Progressive external ophthalmoplegia associated with novelMT-TNmutations

Objectives To describe two patients with progressive external ophthalmoplegia (PEO) and mitochondrial myopathy associated with mutations in mitochondrial DNA, encoding the tRNA(Asn)gene (MT-TN), which have not previously been published with clinical descriptions. Materials & Methods Two unrelated patients with PEO were clinically examined. Muscle biopsy was performed and investigated by exome sequencing, enzyme histochemistry, and immunohistochemistry. The level of heteroplasmy was investigated in single muscle fibers and in other tissues. Results Patient 1 was a 52-year-old man with ptosis, PEO, and exercise intolerance since childhood. Muscle biopsy demonstrated mitochondrial myopathy with frequent cytochromecoxidase (COX)-deficient fibers and a heteroplasmic mutation, m.5669G>A in theMT-TNgene, resulting in a substitution of a highly conserved C to T in the T stem of tRNA(Asn). Patient 2 was a 66-year-old woman with ptosis, PEO, and exercise intolerance since many years. Muscle biopsy demonstrated mitochondrial myopathy with frequent COX-deficient fibers. She had a novel m.5702delA mutation inMT-TN, resulting in loss of a highly conserved U in the anticodon stem of tRNA(Asn). Single fiber analysis in both cases showed highly significant differences in mutation load between COX-deficient and COX-normal fibers and a high threshold level for COX deficiency. The mutations were not found in blood, urine sediment or buccal cells. Conclusion We describe twoMT-TNmutations associated with PEO and mitochondrial myopathy, and their pathogenicity was demonstrated. Together with previous reports, the results indicate thatMT-TNis a hot spot for mutations causing sporadic PEO.

Automated summary

Two patients with progressive external ophthalmoplegia (PEO) and mitochondrial myopathy were found to have mutations in the MT-TN gene, showing that MT-TN may be a hotspot for mutations causing sporadic PEO.