Furthermore, we found a pathogenic variant in the cytoplasmic located aminoacyl-tRNA synthetase IARS to cause complex I deficiency in skin and muscle tissue of a patient with a multi-system disorder, and a defect in the acetylcholine receptor subunit epsilon CHRNE associated with CII deficiency, COX negative muscle fibers and abnormally shaped muscle mitochondria in CPEO with myopathy. Here, IARS1 is linked to External ophthalmoplegia.