A de novo TWNK Variant Mimicked Sporadic Chronic Progressive External Ophthalmoplegia

Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease, with most sporadic cases caused by a single large mitochondrial DNA (mtDNA) deletion. We report the case of a 54-year-old woman with ptosis, external ophthalmoplegia, and proximal muscle weakness without any relevant family history. A muscle biopsy supported the diagnosis of sporadic CPEO. However, a muscle DNA analysis revealed multiple mitochondrial DNA (mtDNA) deletions. Whole-exome sequencing identified a heterozygous pathogenic TWNK variant [c.1121G>A (p.Arg374Gln)] absent in her parents, suggesting a de novo origin. Although TWNK pathogenic variants typically cause autosomal dominant CPEO, this case mimicked a sporadic form, thus highlighting the importance of a nuclear gene analysis in such cases.