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Knowledge on the molecular background of mitochondrial disorders has accumulated during the past two decades, but clinical and molecular features of mitochondrial cardiomyopathies (CMPs) are only starting to be characterized. We studied the detailed cardiologic phenotype of patients with adult-onset CMPs associated with mitochondrial DNA (mtDNA) mutations and their relatives, from three families. We identified a pathogenic T3258C point mutation of mtDNA tRNALeu(UUR) in an adult patient with mitochondrial myopathy and CMP, with acute manifestation of dyspnea and elevated plasma N-terminal pro-B-type natriuretic peptide concentration. Two other families with maternally segregated CMP, fatal in three patients, had the A3243G mutation in tRNALeu(UUR) of mtDNA. Many of the mutation carriers, even if oligosymptomatic, had concentric, non-obstructive hypertrophic CMP with diastolic dysfunction or restrictive hemodynamics, or depression of systolic function especially at times when patients had lactic acidosis. Atrial fibrillation led to manifest heart failure in four patients, fatal in one. In conclusion, tRNALeu(UUR) mutations in mtDNA may underlie mitochondrial non-obstructive, sometimes fatal, hypertrophic CMPs of adult age. Such CMPs are characterized by left ventricular hypertrophy and poor tolerance of atrial arrhythmias, often leading to rapidly deteriorating systolic function and heart failure. These patients benefit of rapid intervention of tachyarrhythmias. These patients may not have neurological symptoms, and may therefore remain underdiagnosed. Our observations emphasize that patients with tRNALeu(UUR) mutations need cardiologic evaluation and follow- up. tRNALeu(UUR) mutations should be screened of patients with hypertrophic CMP and metabolic acidosis, especially if atrial arrhythmia provoked cardiac decompensation.
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