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Original research
Phenotypical differences of C9ORF72 gene-positive and negative amyotrophic lateral sclerosis: a comparative case series
  1. Laura Michelle White1,
  2. Jeremy Boardman2,
  3. James Lilleker1,3,
  4. Amina Chaouch1,
  5. Haga Kargwell1,
  6. John Ealing1,
  7. Hisham Hamdalla1
  1. 1 Manchester Centre for Clinical Neurosciences, Salford Royal Hospital, Salford, UK
  2. 2 Royal Preston Hospital, Preston, UK
  3. 3 Centre for Musculoskeletal Research, The University of Manchester School of Biological Sciences, Manchester, UK
  1. Correspondence to Dr Hisham Hamdalla, Manchester Centre for Clinical Neurosciences, Salford Royal Hospital, Salford, UK; Hisham.hamdalla{at}


Background Hexanucleotide repeat expansions of C9ORF72 account for a significant proportion of autosomal dominant neurodegenerative diseases in the amyotrophic lateral sclerosis (ALS)–frontotemporal dementia spectrum. In the absence of a family history, clinical identification of such patients remains difficult. We aimed to identify differences in demographics and clinical presentation between patients with C9ORF72 gene-positive ALS (C9pALS) versus C9ORF72 gene-negative ALS (C9nALS), to aid identification of these patients in the clinic and examine differences in outcomes including survival.

Methods We retrospectively reviewed the clinical presentations of 32 patients with C9pALS and compared their characteristics with a cohort of 46 patients with C9nALS from the same tertiary neurosciences centre.

Results Patients with C9pALS more commonly presented with mixed upper and lower motor signs (C9pALS 87.5%, C9nALS 65.2%; p=0.0352), but less frequently presented with purely upper motor neuron signs (C9pALS 3.1%, C9nALS 21.7%; p=0.0226). The C9pALS cohort had a higher frequency of cognitive impairment (C9pALS 31.3%, C9nALS 10.9%; p=0.0394) and bulbar disease (C9pALS 56.3%, C9nALS 28.3%; p=0.0186). There were no differences between cohorts in age at diagnosis, gender, limb weakness, respiratory symptoms, presentation with predominantly lower motor neuron signs or overall survival.

Discussion Analysis of this ALS clinic cohort at a UK tertiary neurosciences centre adds to the small but growing understanding of the unique clinical features of patients with C9pALS. In the age of precision medicine with expanding opportunities to manage genetic diseases with disease-modifying therapies, clinical identification of such patients is increasingly important as focused therapeutic strategies become available.

  • Motor Neuron Disease
  • Genetic Testing
  • Neurodegenerative Diseases
  • Dementia

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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  • Contributors JB and LMW drafted the manuscript and performed the data analyses. All authors contributed to the design of the study, editing of the manuscript and approval of the final version.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.