Factors predicting disease progression in C9ORF72 ALS patients.

Jessica Mandrioli, Elisabetta Zucchi, Ilaria Martinelli, Laura Van der Most, Giulia Gianferrari, Cristina Moglia, Umberto Manera, Luca Solero, Rosario Vasta, Antonio Canosa, Maurizio Grassano, Maura Brunetti, Letizia Mazzini, Fabiola De Marchi, Cecilia Simonini, Nicola Fini, Rossella Tupler, Marco Vinceti, Adriano Chiò, Andrea Calvo

Journal: Journal of neurology 2023;270(2):877-890

PMID: 36280624

Full Text on Springer View on PubMed

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.

Address: Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. [email protected].; Department of Neurosciences, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy. [email protected].; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.; Department of Neurosciences, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy.; Department of Neurosciences, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy.; Clinical and Experimental Medicine Ph.D. Program, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.; "Rita Levi Montalcini" Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.; "Rita Levi Montalcini" Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.; SC Neurologia 1U, AOU Città della Salute e della Scienza of Torino, Turin, Italy.; SC Neurologia 1U, AOU Città della Salute e della Scienza of Torino, Turin, Italy.; ALS Center, Neurology Unit, AOU Maggiore della Carità and University of Piemonte Orientale, Novara, Italy.; Department of Neurosciences, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.; Department of Science of Public Health, Research Centre in Environmental, Genetic and Nutritional Epidemiology, University of Modena and Reggio Emilia, Modena, Italy.; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.

DOI: 10.1007/s00415-022-11426-y

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https://dx.doi.org/10.1007/s00415-022-11426-y

MeSH Terms: Humans, Amyotrophic Lateral Sclerosis, C9orf72 Protein, Delayed Diagnosis, Disease Progression, DNA Repeat Expansion, Frontotemporal Dementia