To the best of our knowledge, this study is the first report describing hypertrophic cardiomyopathy in patients with LHON. The pattern of cardiac hypertrophy was heterogeneous: three patients had concentric hypertrophy, one had asymmetric septal hypertrophy, and one had distal hypertrophy. Cardiac symptoms and isolated ECG abnormalities were also common, but in contrast to previous studies,4
we were unable to demonstrate any evidence for ventricular pre-excitation. This may have been because of the small number of patients examined; however, other recent studies have also failed to demonstrate pre-excitation in patients with LHON.5
The fact that hypertrophic cardiomyopathy was observed in a single family of LHON patients with the 3460 mtDNA mutation could be explained by the co-inheritance of familial hypertrophic cardiomyopathy. Extensive screening for sarcomeric protein gene mutations that cause familial hypertrophic cardiomyopathy would be necessary to exclude this possibility, but several observations suggest that the cardiomyopathy was secondary to the 3460 mtDNA mutation; specifically the association between cardiomyopathy and other mitochondrial disorders, the presence of minor cardiac abnormalities in previous studies of patients with LHON, and the presence of 100% co-segregation of the 3460 mutation and cardiac disease.
The 3460, 11778, and 14484 mutations all alter the encoding of complex I, one of the five major protein complexes that make up the mitochondrial oxidative phosphorylation system. Complex I consists of over 40 protein subunits, seven of which (ND1-6, and ND4L) are encoded by mtDNA. The mtDNA encoded subunits are mainly intramembranous and are involved in interactions with ubiquinone and hydrogen ion transfer. The phenotypic heterogeneity with respect to cardiac involvement observed in this study may be explained in part by the different protein subunits that are affected by the 3460, 11778, and 14484 LHON mutations. The 3460 mutation occurs within the gene that encodes the ND1 protein subunit, causing the substitution of hydrophobic alanine for hydrophilic threonine in the NH2 terminus of the polypeptide, which is rich in other hydrophobic residues. This mutation leads to a reduction in complex I dependent electron transfer activity and a 30–35% decrease in ATP synthesis. In contrast, the 11778 mutation which results in the substitution of histidine for arginine in the ND4 subunit does not appear to compromise electron transfer within the complex itself, but may disrupt interactions between the complex and NADH linked substrates. The 14484 mutation leads to the substitution of valine for methionine in a poorly conserved region of the gene which codes for the ND6 subunit. Although the pathogenic basis of the 14484 mutation has not been studied extensively, reductions in complex I activity and ATP synthesis have been reported. In the future a greater understanding of the genotype–phenotype relation in this condition may be obtained from assessment of the degree of mtDNA heteroplasmy in the myocardium.
The findings in this study suggest that patients with LHON should routinely undergo cardiac evaluation with echocardiography and ECG. The relation between individual mutations and cardiac disease, and the natural history of cardiac disease in LHON, warrant further study.