Abstract
Introduction: The C9orf72 hexanucleotide repeat expansion is causal in amyotrophic lateral sclerosis (ALS) and has a negative effect on prognosis. The C9orf72 repeat expansion has been associated with an accelerated deterioration of respiratory function and survival in a cohort of 372 Portuguese patients. Methods: Cases presenting to the Irish ALS clinic with both longitudinal occluded sniff nasal inspiratory pressure (SNIP) and C9orf72 testing were including in the study. Clinical variables and survival characteristics of these patients were collected. Joint longitudinal and time to event models were constructed to explore the longitudinal characteristics of the cohort by C9orf72 status. Results: In total, 630 cases were included, of which 58 (9.2%) carried the C9orf72 repeat expansion. Plots of the longitudinal trend after joint modelling revealed that those carrying the expansion had worse respiratory function throughout the course of their disease than those without. The ALS Functional Rating Scale-revised (ALSFRS-R) respiratory sub-score did not distinguish C9orf72 normal from expanded cases. Furthermore, modelling by site of onset and gender sub-groups revealed that this difference was greatest in male spinal onset cases. Joint models further indicated that occluded SNIP values were of prognostic importance. Conclusions: Our results confirm findings from Portugal that the C9orf72 repeat expansion is associated with accelerated respiratory function decline. Analysis via joint models indicate that respiratory function is of prognostic importance and may explain previous observations of poorer prognosis in male spinal onset patients carrying the C9orf72 expansion.
Highlights
The C9orf72 hexanucleotide repeat expansion is causal in amyotrophic lateral sclerosis (ALS) and has a negative effect on prognosis
The C9orf72 hexanucleotide repeat expansion has been causally linked to amyotrophic lateral sclerosis (ALS)1,2 and frontotemporal dementia (FTD)3
Comparison via likelihood ratio test of initial linear mixed models of C9orf72 status versus time indicated that inclusion of spline terms improved fit (p < 0.001)
Summary
The C9orf hexanucleotide repeat expansion is causal in amyotrophic lateral sclerosis (ALS) and has a negative effect on prognosis. Analysis via joint models indicate that respiratory function is of prognostic importance and may explain previous observations of poorer prognosis in male spinal onset patients carrying the C9orf expansion. The C9orf expansion accounts for up to 10% of those with ALS and 25% of FTD in populations of northern European extraction4 It is associated with a number of distinctive features clinically, namely, earlier disease onset, cognitive and behavioural impairment, distinct neuroimaging changes, family history of neurodegeneration, and decreased survival relative to patients lacking the C9orf expansion. In 2016 we observed across five European cohorts that the negative prognosis associated with carriage of the C9orf expansion is most pronounced in male patients with spinal onset ALS13. We have characterised the longitudinal respiratory decline of 797 ALS and 39 primary lateral sclerosis (PLS) patients from Ireland using the occluded sniff nasal inspiratory pressure (SNIP) respiratory strength measure. The SNIP is a widely used tool that correlates well with diaphragmatic strength and is considered reliable and reproducible in ALS patients
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