The ACTN3 577XX Null Genotype Is Associated with Low Left Ventricular Dilation-Free Survival Rate in Patients with Duchenne Muscular Dystrophy

https://doi.org/10.1016/j.cardfail.2020.08.002Get rights and content

Highlights

  • The ACTN3 genotype is a genetic modifier for Duchenne muscular dystrophy.

  • The ACTN3 genotype with risk of dilated cardiomyopathy in patients was studied.

  • The ACTN3 577XX null genotype has a low left ventricular dilation-free survival rate.

  • The ACTN3 577XX null genotype is a risk factor for left ventricular dilation.

ABSTRACT

Background

Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease caused by mutations in the DMD gene. Dilated cardiomyopathy is the leading cause of death in DMD; therefore, further understanding of this complication is essential to reduce morbidity and mortality.

Methods

A common null variant (R577X) in the ACTN3 gene, which encodes α-actinin-3, has been studied in association with muscle function in healthy individuals; however it has not yet been examined in relationship to the cardiac phenotype in DMD. In this study, we determined the ACTN3 genotype in 163 patients with DMD and examined the correlation between ACTN3 genotypes and echocardiographic findings in 77 of the 163 patients.

Results

The genotypes 577RR(RR), 577RX(RX) and 577XX(XX) were identified in 13 (17%), 44 (57%) and 20 (26%) of 77 patients, respectively. We estimated cardiac involvement-free survival rate analyses using Kaplan-Meier curves. Remarkably, the left ventricular dilation (> 55 mm)-free survival rate was significantly lower in patients with the XX null genotype (P < 0.01). The XX null genotype showed a higher risk for LV dilation (hazard ratio 9.04).

Conclusions

This study revealed that the ACTN3 XX null genotype was associated with a lower left ventricular dilation-free survival rate in patients with DMD. These results suggest that the ACTN3 genotype should be determined at the time of diagnosis of DMD to improve patients’ cardiac outcomes.

Section snippets

Methods

This was a single-center retrospective study. Patients with DMD were registered at the Department of Pediatrics, Kobe University Hospital, between June 1992 and March 2018. The medical records of registered patients with DMD were reviewed retrospectively. The clinical diagnosis of DMD was confirmed by the identification of mutations in DMD. Gene mutations were analyzed in both genomic DNA and mRNA extracted from the muscle or peripheral lymphocytes, as previously described.22 The reading frame

Results

The patients who were diagnosed with DMD and registered in our hospital numbered 452. Genomic DNA from 163 patients with DMD was available for ACTN3 variant analysis. Of 163 patients, 74 patients were excluded because they underwent routine echocardiographic examinations at local hospitals. In addition, 12 patients had evidence of cardiac dysfunction at the time of first echocardiography, and they were excluded because the onset age of cardiac involvement was unknown. A total of 77 patients

Discussion

This study found an association between the ACTN3 577XX null genotype and early progression of DCM in DMD. In the present study, the ACTN3 genotype was determined in the 77 patients with DMD, and the cardiac involvement-free survival rate was compared among genotypes. We observed a significantly earlier progression to LV dilation in patients with the ACTN3 null genotype.

We determined the ACTN3 genotype of 163 enrolled patients, and the allele frequency of R577X was 0.552. The R577X allele

Funding Sources

This study was supported by the Japanese Society for the Promotion of Science Grants-in-Aid for Scientific Research (KAHEN-HI, #18K07845 and #19K17564) and an Intramural Research Grant for Neurological and Psychiatric Disorders from the National Center of Neurology and Psychiatry (#29-3).

Disclosures

Dr. Matsuo is an advisor for JCR Pharma, Japan, and Daiichi Sankyo, Japan. The other authors report no conflicts of interest.

Acknowledgments

We are thankful to the families who participated in this study.

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