Younger age of onset in familial amyotrophic lateral sclerosis is a result of pathogenic gene variants, rather than ascertainment bias
Younger age of onset in familial amyotrophic lateral sclerosis is a result of pathogenic gene variants, rather than ascertainment bias
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.
Journal Article
Mehta, Puja R.
2d2582c7-b064-4208-afce-81f599334e77
Jones, Ashley R.
4014edfb-94f8-4c42-aaf7-0a437e0182bf
Opie-Martin, Sarah
9030499e-3b21-45f6-bd50-43fdcc3d3059
Shatunov, Aleksey
e4422e0f-4878-404a-8e9e-fc45b4d5d9bd
Iacoangeli, Alfredo
50f630e7-cf3a-4040-9294-ab567fce82d7
Al Khleifat, Ahmad
36f3f499-11a5-4b0a-a617-23d44eab04e9
Smith, Bradley N.
d707ebcc-5728-47c9-a143-d6a5a2906055
Topp, Simon
87c7e700-3d61-445d-995c-32e756371526
Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Shaw, Pamela J.
3d0a5c6f-9610-45be-a0bc-5b6888003028
Shaw, Christopher E.
ad432fe6-4928-445b-a3e1-aaba83c6a530
Morgan, Sarah
2843f219-71cb-4748-bd79-6fa035330eac
Pittman, Alan
542e5159-e078-46f7-b126-cce2b8d3b47a
Al-Chalabi, Ammar
8ac40bc3-a3c0-47ad-afa7-37e08f7aab6f
Mehta, Puja R.
2d2582c7-b064-4208-afce-81f599334e77
Jones, Ashley R.
4014edfb-94f8-4c42-aaf7-0a437e0182bf
Opie-Martin, Sarah
9030499e-3b21-45f6-bd50-43fdcc3d3059
Shatunov, Aleksey
e4422e0f-4878-404a-8e9e-fc45b4d5d9bd
Iacoangeli, Alfredo
50f630e7-cf3a-4040-9294-ab567fce82d7
Al Khleifat, Ahmad
36f3f499-11a5-4b0a-a617-23d44eab04e9
Smith, Bradley N.
d707ebcc-5728-47c9-a143-d6a5a2906055
Topp, Simon
87c7e700-3d61-445d-995c-32e756371526
Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Shaw, Pamela J.
3d0a5c6f-9610-45be-a0bc-5b6888003028
Shaw, Christopher E.
ad432fe6-4928-445b-a3e1-aaba83c6a530
Morgan, Sarah
2843f219-71cb-4748-bd79-6fa035330eac
Pittman, Alan
542e5159-e078-46f7-b126-cce2b8d3b47a
Al-Chalabi, Ammar
8ac40bc3-a3c0-47ad-afa7-37e08f7aab6f
Mehta, Puja R., Jones, Ashley R., Opie-Martin, Sarah, Shatunov, Aleksey, Iacoangeli, Alfredo, Al Khleifat, Ahmad, Smith, Bradley N., Topp, Simon, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., Morgan, Sarah, Pittman, Alan and Al-Chalabi, Ammar
(2018)
Younger age of onset in familial amyotrophic lateral sclerosis is a result of pathogenic gene variants, rather than ascertainment bias.
Journal of Neurology Neurosurgery and Psychiatry.
(doi:10.1136/jnnp-2018-319089).
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.
Text
jnnp-2018-319089.full
- Version of Record
More information
Accepted/In Press date: 18 August 2018
e-pub ahead of print date: 30 September 2018
Keywords:
Journal Article
Identifiers
Local EPrints ID: 425090
URI: http://eprints.soton.ac.uk/id/eprint/425090
ISSN: 0022-3050
PURE UUID: c5c10881-57ab-4f4f-a06a-27dc8c7e8f1e
Catalogue record
Date deposited: 10 Oct 2018 16:30
Last modified: 15 Mar 2024 22:02
Export record
Altmetrics
Contributors
Author:
Puja R. Mehta
Author:
Ashley R. Jones
Author:
Sarah Opie-Martin
Author:
Aleksey Shatunov
Author:
Alfredo Iacoangeli
Author:
Ahmad Al Khleifat
Author:
Bradley N. Smith
Author:
Simon Topp
Author:
Karen E. Morrison
Author:
Pamela J. Shaw
Author:
Christopher E. Shaw
Author:
Sarah Morgan
Author:
Alan Pittman
Author:
Ammar Al-Chalabi
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics