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Progressive external ophthalmoplegia associated with novel MT ‐ TN mutations
Author(s) -
Visuttijai Kittichate,
HedbergOldfors Carola,
Lindgren Ulrika,
Nordström Sara,
Elíasdóttir Ólöf,
Lindberg Christopher,
Oldfors Anders
Publication year - 2021
Publication title -
acta neurologica scandinavica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.967
H-Index - 95
eISSN - 1600-0404
pISSN - 0001-6314
DOI - 10.1111/ane.13339
Subject(s) - heteroplasmy , muscle biopsy , myopathy , mitochondrial myopathy , mitochondrial dna , chronic progressive external ophthalmoplegia , exercise intolerance , pathology , biology , mutation , ptosis , mitochondrial disease , biopsy , genetics , microbiology and biotechnology , medicine , gene , heart failure , pharmacology
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 cytochrome c oxidase (COX)‐deficient fibers and a heteroplasmic mutation, m.5669G>A in the MT ‐ TN gene, 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 in MT ‐ 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 two MT ‐ TN mutations associated with PEO and mitochondrial myopathy, and their pathogenicity was demonstrated. Together with previous reports, the results indicate that MT ‐ TN is a hot spot for mutations causing sporadic PEO.