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Original Investigation
November 18, 2019

Survival and Prognostic Factors in C9orf72 Repeat Expansion Carriers: A Systematic Review and Meta-analysis

Author Affiliations
  • 1College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom
  • 2Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
  • 3Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, United Kingdom
  • 4Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom
JAMA Neurol. 2020;77(3):367-376. doi:10.1001/jamaneurol.2019.3924
Key Points

Question  Which factors are associated with survival in patients with the c9orf72 repeat expansion (c9 or c9orf72RE) and amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), ALS-FTD, and atypical phenotypes?

Findings  In this meta-analysis of 1060 c9orf72RE carriers, older age at onset was associated with shorter survival in c9ALS, c9FTD, and c9ALS-FTD, and bulbar onset was associated with shorter survival in c9ALS. Survival in atypical phenotypes was highly variable.

Meaning  Characteristic clinical features influence survival in patients with disease-causing c9orf72RE; these could be considered for care planning of affected individuals, genetic counseling of potential c9orf72RE carriers, and trial design.


Importance  The c9orf72 repeat expansion (c9 or c9orf72RE) confers a survival disadvantage in amyotrophic lateral sclerosis (ALS); its effect on prognosis in frontotemporal dementia (FTD) remains uncertain. Data on prognostic factors in c9orf72RE disorders could inform patient care, genetic counseling, and trial design.

Objective  To examine prognostic factors in c9ALS, c9FTD, c9ALS-FTD, and atypical phenotypes.

Data Sources  The MEDLINE, Embase, Amed, ProQuest, PsychINFO, CINAHL, and LILACS databases were searched between January 2011 and January 2019. Keywords used were c9orf72 and chromosome 9 open reading frame 72. Reference lists, citations of eligible studies, and review articles were also searched by hand.

Study Selection  Studies reporting disease duration for patients with a confirmed c9orf72RE and a neurological and/or psychiatric disorder were included. A second author independently reviewed studies classified as irrelevant by the first author. Analysis began in January 2019.

Data Extraction and Synthesis  Data were extracted by 1 author; a further author independently extracted 10% of data. Data were synthesized in univariate and multivariable Cox regression and are displayed as hazard ratios (HR) and 95% confidence intervals.

Main Outcomes and Measures  Survival after symptom onset.

Results  Overall, 206 studies reporting on 1060 patients were included from 2878 publications identified (c9ALS: n = 455; c9FTD: n = 296; c9ALS-FTD: n = 198; atypical phenotypes: n = 111); 197 duplicate cases were excluded. The median (95% CI) survival (in years) differed significantly between patients with c9ALS (2.8 [2.67-3.00]), c9FTD (9.0 [8.09-9.91]), and c9ALS-FTD (3.0 [2.73-3.27]); survival in atypical phenotypes varied substantially. Older age at onset was associated with shorter survival in c9ALS (HR, 1.03; 95% CI, 1.02-1.04; P < .001), c9FTD (HR, 1.04; 95% CI, 1.02-1.06; P < .001), and c9ALS-FTD (HR, 1.02; 95% CI, 1.004-1.04; P = .016). Bulbar onset was associated with shorter survival in c9ALS (HR, 1.64; 95% CI, 1.27-2.08; P < .001). Age at onset and bulbar onset ALS remained significant in multivariable regression including variables indicating potential diagnostic ascertainment bias, selection bias, and reporting bias. Family history, sex, study continent, FTD subtype, or the presence of additional pathogenic sequence variants were not significantly associated with survival. Clinical phenotypes in patients with neuropathologically confirmed frontotemporal lobar degeneration–TDP-43, motor neuron disease–TDP-43 and frontotemporal lobar degeneration–motor neuron disease–TDP-43 were heterogenous and impacted on survival.

Conclusions and Relevance  Several factors associated with survival in c9orf72RE disorders were identified. The inherent limitations of our methodological approach must be considered; nonetheless, the reported prognostic factors were not significantly associated with the bias indicators examined.

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