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This study aims to identify novel causative genes of COX deficiency with only striated muscle\u2013specific symptoms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole exome sequencing was performed in 2 unrelated individuals who were diagnosed with congenital myopathy and presented COX deficiency in muscle pathology. We assessed the <jats:italic>COX6A2<\/jats:italic> variants using measurements of enzymatic activities and assembly of mitochondrial respiratory chain complexes in the samples from the patients and knockout mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness. One patient had cardiomyopathy. Neither patient exhibited involvement from other organs. Whole exome sequencing identified biallelic missense variants in <jats:italic>COX6A2<\/jats:italic>, which is expressed only in the skeletal muscle and heart. The variants detected were homozygous c.117C\u2009&gt;\u2009A (p.Ser39Arg) and compound heterozygous c.117C\u2009&gt;\u2009A (p.Ser39Arg) and c.127T\u2009&gt;\u2009C (p.Cys43Arg). We found specific reductions in complex IV activities in the skeletal muscle of both individuals. Assembly of complex IV and its supercomplex formation were impaired in the muscle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This study indicates that biallelic variants in <jats:italic>COX6A2<\/jats:italic> cause a striated muscle\u2013specific form of COX deficiency. ANN NEUROL 2019;86:193\u2013202<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25517","type":"journal-article","created":{"date-parts":[[2019,6,3]],"date-time":"2019-06-03T05:49:35Z","timestamp":1559540975000},"page":"193-202","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["<i>COX6A2<\/i> variants cause a muscle\u2010specific cytochrome <i>c<\/i> oxidase deficiency"],"prefix":"10.1002","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2757-3266","authenticated-orcid":false,"given":"Michio","family":"Inoue","sequence":"first","affiliation":[{"name":"Department of Neuromuscular Research, National Institute of Neuroscience National Center of Neurology and Psychiatry  Tokyo Japan"},{"name":"Integrated Graduate School of Medicine, Engineering, and Agricultural Science University of Yamanashi  Yamanashi Japan"},{"name":"Medical Genome Center National Center of Neurology and Psychiatry  Tokyo 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