Novel <i>TOP3A</i> Variant Associated With Mitochondrial Disease
Guido Primiano, Alessandra Torraco, Daniela Verrigni, Andrea Sabino, Enrico Bertini, Rosalba Carrozzo, Gabriella Silvestri, Serenella Servidei
Abstract
<h3>Objectives</h3> Topoisomerase III alpha plays a key role in the dissolution of double Holliday junctions and is required for mitochondrial DNA (mtDNA) replication and maintenance. Sequence variants in the <i>TOP3A</i> gene have been associated with the Bloom syndrome–like disorder and described in an adult patient with progressive external ophthalmoplegia. The purpose of this report is to expand the clinical phenotype of the <i>TOP3A</i>-related diseases and clarify the role of this gene in primary mitochondrial disorders. <h3>Methods</h3> A 44-year-old woman was referred to our hospital because of exercise intolerance and creatine kinase increase. Muscle biopsy and a targeted next-generation sequencing (NGS) analysis were performed. <h3>Results</h3> A histopathologic assessment documented a mitochondrial myopathy, and a molecular analysis revealed a novel homozygous variant in the <i>TOP3A</i> gene associated with multiple mtDNA deletions. <h3>Discussion</h3> This case suggests that <i>TOP3A</i> is one of the several nuclear genes associated with mtDNA maintenance disorder and expands the spectrum of its associated phenotypes, ranging from a clinical condition defined Bloom syndrome–like disorder to canonical mitochondrial syndromes.