Pathologic expansion in the C9orf72 gene is associated with accelerated decline of respiratory function and decreased survival in amyotrophic lateral sclerosis

INTRODUCTION: Respiratory insufficiency is the main cause of death in amyotrophic lateral sclerosis (ALS). As the C9orf72 repeat expansion represents the most common genetic risk factor for this disease, we studied whether C9orf72 modulates respiratory function and survival. METHODS: Demographic and clinical data, and C9orf72 status were collected from 372 ALS patients followed in our centre. Multiple regressions controlling for the C9orf72 expansion, diagnosis delay, region of onset, age, gender, and comorbid frontotemporal dementia were performed to evaluate the functional and respiratory status of the patients at baseline and during disease progression – assessed using the global ALSFRS-R score and its respiratory subscore, and the predicted forced vital capacity (%FVC). A Cox regression controlling for the same variables was carried out to analyse survival. RESULTS: At baseline, 32/372 (8.60%) patients carried the C9orf72 repeat expansion. We found that the C9orf72 mutation is an independent risk factor for a faster %FVC decline (p = .001) and shorter survival (p = .002). CONCLUSIONS: In ALS patients with C9orf72 expansion, shorter survival probably derives from faster respiratory function decline. This finding may indicate a new pathogenic mechanism of C9orf72 in ALS.