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Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of C9ORF72
  1. Azza Ismail1,3,
  2. Johnathan Cooper-Knock1,3,
  3. J Robin Highley1,
  4. Antonio Milano7,
  5. Janine Kirby1,
  6. Emily Goodall1,
  7. James Lowe5,
  8. Ian Scott5,
  9. Cris S Constantinescu4,
  10. Stephen J Walters2,
  11. Sian Price3,
  12. Christopher J McDermott1,3,
  13. Stephen Sawcer6,
  14. D Alastair S Compston6,
  15. Basil Sharrack1,3,
  16. Pamela J Shaw1,3
  1. 1Academic Neurology Unit and Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK
  2. 2School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
  3. 3Department of Neurology, Academic Directorate of Neuroscience, Royal Hallamshire Hospital, Sheffield, UK
  4. 4Department of Neurology, University of Nottingham and Queen's Medical Centre, Nottingham, UK
  5. 5Department of Neuropathology, University of Nottingham and Queen's Medical Centre, Nottingham, UK
  6. 6Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
  7. 7Sheffield Diagnostic Genetic Service, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield,UK
  1. Correspondence to Professor Pamela J Shaw, Academic Neurology Unit, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK;{at}


Background Crossover in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) has been described but is poorly understood. A GGGGCC hexanucleotide repeat expansion of C9ORF72 has recently been identified in a significant proportion of patients with ALS.

Methods In approximately 650 patients diagnosed with ALS from the North of England we identified seven patients who initially presented with MS. DNA obtained from five patients with MS-ALS and 215 patients with MS alone was screened for the C9ORF72 expansion. Post-mortem material was examined from two patients with MS-ALS. Gene expression profiling was performed on lymphoblastoid cells and levels of CXCL10 were measured in cerebrospinal fluid (CSF) from patients with ALS with and without the C9ORF72 expansion and controls.

Results Concurrence of MS and ALS is higher than expected in our population. The C9ORF72 expansion was identified in 80% of patients with MS-ALS but not in those with MS alone. In the presence of preceding MS, C9ORF72-ALS was more rapidly progressive. MetaCore analysis identified alteration of the NF-кB pathway in C9ORF72-ALS and non-C9ORF72-ALS. NF-кB activation is associated with increased expression of the neuroprotective cytokine CXCL10 but, in C9ORF72-ALS, CXCL10 is downregulated and CSF levels are reduced.

Conclusions We propose that MS-associated neuroinflammation may affect penetrance and progression of the C9ORF72 expansion. In particular, the NF-кB pathway is activated in MS and appears to be dysfunctional in C9ORF72-ALS. Aberrant downregulation of CXCL10 may explain the predisposition of C9ORF72 expansion carriers to develop ALS in the context of MS and NF-кB activation, and offers a potential therapeutic target.

  • Motor Neuron Disease
  • Multiple Sclerosis
  • Genetics
  • Neuroimmunology
  • Neurogenetics

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