Delineation and Phenotypic Expansion of TOP3A-Related Mitochondrial Disease in Childhood

TOP3A-related mitochondrial disease is a rare autosomal recessive primary mitochondrial cytopathy caused by loss-of-function of the mitochondrial-specific isoform of topoisomerase 3α, leading to multiple mitochondrial DNA deletions and mitochondrial DNA depletion. This condition has been associated with two different phenotypes. Very young patients present with severe growth faltering and early mortality, that is consistent with a Bloom syndrome-like disorder. Adult-onset chronic progressive external ophthalmoplegia, myopathy, and sensory ataxia, with rare hypertrophic cardiomyopathy (a MIRAS-like phenotype), reflects a mitochondrial disorder. In this article, we expand the phenotype spectrum of TOP3A-related mitochondrial disease with a mitochondrial childhood onset form and present four previously unreported patients, including the outcomes of heart transplantation for three patients. Histopathological, electron microscopical, biochemical, and molecular characterization of muscle and heart tissue indicated mitochondrial dysfunction with combined complex deficiency associated with a mitochondrial DNA maintenance disorder primarily expressed in the heart. Heart transplantation was successful in patients with TOP3A-related mitochondrial disease that presented with cardiomyopathy in childhood, although there is slowly progressive neurological disease. In childhood, TOP3A-related disease presents with a combination of developmental delays, sensorineural hearing loss, cardiomyopathy with rhythm abnormalities, stroke-like episodes, and Leigh-like phenotype, and, in some, epilepsy. These mitochondrial phenotypes are different from the infantile Bloom-like syndrome and the adult-onset form.