Elsevier

International Journal of Cardiology

Volume 279, 15 March 2019, Pages 115-121
International Journal of Cardiology

Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background

https://doi.org/10.1016/j.ijcard.2019.01.017Get rights and content

Highlights

  • Prognosis and genetic cause of mitochondrial cardiomyopathy (CM) remains unrevealed.

  • Of 137 children with mitochondrial disease, 21% had CM with various genetic causes.

  • CM patients had lower survival rates than did non-CM patients (p < 0.001).

  • Genetic analysis coupled with detailed phenotyping could be useful for prognosis.

Abstract

Background

Cardiomyopathy is a reported indicator of poor prognosis in children with mitochondrial disease. However, the association between prognosis and the genetic background of cardiomyopathy in children with mitochondrial disease has yet to be fully elucidated.

Methods and results

Of 137 children with mitochondrial disease whose genetic diagnosis was made between 2004 and 2018, 29 had mitochondrial cardiomyopathy (21%). After a median follow-up of 35 months, the overall survival rate was significantly lower in patients with cardiomyopathy than in those without (p < 0.001). Ten-year Kaplan-Meier estimates of overall survival were 18 and 67%, respectively. Among the 21 cardiomyopathy patients who died, two died within one month of birth (COQ4 in one patient, and COX10 in one patient), ten died within one year (BOLA3 in three patients, QRSL1 in two patients, large chromosomal deletions in two patients, MT-ATP6/8 in one patient, MT-TL1 in one patient, and TAZ gene in one patient), and nine died after one year (MT-ND5 in three patients, MT-TL1 in three patients, ACAD9 in one patient, KARS in one patient, and MT-TV in one patient). In the three patients with mitochondrial DNA mutations whose cardiac tissues were available, high heteroplasmy rates in the cardiac tissue were observed for m.8528T>C (90%, died at 2 months of age) and m.3243A>G (90 and 80%, died at 12 and 13 years of age, respectively).

Conclusions

In children with mitochondrial disease, cardiomyopathy was common (21%) and was associated with increased mortality. Genetic analysis coupled with detailed phenotyping could be useful for prognosis.

Introduction

Mitochondrial diseases, or disorders of the mitochondrial respiratory chain (MRC) complexes, are caused by defects in oxidative phosphorylation (OXPHOS) [1,2]. The MRC complexes, embedded within the inner mitochondrial membrane, are composed of five enzyme complexes. Energy generated by MRC complexes is used to produce ATP through OXPHOS. Proteins of MRC complexes are under the control of both nuclear and mitochondrial DNA; defects in those can result in OXPHOS dysfunction [3]. The heart is highly dependent on oxidative metabolism, therefore, cardiac involvement in mitochondrial disease is commonly observed and can present as a major clinical symptom or as part of a multisystem disorder [4]. Among children with mitochondrial disease, those with cardiomyopathy have been reported to have a worse prognosis [5]. However, the association between prognosis and the genetic background of cardiomyopathy in children with mitochondrial disease has yet to be fully elucidated. Therefore, we investigated the prognosis and genetic background of cardiomyopathy in children with mitochondrial disease.

Section snippets

Patients

A total of 137 children under the age of 15 years old were included in this study. Between 2004 and 2018, pediatricians and neurologists throughout Japan referred patients with suspected mitochondrial respiratory chain complex deficiency, due to clinical manifestations compatible with mitochondrial disease, to Saitama Medical University or Chiba Children's Hospital for enzyme assay and/or genetic analysis. All patients had their diagnosis genetically confirmed with known pathogenic nuclear DNA

Patient characteristics

A summary of clinical, genetic, and biochemical findings in 29 children with mitochondrial disease and cardiomyopathy is given in Table 1. Characteristics of the total study populations are summarized in Supplementary Table S1. Between patients with or without cardiomyopathy, sex did not significantly differ (48% and 56%, for males and females, respectively, p = 0.49). However, earlier age of onset is observed in patients with cardiomyopathy compared with those without cardiomyopathy (median

Epidemiology

Cardiomyopathy has been reported affect up to 20% of patients with mitochondrial disease [5]. Our results showed that cardiomyopathy affects 21% in children with mitochondrial disease, consistent with previous studies. Although this study was based on patients referred to our institutions, referral was made from pediatricians or neurologists across Japan and it may reflect the epidemiology of mitochondrial cardiomyopathy in Japan.

In this study, we only assessed cardiomyopathy patients, as a

Conclusions

Cardiomyopathy was seen in 29 out of 137 children (21%) with mitochondrial disease in our study. The overall survival rate was significantly lower in patients with cardiomyopathy than in those without cardiomyopathy (p < 0.001, log-rank test), with ten-year Kaplan-Meier estimates of overall survival of 18 and 67%, respectively. Analysis of the genetic background of cardiomyopathy in children with mitochondrial disease coupled with detailed phenotyping could be useful for prognosis.

The following

Funding

This work was supported by the Japan Heart Foundation Dr. Hiroshi Irisawa & Dr. Aya Irisawa Memorial Research Grant; JSPS KAKENHI Grant Number JP18K15863; MEXT-Supported Program for the Private University Research Branding Project, and the Practical Research Project (18ek0109273 and 18ek0109177) for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, AMED.

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.

Acknowledgments

This work was supported by the Japan Heart Foundation Dr. Hiroshi Irisawa & Dr. Aya Irisawa Memorial Research Grant, JSPS KAKENHI Grant Number JP18K15863, MEXT-Supported Program for the Private University Research Branding Project, and the Practical Research Project (18ek0109273 and 18ek0109177) for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, AMED. The authors also acknowledge the Statistical Consulting Service at Biostatics section, National Center for

References (24)

  • M. Kohda et al.

    A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies

    PLoS Genet.

    (2016)
  • M.G. Bates et al.

    Cardiac involvement in mitochondrial DNA disease: clinical spectrum, diagnosis, and management

    Eur. Heart J.

    (2012)
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