Tags

Type your tag names separated by a space and hit enter

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

Abstract

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.

Authors+Show Affiliations

College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom.Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom. Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, United Kingdom. Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom.College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom.Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom. Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, United Kingdom. Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31738367

Citation

Glasmacher, Stella A., et al. "Survival and Prognostic Factors in C9orf72 Repeat Expansion Carriers: a Systematic Review and Meta-analysis." JAMA Neurology, 2019.
Glasmacher SA, Wong C, Pearson IE, et al. Survival and Prognostic Factors in C9orf72 Repeat Expansion Carriers: A Systematic Review and Meta-analysis. JAMA Neurol. 2019.
Glasmacher, S. A., Wong, C., Pearson, I. E., & Pal, S. (2019). Survival and Prognostic Factors in C9orf72 Repeat Expansion Carriers: A Systematic Review and Meta-analysis. JAMA Neurology, doi:10.1001/jamaneurol.2019.3924.
Glasmacher SA, et al. Survival and Prognostic Factors in C9orf72 Repeat Expansion Carriers: a Systematic Review and Meta-analysis. JAMA Neurol. 2019 Nov 18; PubMed PMID: 31738367.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Survival and Prognostic Factors in C9orf72 Repeat Expansion Carriers: A Systematic Review and Meta-analysis. AU - Glasmacher,Stella A, AU - Wong,Charis, AU - Pearson,Iona E, AU - Pal,Suvankar, Y1 - 2019/11/18/ PY - 2020/11/18/pmc-release PY - 2019/11/19/entrez PY - 2019/11/19/pubmed PY - 2019/11/19/medline JF - JAMA neurology JO - JAMA Neurol N2 - 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. SN - 2168-6157 UR - https://www.unboundmedicine.com/medline/citation/31738367/Survival_and_Prognostic_Factors_in_C9orf72_Repeat_Expansion_Carriers:_A_Systematic_Review_and_Meta-analysis L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2019.3924 DB - PRIME DP - Unbound Medicine ER -