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Original research
Amyotrophic lateral sclerosis patients with various gene mutations show diverse motor phenotypes and survival in China
  1. Qirui Jiang1,
  2. Junyu Lin1,
  3. Qianqian Wei1,
  4. Tianmi Yang1,
  5. Yanbing Hou1,
  6. Lingyu Zhang1,
  7. Ruwei Ou2,
  8. Yi Xiao1,
  9. Shichan Wang1,
  10. Xiaoting Zheng1,
  11. Chunyu Li1,
  12. Huifang Shang1
  1. 1Department of Neurology, Sichuan University West China Hospital, Chengdu, Sichuan, China
  2. 2Sichuan University West China Hospital, Chengdu, Sichuan, China
  1. Correspondence to Professor Huifang Shang, Department of Neurology, Sichuan University West China Hospital, Chengdu, Sichuan, China; hfshang2002{at}126.com; Dr Chunyu Li, Department of Neurology, Laboratory of Neurodegenerative Disorders, West China Hospital, Sichuan University, Chengdu, China; 1187269237{at}qq.com

Abstract

Background Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterised by progressive degeneration of motor neurons. Genetic factors have a substantial impact on ALS. Therefore, this study aimed to explore the correlation between genotype (SOD1, TARDBP, FUS, C9orf72) and phenotype in ALS.

Methods Genetic analysis was performed on 2038 patients with ALS, among which 1696 patients with sporadic ALS (SALS) as controls for genotype-phenotype analysis, and 1602 SALS as controls for survival analysis. Logistic regression and Cox proportional hazards models were used for statistical analysis.

Results A total of 172 patients with ALS with the gene mutations were included in the statistical analysis (SOD1, n=65; FUS, n=43; TARDBP, n=27; C9orf72, n=37). SOD1 mutations were more frequent in flail leg phenotype (OR 7.317, p=0.001) and less in bulbar phenotype (OR 0.222, p=0.038). C9orf72 expansions exhibited higher frequency in bulbar phenotype (OR 2.770, p=0.008). SOD1 and FUS mutations were significantly associated with earlier age of onset (HR 2.039, p<0.001; HR 1.762, p=0.001). The patients with SOD1 mutations, C9orf72 expansions and those carrying pathogenic FUS mutations had significantly increased death risk (HR 2.217, p<0.001; HR 1.694, p=0.008; HR 1.652, p=0.036). The increased risk of death in ALS with C9orf72 expansions was significant in females (HR 2.419, p=0.014) but not in males (HR 1.442, p=0.128).

Conclusion Our study revealed distinct motor phenotypic tendencies in patients with ALS with different genotypes, indicating variations in the vulnerability of motor neurons during the disease’s progression. Furthermore, we made novel discoveries regarding survival of different gene mutations, warranting further investigation.

  • genotype
  • motor neuron disease
  • phenotype
  • prognosis

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Footnotes

  • QJ and JL contributed equally.

  • Contributors QJ: Conceptualisation (lead); data curation (equal); writing—original draft (lead); formal analysis (equal); writing—review and editing (equal). J-YL: Conceptualisation (equal); writing—original draft (equal); formal analysis (equal); writing—review and editing (equal). QW: Methodology (equal), data curation (equal), funding acquisition (equal). YH, LZ and RO: Methodology (equal), data curation (equal). TY, YX, SW and XZ: Data curation (equal). CL and HS: Conceptualisation (equal); funding acquisition (equal); review and editing (equal). HS: guarantor.

  • Funding This article was supported by the Sichuan Science and Technology Program (Grant No. 2022ZDZX0023), the National Natural Science Foundation of China (Grant No. 82371430), the National Natural Science Foundation of China (Grant No. 82101485), and Science and Technology commission foundation of Chengdu City (Grant No. 2021-YF05-00242-SN).

  • 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.