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Genetic defects of mitochondrial energy supply can give rise to a variety of symptoms and virtually any organ or tissue can be involved.1 In particular, cardiomyopathy can be the presenting symptom of a respiratory enzyme deficiency in infancy. Alternatively, cardiomyopathy frequently occurs in the course of these diseases.2 Multi-organ involvement is usually regarded as a contraindication for heart transplantation in metabolic disorders. Yet, since the clinical expression of respiratory enzyme deficiency can be limited to the myocardium, it is reasonable to consider heart transplantation in mitochondrial cardiomyopathy.3 Here, we report on successful orthotopic heart transplantation in seven children (four girls, three boys) with severe mitochondrial cardiomyopathy. Mean (SD) age at time of diagnosis was 7.5 (6.1) years (range 1 month to 16 years). All had dilated cardiomyopathy with hypertrophied walls. Six had a positive family history of cardiomyopathy or unexplained sudden death. All patients were screened for skeletal myopathy, ocular myopathy, pigmentary retinopathy, and renal and liver dysfunction. Respiratory enzyme activities (cytochrome-coxidase, succinate cytochrome creductase, and rotenone sensitive reduced nicotinamide adenine dinucleotide cytochrome c reductase) were spectrophotometrically measured in homogenates from frozen endomyocardial biopsy specimens according to previously published procedures.4 Skeletal muscle biopsy was performed in 6/7 patients. In addition, enzyme studies were performed in fibroblasts in 2/7 patients. Finally, one patient had a mild proteinuria and raised liver enzymes. She underwent a liver and kidney biopsy before heart transplantation.
A complex I (NADH-ubiquinone reductase) defect was diagnosed in two patients. This defect was confined to the myocardium in one patient, while another patient, with no evidence of clinical myopathy, expressed the defect in skeletal muscle as well. One patient had a complex III deficiency (ubiquinol cytochrome creductase) in the myocardium but also in the kidney and liver. Four patients had a multiple defect limited to the myocardium : complex I + IV (cytochrome oxidase) in two patients, generalised defect in two twin sisters (table 1). Mitochondrial DNA deletions or point mutations previously reported in cardiomyopathy were not observed in these patients. Patient 7 had a mutation in the cd2 helix of the mitochondrial cytochrome b gene.
One patient died while on the waiting list (patient 6). Orthotopic heart transplantation was performed in six children at our institution. Immunosuppressive prophylaxis included cyclosporine, azathioprine, and prednisone. Patient 7 died one month after heart transplantation because of dysfunction of the graft. Another patient died seven years after successful heart transplantation following aortic valve replacement for infective endocarditis with right coronary artery septic aneurysm (patient 2). Finally, patient 4 died of subacute rejection with severe coronary lesions after seven years. The remaining three patients are doing well after a mean follow up of 55.6 (9) months (range 2.6–6.5 years). The frequency of acute rejection episodes were identical in this series as compared to the population of transplanted children followed up in our institution. Extracardiac expression of the mitochondrial disorder was not observed during the follow up. Patient 2 (follow up 62 months) in whom the mitochondrial respiratory chain (MRC) defect was also present in skeletal muscle maintains normal muscular testing.
The issue of whether alterations in oxidative phosphorylation play a primary role in causing cardiomyopathy, or whether they occur as a secondary effect of oxidative damage in cardiac tissue remains to be determined. Remes and colleagues demonstrated that the occurrence of mitochondrial DNA deletions in the hearts of patients with idiopathic dilated cardiomyopathy was quantitatively similar to the control hearts and concluded that these deletions have no causal relation with the development of the cardiomyopathy.5 In our series, we have, however, strong evidence for a causal relation between the alteration of MRC function and the cardiomyopathy. Firstly, enzyme studies performed by using endomyocardial biopsies provided evidence of MRC dysfunction and values for protein indicated no detectable proteolytic breakdown, which can be potentially problematic when studying explanted hearts. Secondly, there was a familial history of cardiomyopathy or of acute cardiac events in 6/7 of our patients with dilated cardiomyopathy. The MRC disorder in siblings was proven in 3/4 of these families. In patient 1, the complex I defect was found in myocardium but also in skeletal muscle. Finally, the remaining patient had a complex III-quinones deficiency both in endomyocardial biopsy samples and in macrobiopsies from the explanted heart. Additionally, she had a multiorgan expression of the defect that was found in the kidneys, liver, and skeletal muscle. Finally, she was the only patient in whom we identified a mutation.
Heart transplantation is usually contraindicated in metabolic diseases when the enzyme defect is ubiquitous and the expression of the disease multisystemic. Consequently, one may argue that transplanting the heart of patients with the MRC defect does not prevent extracardiac complications related to this defect. In our series, the MRC disorder was apparently heart specific in all patients but two, and it would have remained undetected if endomyocardial biopsy was not routinely performed in the metabolic screening of severe cardiomyopathies. Without data concerning the biochemical expression in other tissues except skeletal muscle, lymphocytes or skin fibroblasts, however, we cannot exclude the possibility that the defect is latent in these tissues. Nevertheless, we did not observe clinically patent extracardiac expression of the mitochondrial defect after heart transplantation. Therefore, we believe that MRC disorders causing isolated severe cardiomyopathy in children do not contraindicate heart transplantation.
Extensive metabolic investigations including endomyocardial biopsy for enzyme investigations in adolescents or adults with isolated and apparently “idiopathic” cardiomyopathy is probably unreasonable. Most of the multisystemic MRC defects are diagnosed during infancy or early childhood. We believe, conversely, that extensive clinical and metabolic investigations are necessary when heart transplantation is indicated in young infants. Indeed, cardiomyopathy may reveal the mitochondrial disease while extracardiac involvement may still be absent. Consequently, the diagnosis of an MRC disorder causing the cardiomyopathy appears essential to guide extracardiac investigations and potentially predict delayed multisystemic expression of the defect.