Mandrioli J, Zucchi E, Martinelli I, Van der Most L, Gianferrari G, Moglia C, Manera U, Solero L, Vasta R, Canosa A, Grassano M, Brunetti M, Mazzini L, De Marchi F, Simonini C, Fini N, Tupler R, Vinceti M, Chiò A, Calvo A
J Neurol. 2022 Oct 25. doi: 10.1007/s00415-022-11426-y
Abstract
Objective: To unveil clinical features, comorbidities, disease progression and prognostic factors in a population-based cohort of ALS patients carrying C9ORF72 expansion (C9 + ALS).
Methods: This is a retrospective observational study on ALS patients residing in Emilia Romagna and Piedmont-Valle D’Aosta regions whose data are available through population based registers. We analysed patients who underwent genetic testing, focusing on C9 + ALS subgroup.
Results: Among 2204 genotyped patients of the two registers, 150 were C9 + ALS. In comparison with patients without mutation, a higher proportion of family history (12.85 vs 68%, p < 0.001) and frontotemporal dementia (3.93% vs 10.67%, p < 0.001) was detected in C9 + ALS. C9 + ALS presented a faster disease progression as measured by monthly decline in ALS Functional Rating Scale-Revised (1.86 ± 3.30 vs 1.45 ± 2.35, p < 0.01) and in forced vital capacity (5.90 ± 5.24 vs 2.97 ± 3.47, p < 0.01), a shorter diagnostic delay (8.93 ± 6.74 vs 12.68 ± 12.86 months, p < 0.01) and earlier onset (58.91 ± 9.02 vs 65.04 ± 11.55 years, p < 0.01). Consistently, they reached death or tracheostomy earlier than other patients (31 vs 37 months, HR = 1.52, 95% C.I. 1.27-1.82, p < 0.001). With respect to other genotyped patients, C9 + ALS patients did not present a significantly higher prevalence of concomitant diseases. Independent prognostic factors of survival of C9 + ALS included sex, age, progression rate, presence of frontotemporal dementia and thyroid disorders, with the latter being associated with prolonged ALS survival (43 vs 29 months, HR = 0.42, 95% C.I. 0.24-0.74, p = 0.003).
Conclusion: Even in the context of a more aggressive disease, C9 + ALS had a longer survival in presence of thyroid disorders. This finding may suggest protective pathogenic pathways in C9 + ALS to be explored, looking for therapeutic strategies to slow disease course.
Keywords: Amyotrophic lateral sclerosis; C9ORF72; Population-based register; Prognostic factor; Survival; Thyroid disorders.