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Meta-Analysis
. 2025 Jun 27;26(13):6199.
doi: 10.3390/ijms26136199.

The Differential Effects of Genetic Mutations in ALS and FTD Genes on Behavioural and Cognitive Changes: A Systematic Review and Meta-Analysis

Ana Maria Jiménez-García  1 , Maria Eduarda Tortorella  2 , Agnes Lumi Nishimura  2   3 , Natalia Arias  1   4   5
Affiliations
Meta-Analysis

The Differential Effects of Genetic Mutations in ALS and FTD Genes on Behavioural and Cognitive Changes: A Systematic Review and Meta-Analysis

Ana Maria Jiménez-García et al. Int J Mol Sci. .

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are linked by shared genetic mutations and overlapping clinical features, forming a clinical spectrum. This systematic review and meta-analysis analysed 97 studies, including 3212 patients with key ALS/FTD gene mutations, to identify gene-specific behavioural profiles. Chromosome 9 open reading frame 72 (C9orf72) mutations were strongly associated with psychotic symptoms and aggression, while superoxide dismutase 1 (SOD1) mutations had minimal cognitive effects. Progranulin (PGRN) mutations correlated with apathy and hallucinations, microtubule-associated protein tau (MAPT) mutations with disinhibition, and charged multivesicular body protein 2B (CHMP2B) with social impairments. Fused in sarcoma (FUS) mutations caused early sleep disturbances, TANK-binding kinase 1 (TBK1) led to disinhibition, and presenilin 1 and 2 (PSEN1/2) was linked to severe aggression. Prodromal cognitive changes in PGRN, MAPT, and CHMP2B mutations suggested early disease onset. Despite overlapping symptoms and clinical heterogeneity, understanding gene-specific patterns could inform tailored care strategies to enhance the quality of life for ALS and FTD patients. This study calls for refined guidelines integrating genetic behavioural profiles to improve patient and family support.

Keywords: C9orf72seq; MAPT; PGRN; amyotrophic lateral sclerosis (ALS); behavioural symptoms; cognitive impairment; frontotemporal dementia (FTD); genetic mutations.

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Conflict of interest statement

Author N.A. was employed by the company INEUROPA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Flowchart of the literature search according to Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). ALS—Amyotrophic Lateral Sclerosis, FTD—Frontotemporal Dementia.
Figure 2
Figure 2
Meta-analysis using a random effects model of selected studies relating to visuospatial memory assessed with the Benson Recall in all patients (p = 0.0018) (A) and only the MAPT mutation patients (p = 0.37) (B) [21,56,64]. The plot shows the effect estimates and corresponding confidence intervals (CIs) for each study included in the meta-analysis. The relative weight or contribution of each study to the overall effect estimate is also included in percentages. The overall weighted effect is indicated by a diamond at the bottom of the figure. The labels “1”, “2”, and “3” indicate the genetic groups included in the analysis: 1 = C9orf72 mutation carriers; 2 = GRN mutation carriers; 3 = MAPT mutation carriers The figure was generated with R software version 4.3.1.
Figure 3
Figure 3
Meta-analysis using a random effects model of selected studies relating to semantic fluency assessed with the “animals in 1 min” in all patients (p < 0.0001) (A), only the GRN mutation patients (p = 0.13) (B), and only the MAPT mutation patients (p = 0.14) (C) [21,64,82]. The plot shows the effect estimates and corresponding confidence intervals (CIs) for each study included in the meta-analysis. The relative weight or contribution of each study to the overall effect estimate is also included in percentages. The overall weighted effect is indicated by a diamond at the bottom of the figure. The labels “1”, “2”, and “3” indicate the genetic groups included in the analysis: 1 = C9orf72 mutation carriers; 2 = GRN mutation carriers; 3 = MAPT mutation carriers. The figure was generated with R software version 4.3.1.
See this image and copyright information in PMC

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