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Factors predicting disease progression in C9ORF72 ALS patients

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

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.

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Data availability

Data are available from the authors upon reasonable request.

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Acknowledgements

The authors thank all the ERRALS and all the PARALS members.

Funding

The Emilia Romagna Registry for ALS (ERRALS) is supported by a Grant from the Emilia Romagna Regional Health Authority. This work was in part supported by the Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata, grant RF-2016-02,362,405), the European Commission’s Health Seventh Framework Programme (FP7/2007–2013 under grant agreement 259,867), the Italian Ministry of Education, University and Research (Progetti di Ricerca di Rilevante Interesse Nazionale, PRIN, grant 2017SNW5MB), the Joint Programme—Neurodegenerative Disease Research (ALS-Care, Strength and Brain-Mend projects), granted by the Italian Ministry of Education, University and Research, the Horizon 2020 Programme (project Brainteaser under grant agreement 101,017,598). This study was performed under the Department of Excellence grant of the Italian Ministry of Education, University and Research to the ‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, Italy and to the AGING Project for Department of Excellence at the Department of Translational Medicine (DIMET), Università del Piemonte Orientale, Novara,. Italy.

Author information

Author notes

  1. Jessica Mandrioli, Elisabetta Zucchi, Adriano Chiò and Andrea Calvo contributed equally to the work.

Authors and Affiliations

  1. Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy

    Jessica Mandrioli, Elisabetta Zucchi, Laura Van der Most, Giulia Gianferrari, Rossella Tupler & Marco Vinceti

  2. Department of Neurosciences, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy

    Jessica Mandrioli, Elisabetta Zucchi, Ilaria Martinelli, Laura Van der Most, Cecilia Simonini & Nicola Fini

  3. Clinical and Experimental Medicine Ph.D. Program, University of Modena and Reggio Emilia, Modena, Italy

    Ilaria Martinelli

  4. “Rita Levi Montalcini” Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy

    Cristina Moglia, Umberto Manera, Luca Solero, Rosario Vasta, Antonio Canosa, Maurizio Grassano, Adriano Chiò & Andrea Calvo

  5. SC Neurologia 1U, AOU Città della Salute e della Scienza of Torino, Turin, Italy

    Antonio Canosa, Maurizio Grassano, Maura Brunetti, Adriano Chiò & Andrea Calvo

  6. ALS Center, Neurology Unit, AOU Maggiore della Carità and University of Piemonte Orientale, Novara, Italy

    Letizia Mazzini & Fabiola De Marchi

  7. Department of Science of Public Health, Research Centre in Environmental, Genetic and Nutritional Epidemiology, University of Modena and Reggio Emilia, Modena, Italy

    Marco Vinceti

  8. Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA

    Marco Vinceti

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Contributions

Conception and design of the study: JM, EZ, IM, RT, MV, ACh, ACal. Acquisition and analysis of data: JM, EZ, IM, LVDM, GG, CM, UM, LS, RV, ACan, GM, MB, LM, FDM, CS, NF, VM. Drafting a significant portion of the manuscript or figures: JM, EZ, RT, ACh, ACal. Funding: JM, LM, ACh, Aca. All authors had access to all the study data and read, contributed to, reviewed and approved the submission of the manuscript for final publication.

Corresponding author

Correspondence to Jessica Mandrioli.

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Mandrioli, J., Zucchi, E., Martinelli, I. et al. Factors predicting disease progression in C9ORF72 ALS patients. J Neurol 270, 877–890 (2023). https://doi.org/10.1007/s00415-022-11426-y

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

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