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C9orf72 expansion is associated with accelerated decline of respiratory function and decreased survival in amyotrophic lateral sclerosis
  1. Gabriel Miltenberger-Miltenyi1,
  2. Vasco A Conceição1,
  3. Marta Gromicho1,
  4. Ana Catarina Pronto-Laborinho1,
  5. Susana Pinto1,
  6. Peter M Andersen2,
  7. Mamede de Carvalho1,3
  1. 1 Physiology Institute, Faculty of Medicine, Instituto de Medicina Molecular, University of Lisbon, Lisbon, Portugal
  2. 2 Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden
  3. 3 Department of Neurosciences and Mental Health, Hospital de Santa Maria-CHLN, Lisbon, Portugal
  1. Correspondence to Dr. Gabriel Miltenberger-Miltenyi, Physiology Institute, Faculty of Medicine, Instituto de Medicina Molecular, University of Lisbon, 1648-028 Lisbon, Portugal; gmiltenyi{at}

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with short survival, mainly due to respiratory failure.1 2 A pathological repeat expansion in the C9orf72 gene is observed in about 10% of the European ALS population and is associated with a worse prognosis.2 3 Still, the exact function of this gene is unknown.

To understand the role of the C9orf72 expansion in disease prognosis, we tested the impact of this mutation on the respiratory function in ALS.



We studied 372 consecutive patients with ALS (according to the revised El Escorial and Awaji criteria) followed in our centre between 2000 and 2017. No patient was on non-invasive ventilation (NIV) or gastrostomized at study entry. All patients were treated with riluzole.

Demographic and clinical data were collected and C9orf72 expansion was determined. Patients were evaluated at entry and, at least, at two subsequent time points over disease progression. Participants signed informed consents.

Baseline assessment

Patients were categorised regarding the absence (C9orf720) or presence (C9orf72exp) of the C9orf72 expansion. Diagnosis delay, region of onset, age at diagnosis, gender and comorbid frontotemporal dementia (FTD) were included as independent variables during regression analysis as these have been previously reported as prognostic factors in ALS.1–3 Given that patients with ALS predominantly have spinal and bulbar onset forms,1 2 coefficients for each of these were included in the regressions. Remaining onset forms (respiratory/axial, diffuse and combined) were clustered together.

First, we directly compared the mutated and non-mutated groups using Wilcoxon rank-sum and …

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