The C9orf72 expansion is associated with accelerated respiratory function decline in a large Amyotrophic Lateral Sclerosis cohort

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.

Cerebrospinal Fluid Neurofilament Light Chain (NfL) Predicts Disease Aggressiveness in Amyotrophic Lateral Sclerosis: An Application of the D50 Disease Progression Model

“…Given that CSF NfL levels are reported to be higher in patients with C9orf72 mutations ( Huang et al, 2020 ) and lower in those with SOD1 mutations ( Zetterberg et al, 2007 ), this may also represent a confounding factor. Further studies are needed to clarify if genotype-specific differences exist independent of disease aggressiveness, as, for example, C9orf72 expansion carriers are known to have a worse prognosis relative to patients with sporadic ALS or other familial mutations ( Miltenberger-Miltenyi et al, 2019 ; Rooney et al, 2019 ). The presence of clinically overt FTD was assessed, but this should be examined in more detail in future studies, as previous data have indicated links between cognitive deterioration and NfL levels ( Illán-Gala et al, 2018 ; Delaby et al, 2020 ).…”

Cognitive reserve in amyotrophic lateral sclerosis (ALS): a population-based longitudinal study

“…The time by CR interaction term represents 33 diagnostic delay, 34 site of onset 35 and C9orf72 repeat expansion status (see table 2). 36 The longitudinal mixed model and Cox survival models were then used to create joint longitudinal and time-to-event models (joint models), using the R package JMBayes. 37 This analysis enabled the model to control for non-random drop-out in our longitudinal data, resulting in less biased effect estimates.…”

Dynamic Bayesian networks for stratification of disease progression in amyotrophic lateral sclerosis

“…Indeed, age is not particularly relevant for patient stratification [25]. The genetic related variables (i.e., familial history of ALS and C9orf72 HRE) were also found to have minimal influence on all progressing groups, despite the association between C9orf72 HRE and accelerated respiratory function decline [26,27]. The time‐independent clinical variables gender, El Escorial criteria at diagnosis and region of onset have residual influence.…”