Psychiatry, 90 (3). pp. 268-271. ISSN 1468-330X https://doi.org/10.1136/jnnp-2018-319089
SGUL Authors: Pittman, Alan Michael

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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.

Item Type: Article
Additional Information: © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: http://creativecommons.org/licenses/by/4.0/
Keywords: 11 Medical And Health Sciences, 17 Psychology And Cognitive Sciences, Neurology & Neurosurgery
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: J Neurol Neurosurg Psychiatry
ISSN: 1468-330X
Language: eng
Dates:
DateEvent
14 February 2019Published
30 September 2018Published Online
18 August 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
MR/L501529/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/R024804/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
ES/L008238/1Economic and Social Research Councilhttp://dx.doi.org/10.13039/501100000269
PubMed ID: 30270202
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110282
Publisher's version: https://doi.org/10.1136/jnnp-2018-319089

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