iarjimphIARJIMPHIARJIMPH2709-331Xhttps://doi.org/10.47310/iarjimph.2021.v02i01.002Extensive Work-Up for Ophthalmoplegia Due to Single mtDNA Deletions is RequiredJosefFinstererKlinik Landstrasse, Vienna, AustriaWith interest we read the article by Kim et al. about 10 patients with chronic progressive external ophthalmoplegia (CPEO) due to single mtDNA deletions of different size and location of whom 9 had symmetric ophthalmoplegia and 1 asymmetric ophthalmoplegia [1]. Of the 9 patients with symmetric ophthalmoplegia, four showed exotropia, three exotropia with vertical deviation, and two had ortotropia [1]. Five patients reported diplopia associated with strabism [1]. Three patients without diplopia had exotropia of 20-50 prism diopters [1]. We have the following comments and concerns. Single mtDNA deletions usually occur in a heteroplasmic form, meaning that wild-type mtDNA coexists with mutated mtDNA in a certain relation (heteroplasmy rate). We should know heteroplasmy rates of the 10 included patients and if they were determined in blood or another tissue. Heteroplasmy rates may vary significantly between tissues, why it is crucial to determine it not only in a single tissue. Particularly high heteroplasmy rates can be found in clinically affected tissues. Though single mtDNA deletions usually occur spontaneously, they may be inherited via a maternal trait in 4% of the cases [2]. Thus, it is worthwhile to know the family history of the 10 included patients, particularly if any mother or other first degree relative had CPEO as well. Knowing the family history and the genetic status of first-degree relatives is crucial for assessing the disease course and for genetic counselling. Since patients may be offered strabism surgery if diplopia is severe, we should know how many of the 5 patients with diplopia had undergone strabism surgery before or after the investigation. Since CPEO due to single mtDNA deletions can be associated with retinopathy [3], we should be informed about the results of fundoscopy, particular how many patients had retinitis pigmentosa (salt and pepper retinopathy). Since several drugs may cause diplopia, we need to know the current medication in the five patients with diplopia.  Frequently, CPEO not only manifests in the extra-ocular eye muscles but also in organs or tissues other than the skeletal muscles (CPEO plus) [4rodrigues]. Organs affected in CPEO plus include the central nervous system (CNS), the ears, the gastrointestinal tract, and the peripheral nerves [4]. Patients with CPEO plus may present with dysphagia [4], dystonia (POLG1 variant) [5], dysarthria [4], epilepsy [4], vestibular dysfunction [5], or neuropathy [4]. We should know if the 10 included patients were prospectively investigated for multisystem disease.  Overall, the interesting study by Kim et al. could be more meaningful by providing an extensive family history, results of clinical or genetic investigations of first-degree relatives, results of prospective investigations for multisystem disease in the index patient, the current medication, and heteroplasmy rates in different tissues. Since patients with CPEO are rare, those available should be extensively investigated to broaden our knowledge about this enigmatic and challenging disease.