Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background☆
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.
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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
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All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.