2016
DOI: 10.1136/jnnp-2016-314093
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C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis

Abstract: IntroductionThe C9orf72 repeat expansion has been reported as a negative prognostic factor in amyotrophic lateral sclerosis (ALS). We have examined the prognostic impact of the C9orf72 repeat expansion in European subgroups based on gender and site of onset. Methods C9orf72 status and demographic/clinical data from 4925 patients with ALS drawn from 3 prospective ALS registers (Ireland, Italy and the Netherlands), and clinical data sets in the UK and Belgium. Flexible parametric survival models were built inclu… Show more

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Cited by 34 publications
(26 citation statements)
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“…For instance, disease phenotype is more penetrant and rapidly progressing in females in one transgenic line of C9orf72 mice (Liu et al, 2016). However, studies on C9orf72 patient cohorts report conflicting results, with women having either a better (Rooney et al, 2017;Trojsi et al, 2019) or a worse (Watanabe et al, 2015) survival time after onset. Likewise, the incidence of sporadic ALS, but not familial ALS, is higher in men than in women, but bulbar-onset ALS is more common in women and is associated with a poor prognosis (McCombe and Henderson, 2010;Kiernan et al, 2011).…”
Section: Discussionmentioning
confidence: 99%
“…For instance, disease phenotype is more penetrant and rapidly progressing in females in one transgenic line of C9orf72 mice (Liu et al, 2016). However, studies on C9orf72 patient cohorts report conflicting results, with women having either a better (Rooney et al, 2017;Trojsi et al, 2019) or a worse (Watanabe et al, 2015) survival time after onset. Likewise, the incidence of sporadic ALS, but not familial ALS, is higher in men than in women, but bulbar-onset ALS is more common in women and is associated with a poor prognosis (McCombe and Henderson, 2010;Kiernan et al, 2011).…”
Section: Discussionmentioning
confidence: 99%
“…Notably, we and others already evoked sex-mediated modifiers of C9ORF72 disease in FTD as well as in ALS. 11 , 20 , 21 Of interest, X-linked modifiers have also been recently suggested in other repeat expansion disorders such as spinocerebellar ataxia type 2 in which the residual heritability not explained by the expansion length seems to be partially driven by X-linked factors. 22 This may suggest common genetic mechanisms modulating AAO in repeat expansion diseases.…”
Section: Discussionmentioning
confidence: 99%
“…ALS shows sexual dimorphism in incidence, age of onset, and anatomical site of onset, with males usually having higher incidence, earlier age of onset, and presenting with spinal onset symptoms, as opposed to bulbar onset (McCombe & Henderson, ). While this evidence is largely based on cohorts of sporadic ALS patients, accounting for 90% of the disease, other evidence suggests a male predominance in familial ALS patients with SOD1 mutations (Kim et al, ) and C9orf72 repeat expansions (Rooney et al, ). Sex‐related effects are reproduced in the SOD1 G93A mouse model of ALS with males showing earlier disease onset with decreased survival, depending on the background strain (Pfohl, Halicek, & Mitchell, ).…”
Section: Introductionmentioning
confidence: 99%