{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:27:51Z","timestamp":1790832471279,"version":"4.1.0"},"reference-count":172,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T00:00:00Z","timestamp":1706313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Chronic progressive external ophthalmoplegia (CPEO) is a rare disorder that can be at the forefront of several mitochondrial diseases. This review overviews mitochondrial CPEO encephalomyopathies to enhance accurate recognition and diagnosis for proper management. Methods: This study is conducted based on publications and guidelines obtained by selective review in PubMed. Randomized, double-blind, placebo-controlled trials, Cochrane reviews, and literature meta-analyses were particularly sought. Discussion: CPEO is a common presentation of mitochondrial encephalomyopathies, which can result from alterations in mitochondrial or nuclear DNA. Genetic sequencing is the gold standard for diagnosing mitochondrial encephalomyopathies, preceded by non-invasive tests such as fibroblast growth factor-21 and growth differentiation factor-15. More invasive options include a muscle biopsy, which can be carried out after uncertain diagnostic testing. No definitive treatment option is available for mitochondrial diseases, and management is mainly focused on lifestyle risk modification and supplementation to reduce mitochondrial load and symptomatic relief, such as ptosis repair in the case of CPEO. Nevertheless, various clinical trials and endeavors are still at large for achieving beneficial therapeutic outcomes for mitochondrial encephalomyopathies. Key Messages: Understanding the varying presentations and genetic aspects of mitochondrial CPEO is crucial for accurate diagnosis and management.<\/jats:p>","DOI":"10.3390\/brainsci14020135","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T04:57:07Z","timestamp":1706504227000},"page":"135","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Mitochondrial Chronic Progressive External Ophthalmoplegia"],"prefix":"10.3390","volume":"14","author":[{"given":"Ali","family":"Ali","sequence":"first","affiliation":[{"name":"Neuro-Ophthalmology Unit, Ibn Sina Hospital, Al-Bahar Ophthalmology Center, Kuwait City 70035, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Esmaeil","sequence":"additional","affiliation":[{"name":"Neuro-Ophthalmology Unit, Ibn Sina Hospital, Al-Bahar Ophthalmology Center, Kuwait City 70035, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6633-3567","authenticated-orcid":false,"given":"Raed","family":"Behbehani","sequence":"additional","affiliation":[{"name":"Neuro-Ophthalmology Unit, Ibn Sina Hospital, Al-Bahar Ophthalmology Center, Kuwait City 70035, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,27]]},"reference":[{"key":"ref_1","first-page":"5109","article-title":"A national epidemiological study of chronic progressive external ophthalmoplegia in the United Kingdom\u2014Molecular genetic features and neurological burden","volume":"55","author":"Griffiths","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1001\/archopht.1958.00940080296016","article-title":"Retinitis pigmentosa, external ophthalmophegia, and complete heart block: Unusual syndrome with histologic study in one of two cases","volume":"60","author":"Kearns","year":"1958","journal-title":"AMA Arch. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1001\/archneur.1972.00490090019001","article-title":"Oculocraniosomatic neuromuscular disease with \u201cragged-red\u201d fibers","volume":"26","author":"Olson","year":"1972","journal-title":"Arch. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1159\/000305086","article-title":"Electron microscopic findings in 3 cases of chronic progressive ocular muscular dystrophy","volume":"153","author":"Zintz","year":"1967","journal-title":"Ophthalmologica"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1111\/j.1755-3768.1976.tb01285.x","article-title":"Lowes, MProgressive external ophthalmoplegia. Evidence for a generalised mitochondrial disease with a defect in pyruvate metabolism","volume":"54","author":"Lou","year":"1976","journal-title":"Acta Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/331717a0","article-title":"Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies","volume":"331","author":"Holt","year":"1988","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/339309a0","article-title":"An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region","volume":"339","author":"Zeviani","year":"1989","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1126\/science.289.5480.782","article-title":"Role of adenine nucleotide translocator 1 in mtDNA maintenance","volume":"289","author":"Kaukonen","year":"2000","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13","DOI":"10.4103\/0971-5916.154489","article-title":"Mitochondrial disorders: Challenges in diagnosis & treatment","volume":"141","author":"Thangaraj","year":"2015","journal-title":"Indian J. Med. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3340","DOI":"10.1167\/iovs.09-4659","article-title":"Mitochondrial DNA Defects and Selective Extraocular Muscle Involvement in CPEO","volume":"51","author":"Greaves","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1042\/EBC20170096","article-title":"The mitochondrial DNA genetic bottleneck: Inheritance and beyond","volume":"62","author":"Zhang","year":"2018","journal-title":"Essays Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"25172","DOI":"10.1073\/pnas.1906331116","article-title":"Bottleneck and selection in the germline and maternal age influence transmission of mitochondrial DNA in human pedigrees","volume":"116","author":"Zaidi","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s13353-017-0424-3","article-title":"Nuclear genes involved in mitochondrial diseases caused by instability of mitochondrial DNA","volume":"59","author":"Rusecka","year":"2018","journal-title":"J. Appl. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s10792-017-0781-2","article-title":"Strabismus surgery for diplopia in chronic progressive external ophthalmoplegia","volume":"39","author":"Chatzistefanou","year":"2019","journal-title":"Int. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/sj.eye.6701488","article-title":"Ocular motility findings in chronic progressive external ophthalmoplegia","volume":"19","author":"Richardson","year":"2005","journal-title":"Eye"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1017\/S031716710001115X","article-title":"Multisystem Disorder in Late-Onset Chronic Progressive External Ophthalmoplegia","volume":"38","author":"Pfeffer","year":"2011","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1080\/01676830.2018.1445760","article-title":"3D printing for low cost, rapid prototyping of eyelid crutches","volume":"38","author":"Sun","year":"2019","journal-title":"Orbit"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1136\/bjo.2008.144816","article-title":"Frontalis sling operation using silicone rod for the correction of ptosis in chronic progressive external ophthalmoplegia","volume":"92","author":"Ahn","year":"2008","journal-title":"Br. J. Ophthalmol."},{"key":"ref_19","first-page":"185","article-title":"Management of myogenic ptosis in chronic progressive external ophtalmoplegia","volume":"13","author":"Rajabi","year":"2014","journal-title":"Iran. J. Neurol."},{"key":"ref_20","unstructured":"Shemesh, A., and Margolin, E. (2023). StatPearls, StatPearls Publishing."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s40942-017-0077-8","article-title":"Macular findings in Spectral Domain Optical Coherence Tomography and OCT Angiography in a patient with Kearns\u2013Sayre syndrome","volume":"3","author":"Ortiz","year":"2017","journal-title":"Int. J. Retin. Vitr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e12711","DOI":"10.1111\/and.12711","article-title":"A case of hypopituitarism accompanying Kearns\u2013Sayre syndrome treated with human chorionic gonadotropin: A case report and literature review","volume":"49","author":"Kang","year":"2017","journal-title":"Andrologia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1210\/endrev\/bnab036","article-title":"Endocrine Manifestations and New Developments in Mitochondrial Disease","volume":"43","author":"Ng","year":"2021","journal-title":"Endocr. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.1442-2050.2001.00152.x","article-title":"Manometric study in Kearns\u2013Sayre syndrome","volume":"14","author":"Katsanos","year":"2001","journal-title":"Dis. Esophagus"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"59","DOI":"10.5693\/djo.02.2019.09.001","article-title":"Endothelial dysfunction in a child with Pearson marrow-pancreas syndrome managed with Descemet stripping automated endothelial keratoplasty using a suture pull-through technique","volume":"25","author":"Vadhul","year":"2019","journal-title":"Digit. J. Ophthalmol."},{"key":"ref_26","first-page":"e33963","article-title":"A Case Report on Pearson Syndrome with Emphasis on Genetic Screening in Patients Presenting with Sideroblastic Anemia and Lactic Acidosis","volume":"15","author":"Shoeleh","year":"2023","journal-title":"Cureus"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e12681","DOI":"10.1111\/anec.12681","article-title":"Pearson marrow-pancreas syndrome with cardiac conduction abnormality necessitating prophylactic pacemaker implantation","volume":"25","author":"Jennifer","year":"2020","journal-title":"Ann. Noninvasive Electrocardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"161","DOI":"10.24911\/SJP.106-1534158413","article-title":"Pearson syndrome: A rare inborn error of metabolism with bone marrow morphology providing a clue to diagnosis","volume":"19","author":"Reddy","year":"2019","journal-title":"Sudan. J. Paediatr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s10545-014-9778-4","article-title":"Paediatric single mitochondrial DNA deletion disorders: An overlapping spectrum of disease","volume":"38","author":"Broomfield","year":"2015","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/sj.bmt.1705638","article-title":"Allogeneic bone marrow transplantation for Pearson\u2019s syndrome","volume":"39","author":"Faraci","year":"2007","journal-title":"Bone Marrow Transplant."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e2021334","DOI":"10.4322\/acr.2021.334","article-title":"Leigh syndrome in an infant: Autopsy and histopathology findings","volume":"11","author":"Saini","year":"2021","journal-title":"Autops. Case Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/ana.24551","article-title":"Leigh syndrome: One disorder, more than 75 monogenic causes","volume":"79","author":"Lake","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kistol, D., Tsygankova, P., Krylova, T., Bychkov, I., Itkis, Y., Nikolaeva, E., Mikhailova, S., Sumina, M., Pechatnikova, N., and Kurbatov, S. (2023). Leigh Syndrome: Spectrum of Molecular Defects and Clinical Features in Russia. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021597"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e18634","DOI":"10.1097\/MD.0000000000018634","article-title":"A meta-analysis and systematic review of Leigh syndrome: Clinical manifestations, respiratory chain enzyme complex deficiency, and gene mutations","volume":"99","author":"Chang","year":"2020","journal-title":"Medicine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1136\/bjophthalmol-2014-305704","article-title":"Ophthalmological manifestations in patients with Leigh syndrome","volume":"99","author":"Han","year":"2015","journal-title":"Br. J. Ophthalmol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1136\/jmedgenet-2017-104891","article-title":"Phenotype-genotype correlations in Leigh syndrome: New insights from a multicentre study of 96 patients","volume":"55","author":"Sofou","year":"2018","journal-title":"J. Med. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/8904_2014_375","article-title":"Leigh Syndrome Caused by the MT-ND5 m.13513G>A Mutation: A Case Presenting with WPW-Like Conduction Defect, Cardiomyopathy, Hypertension and Hyponatraemia","volume":"19","author":"Brecht","year":"2015","journal-title":"JIMD Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1186\/s13023-021-02029-3","article-title":"Clinical, imaging, biochemical and molecular features in Leigh syndrome: A study from the Italian network of mitochondrial diseases","volume":"16","author":"Ardissone","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1002\/ana.25789","article-title":"Pediatric Leigh Syndrome: Neuroimaging Features and Genetic Correlations","volume":"88","author":"Alves","year":"2020","journal-title":"Ann. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1136\/jnnp-2012-304426","article-title":"A guide to diagnosis and treatment of Leigh syndrome","volume":"85","author":"Baertling","year":"2014","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s10545-017-0042-6","article-title":"Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: A study of 106 Japanese patients","volume":"40","author":"Ogawa","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/s41419-019-2036-9","article-title":"Mitochondrial 3243A>G mutation confers pro-atherogenic and pro-inflammatory properties in MELAS iPS derived endothelial cells","volume":"10","author":"Pek","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1212\/WNL.0b013e31823a0c7f","article-title":"Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype","volume":"77","author":"Kaufmann","year":"2011","journal-title":"Neurology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e1955","DOI":"10.1002\/mgg3.1955","article-title":"Molecular and neurological features of MELAS syndrome in paediatric patients: A case series and review of the literature","volume":"10","author":"Seed","year":"2022","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"81","DOI":"10.4103\/0974-9233.51998","article-title":"Mitochondrial disorders with significant ophthalmic manifestations","volume":"15","author":"Nasser","year":"2008","journal-title":"Middle East Afr. J. Ophthalmol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1212\/WNL.0000000000000169","article-title":"Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers","volume":"82","author":"Weiduschat","year":"2014","journal-title":"Neurology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.ymgme.2012.06.018","article-title":"Citrulline and arginine utility in treating nitric oxide deficiency in mitochondrial disorders","volume":"107","author":"Emrick","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.2169\/internalmedicine.52.0188","article-title":"MELAS and reversible vasoconstriction of the major cerebral arteries","volume":"52","author":"Yoshida","year":"2013","journal-title":"Intern. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"843386","DOI":"10.3389\/fneur.2022.843386","article-title":"MRI Features of Stroke-Like Episodes in Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes","volume":"13","author":"Cheng","year":"2022","journal-title":"Front. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"201","DOI":"10.12688\/wellcomeopenres.15599.1","article-title":"Consensus-based statements for the management of mitochondrial stroke-like episodes","volume":"4","author":"Ng","year":"2019","journal-title":"Wellcome Open Res."},{"key":"ref_51","first-page":"e32709","article-title":"Arginine for the Treatment of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes: A Systematic Review","volume":"14","author":"Argudo","year":"2022","journal-title":"Cureus"},{"key":"ref_52","first-page":"144","article-title":"Immunonutrition for the acute treatment of MELAS syndrome. Endocrinolog\u00eda","volume":"69","year":"2022","journal-title":"Diabetes Nutr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"675816","DOI":"10.3389\/fneur.2021.675816","article-title":"Epilepsy Associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes","volume":"12","author":"Li","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41582-018-0101-0","article-title":"POLG-related disorders and their neurological manifestations","volume":"15","author":"Rahman","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1002\/jimd.12211","article-title":"Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases","volume":"43","author":"Hikmat","year":"2020","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/978-1-4939-3040-1_16","article-title":"Purification and Comparative Assay of Human Mitochondrial Single-Stranded DNA-Binding Protein","volume":"1351","author":"Ciesielski","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1093\/hmg\/ddn359","article-title":"Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling","volume":"18","author":"Goffart","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Bermejo-Guerrero, L., de Fuenmayor-Fern\u00e1ndez de la Hoz, C.P., Serrano-Lorenzo, P., Bl\u00e1zquez-Encinar, A., Guti\u00e9rrez-Guti\u00e9rrez, G., Mart\u00ednez-Vicente, L., Gal\u00e1n-D\u00e1vila, L., Garc\u00eda-Garc\u00eda, J., Arenas, J., and Muelas, N. (2021). Clinical, Histological, and Genetic Features of 25 Patients with Autosomal Dominant Progressive External Ophthalmoplegia (ad-PEO)\/PEO-Plus Due to TWNK Mutations. J. Clin. Med., 11.","DOI":"10.3390\/jcm11010022"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"860","DOI":"10.3389\/fgene.2020.00860","article-title":"TYMP Variants Result in Late-Onset Mitochondrial Myopathy With Altered Muscle Mitochondrial DNA Homeostasis","volume":"11","author":"Ronchi","year":"2020","journal-title":"Front. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s10072-010-0225-5","article-title":"A second MNGIE patient without typical mitochondrial skeletal muscle involvement","volume":"31","author":"Cardaioli","year":"2010","journal-title":"Neurol. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1373\/clinchem.2003.026179","article-title":"Definitive Diagnosis of Mitochondrial Neurogastrointestinal Encephalomyopathy by Biochemical Assays","volume":"50","author":"Spinazzola","year":"2004","journal-title":"Clin. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Filosto, M., Piccinelli, S.C., Caria, F., Cassarino, S.G., Baldelli, E., Galvagni, A., Volonghi, I., Scarpelli, M., and Padovani, A. (2018). Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE-MTDPS1). J. Clin. Med., 7.","DOI":"10.3390\/jcm7110389"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1093\/brain\/awab056","article-title":"Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy","volume":"144","author":"Bonora","year":"2021","journal-title":"Brain"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.1093\/brain\/aws231","article-title":"Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics","volume":"135","author":"Pitceathly","year":"2012","journal-title":"Brain"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.bbadis.2017.02.017","article-title":"Mitochondrial DNA maintenance defects","volume":"1863","author":"Craigen","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Takata, A., Kato, M., Nakamura, M., Yoshikawa, T., Kanba, S., Sano, A., and Kato, T. (2011). Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia. Genome Biol., 12.","DOI":"10.1186\/gb-2011-12-9-r92"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s41436-019-0613-z","article-title":"The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency","volume":"22","author":"Keshavan","year":"2020","journal-title":"Genet. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1001\/archneurol.2009.139","article-title":"Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B","volume":"66","author":"Shaibani","year":"2009","journal-title":"Arch. Neurol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Lee, H., and Yoon, Y. (2018). Mitochondrial Membrane Dynamics-Functional Positioning of OPA1. Antioxidants, 7.","DOI":"10.3390\/antiox7120186"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Zeng, T., Liao, L., Guo, Y., Liu, X., Xiong, X., Zhang, Y., Cen, S., Li, H., and Wei, S. (2020). Concurrent OPA1 mutation and chromosome 3q deletion leading to Behr syndrome: A case report. BMC Pediatr., 20.","DOI":"10.1186\/s12887-020-02309-0"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/ana.24410","article-title":"Syndromic parkinsonism and dementia associated with OPA1 missense mutations","volume":"78","author":"Carelli","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1093\/brain\/awq007","article-title":"Multi-system neurological disease is common in patients with OPA1 mutations","volume":"133","author":"Griffiths","year":"2010","journal-title":"Brain"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/1750-1172-7-46","article-title":"Dominant optic atrophy","volume":"7","author":"Romagnoli","year":"2012","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1002\/acn3.51026","article-title":"Idebenone increases chance of stabilization\/recovery of visual acuity in OPA1-dominant optic atrophy","volume":"7","author":"Gedikbasi","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1191159","DOI":"10.3389\/fgene.2023.1191159","article-title":"Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases","volume":"14","author":"Gedikbasi","year":"2023","journal-title":"Front. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"225","DOI":"10.3233\/JND-210786","article-title":"Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies","volume":"9","author":"Berardo","year":"2022","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3550","DOI":"10.1007\/s00415-021-10957-0","article-title":"Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis","volume":"269","author":"Moore","year":"2022","journal-title":"J. Neurol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/ana.25506","article-title":"Deoxynucleoside Therapy for Thymidine Kinase 2\u2013Deficient Myopathy","volume":"86","author":"Mavillard","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_79","first-page":"5918632","article-title":"CPEO and Mitochondrial Myopathy in a Patient with DGUOK Compound Heterozygous Pathogenetic Variant and mtDNA Multiple Deletions","volume":"2019","author":"Montano","year":"2019","journal-title":"Case Rep. Neurol. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"64","DOI":"10.3109\/10409238.2011.632763","article-title":"Defects in mitochondrial DNA replication and human disease","volume":"47","author":"Copeland","year":"2011","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1002\/lt.21556","article-title":"Abnormal neurological features predict poor survival and should preclude liver transplantation in patients with deoxyguanosine kinase deficiency","volume":"14","author":"Dimmock","year":"2008","journal-title":"Liver Transplant."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1002\/humu.9519","article-title":"Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase","volume":"29","author":"Dimmock","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"487","DOI":"10.3892\/br.2017.892","article-title":"Renal manifestations of primary mitochondrial disorders (Review)","volume":"6","author":"Finsterer","year":"2017","journal-title":"Biomed. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.1093\/brain\/awx301","article-title":"DGUOK recessive mutations in patients with CPEO, mitochondrial myopathy, parkinsonism and mtDNA deletions","volume":"141","author":"Caporali","year":"2017","journal-title":"Brain"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1002\/lt.23830","article-title":"Long-term outcomes after liver transplantation for deoxyguanosine kinase deficiency: A single-center experience and a review of the literature","volume":"20","author":"Grabhorn","year":"2014","journal-title":"Liver Transplant."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"8749","DOI":"10.1093\/nar\/gkac661","article-title":"Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion","volume":"50","author":"Misic","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"906667","DOI":"10.3389\/fgene.2022.906667","article-title":"Case Report: Rare Homozygous RNASEH1 Mutations Associated with Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions","volume":"13","author":"Manini","year":"2022","journal-title":"Front. Genet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e149","DOI":"10.1212\/NXG.0000000000000149","article-title":"Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease","volume":"3","author":"Bugiardini","year":"2017","journal-title":"Neurol. Genet."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"5861","DOI":"10.1093\/nar\/gkw468","article-title":"MGME1 processes flaps into ligatable nicks in concert with DNA polymerase \u03b3 during mtDNA replication","volume":"44","author":"Uhler","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1093\/nar\/gkt029","article-title":"Identification of a novel human mitochondrial endo-\/exonuclease Ddk1\/c20orf72 necessary for maintenance of proper 7S DNA levels","volume":"41","author":"Szczesny","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/bs.enz.2019.08.004","article-title":"Mitochondrial DNA degradation: A quality control measure for mitochondrial genome maintenance and stress response","volume":"45","author":"Zhao","year":"2019","journal-title":"Enzymes"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/ng.2501","article-title":"Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease","volume":"45","author":"Kornblum","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.nmd.2023.06.004","article-title":"A case of mitochondrial DNA depletion syndrome type 11\u2014Expanding the genotype and phenotype","volume":"33","author":"Rocha","year":"2023","journal-title":"Neuromuscul. Disord."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.bbabio.2009.01.014","article-title":"Adenine nucleotide translocator 1 deficiency increases resistance of mouse brain and neurons to excitotoxic insults","volume":"1787","author":"Lee","year":"2009","journal-title":"Biochim. Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1136\/jmedgenet-2011-100504","article-title":"Complete loss of expression of the ANT1 gene causing cardiomyopathy and myopathy","volume":"49","author":"Chassagne","year":"2012","journal-title":"J. Med. Genet."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1007\/s00109-016-1413-4","article-title":"Transgenic overexpression of adenine nucleotide translocase 1 protects ischemic hearts against oxidative stress","volume":"94","author":"Klumpe","year":"2016","journal-title":"J. Mol. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2964","DOI":"10.1093\/hmg\/ddr200","article-title":"adPEO mutations in ANT1 impair ADP-ATP translocation in muscle mitochondria","volume":"20","author":"Kawamata","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3453","DOI":"10.1073\/pnas.1300690110","article-title":"Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup","volume":"110","author":"Strauss","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e60827","DOI":"10.7554\/eLife.60827","article-title":"Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte","volume":"9","author":"Zhang","year":"2020","journal-title":"eLife"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"101560","DOI":"10.1016\/j.molmet.2022.101560","article-title":"Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice","volume":"64","author":"Schaefer","year":"2022","journal-title":"Mol. Metab."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"20285","DOI":"10.1074\/jbc.RA118.004788","article-title":"The mitochondrial inner membrane protein MPV17 prevents uracil accumulation in mitochondrial DNA","volume":"293","author":"Alonzo","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"641264","DOI":"10.3389\/fncel.2021.641264","article-title":"MPV17 Mutations Are Associated with a Quiescent Energetic Metabolic Profile","volume":"15","author":"Jacinto","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.nmd.2012.03.006","article-title":"MPV17 mutation causes neuropathy and leukoencephalopathy with multiple mtDNA deletions in muscle","volume":"22","author":"Blakely","year":"2012","journal-title":"Neuromuscul. Disord."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/ejhg.2013.112","article-title":"Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene","volume":"22","author":"Uusimaa","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1002\/jimd.12142","article-title":"Plasma FGF-21 and GDF-15 are elevated in different inherited metabolic diseases and are not diagnostic for mitochondrial disorders","volume":"42","author":"Tsygankova","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1002\/ana.24506","article-title":"Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders","volume":"78","author":"Yatsuga","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1212\/WNL.0000000000002705","article-title":"A comparison of current serum biomarkers as diagnostic indicators of mitochondrial diseases","volume":"86","author":"Davis","year":"2016","journal-title":"Neurology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1212\/01.WNL.0000033795.17156.00","article-title":"Diagnostic criteria for respiratory chain disorders in adults and children","volume":"59","author":"Bernier","year":"2002","journal-title":"Neurology"},{"key":"ref_109","first-page":"188","article-title":"New diagnostic pathways for mitochondrial disease","volume":"4","author":"Eloise","year":"2020","journal-title":"J. Transl. Genet. Genom."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1002\/mus.20368","article-title":"Exercise training in mitochondrial myopathy: A randomized controlled trial","volume":"32","author":"Cejudo","year":"2005","journal-title":"Muscle Nerve"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"349","DOI":"10.3389\/fphys.2020.00349","article-title":"Aerobic Exercise Training in Patients with mtDNA-Related Mitochondrial Myopathy","volume":"11","author":"Jeppesen","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1186\/s13023-021-01927-w","article-title":"Ketogenic diet for mitochondrial disease: A systematic review on efficacy and safety","volume":"16","author":"Zweers","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.bbadis.2016.11.017","article-title":"Mitochondrial defects arise from nucleoside\/nucleotide reverse transcriptase inhibitors in neurons: Potential contribution to HIV-associated neurocognitive disorders","volume":"1863","author":"Hung","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"212588","DOI":"10.7573\/dic.212588","article-title":"Mitochondrial disorders and drugs: What every physician should know","volume":"8","author":"Orsucci","year":"2019","journal-title":"Drugs Context"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1097\/WCO.0000000000000743","article-title":"Advances in primary mitochondrial myopathies","volume":"32","author":"Emmanuele","year":"2019","journal-title":"Curr. Opin. Neurol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jgg.2017.11.008","article-title":"The current landscape for the treatment of mitochondrial disorders","volume":"45","author":"Slone","year":"2018","journal-title":"J. Genet. Genom."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e2328","DOI":"10.1002\/mgg3.2328","article-title":"The clinical, myopathological, and genetic analysis of 155 Chinese mitochondrial ophthalmoplegia patients with mitochondrial DNA single large deletions","volume":"12","author":"Zhao","year":"2023","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.4103\/0366-6999.191855","article-title":"Diagnosis and Management of Kearns-Sayre Syndrome Rely on Comprehensive Clinical Evaluation","volume":"129","author":"Yu","year":"2016","journal-title":"Chin. Med. J."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"802402","DOI":"10.3389\/fgene.2022.802402","article-title":"Case Report: Clinical and Genetic Characteristics of Pearson Syndrome in a Chinese Boy and 139 Patients","volume":"13","author":"Ying","year":"2022","journal-title":"Front. Genet."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s00417-002-0555-y","article-title":"Pigmentary retinopathy in patients with the MELAS mutation 3243A\u2192G in mitochondrial DNA","volume":"240","author":"Latvala","year":"2002","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_121","first-page":"1490181","article-title":"MELAS Syndrome with Cardiac Involvement: A Multimodality Imaging Approach","volume":"2016","author":"Seitun","year":"2016","journal-title":"Case Rep. Cardiol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1097\/NRL.0000000000000457","article-title":"Comprehensive Diagnostic Criteria for MELAS Syndrome; a Case Study Involving an Elderly Patient With MT-TWm.5541C>T Mutation","volume":"28","author":"Wu","year":"2023","journal-title":"Neurologist"},{"key":"ref_123","first-page":"e22716","article-title":"Intractable Epilepsy in Maternally Inherited Leigh Syndrome (MILS) Due to the Sporadic Variant m.8993T>G in MT-ATP6: A Case Report","volume":"14","author":"Finsterer","year":"2022","journal-title":"Cureus"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1097\/CND.0000000000000422","article-title":"Neuropathy, Ataxia, and Retinitis Pigmentosa Syndrome","volume":"24","author":"Finsterer","year":"2023","journal-title":"J. Clin. Neuromuscul. Dis."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1077395","DOI":"10.3389\/fopht.2022.1077395","article-title":"Leber\u2019s hereditary optic neuropathy: Update on current diagnosis and treatment","volume":"2","author":"Esmaeil","year":"2023","journal-title":"Front. Ophthalmol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"728043","DOI":"10.3389\/fendo.2021.728043","article-title":"The Mutations and Clinical Variability in Maternally Inherited Diabetes and Deafness: An Analysis of 161 Patients","volume":"12","author":"Yang","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.pediatrneurol.2017.12.005","article-title":"MERRF Classification: Implications for Diagnosis and Clinical Trials","volume":"80","author":"Finsterer","year":"2018","journal-title":"Pediatr. Neurol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1136\/jnnp-2013-306748","article-title":"SANDO syndrome in a cohort of 107 patients with CPEO and mitochondrial DNA deletions","volume":"86","author":"Hanisch","year":"2015","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1016\/j.nmd.2020.04.008","article-title":"MRI findings in SANDO variety of the ataxia-neuropathy spectrum with a novel mutation in POLG (c.3287G>T): A case report","volume":"30","year":"2020","journal-title":"Neuromuscul. Disord."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1001\/archneur.62.5.745","article-title":"New DGK gene mutations in the hepatocerebral form of mitochondrial DNA depletion syndrome","volume":"62","author":"Mancuso","year":"2005","journal-title":"Arch. Neurol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.ymgme.2009.10.003","article-title":"MPV17-associated hepatocerebral mitochondrial DNA depletion syndrome: New patients and novel mutations","volume":"99","author":"Li","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1002\/humu.23387","article-title":"MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects","volume":"39","author":"Wang","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.ajhg.2012.12.014","article-title":"Mutations in DNA2 Link Progressive Myopathy to Mitochondrial DNA Instability","volume":"92","author":"Ronchi","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Borsche, M., Dulovic-Mahlow, M., Baumann, H., Tunc, S., L\u00fcth, T., Schaake, S., \u00d6zcakir, S., Westenberger, A., M\u00fcnchau, A., and Knappe, E. (Cerebellum, 2023). POLG2-Linked Mitochondrial Disease: Functional Insights from New Mutation Carriers and Review of the Literature, Cerebellum, ahead of print.","DOI":"10.1007\/s12311-023-01557-x"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.1002\/mdc3.13538","article-title":"Levodopa Responsive Dystonia Parkinsonism, Intellectual Disability, and Optic Atrophy Due to a Heterozygous Missense Variant in AFG3L2","volume":"9","author":"Wong","year":"2022","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_136","unstructured":"Darras, B.T., Jones, H.R., Ryan, M.M., and De Vivo, D.C. (2015). Neuromuscular Disorders of Infancy, Childhood, and Adolescence, Academic Press. [2nd ed.]."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1001\/jamaneurol.2014.1753","article-title":"Clonal Expansion of Secondary Mitochondrial DNA Deletions Associated With Spinocerebellar Ataxia Type 28","volume":"72","author":"Gorman","year":"2015","journal-title":"JAMA Neurol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1093\/brain\/awu060","article-title":"Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance","volume":"137","author":"Pfeffer","year":"2014","journal-title":"Brain"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"e16775","DOI":"10.15252\/emmm.202216775","article-title":"Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability","volume":"15","author":"Erdinc","year":"2023","journal-title":"EMBO Mol. Med."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1111\/cge.14287","article-title":"Chronic progressive external ophthalmoplegia plus syndrome due to homozygous missense variant in TOP3A gene","volume":"103","author":"Sotoca","year":"2023","journal-title":"Clin. Genet."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"e145660","DOI":"10.1172\/JCI145660","article-title":"RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis","volume":"132","author":"Shintaku","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.ajhg.2017.08.015","article-title":"Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies","volume":"101","author":"Feichtinger","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1002\/humu.24081","article-title":"Homozygous mutations in C1QBP as cause of progressive external ophthalmoplegia (PEO) and mitochondrial myopathy with multiple mtDNA deletions","volume":"41","author":"Marchet","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1111\/cge.13652","article-title":"Identification of a novel heterozygous guanosine monophosphate reductase (GMPR) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance","volume":"97","author":"Sommerville","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"2326409817707771","DOI":"10.1177\/2326409817707771","article-title":"Coenzyme Q10 in the Treatment of Mitochondrial Disease","volume":"5","author":"Neergheen","year":"2017","journal-title":"J. Inborn Errors Metab. Screen."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1590\/1414-431x20143467","article-title":"Effect of L-carnitine on exercise performance in patients with mitochondrial myopathy","volume":"48","author":"Gimenes","year":"2015","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Virmani, M.A., and Cirulli, M. (2022). The Role of l-Carnitine in Mitochondria, Prevention of Metabolic Inflexibility and Disease Initiation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052717"},{"key":"ref_148","first-page":"285","article-title":"Riboflavin metabolism: Role in mitochondrial function","volume":"4","author":"Shanti","year":"2020","journal-title":"J. Transl. Genet. Genom."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/jimd.12125","article-title":"Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies","volume":"42","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.jns.2019.07.007","article-title":"Genetic heterogeneity of mitochondrial genome in thiamine deficient Leigh syndrome patients","volume":"404","author":"Mani","year":"2019","journal-title":"J. Neurol. Sci."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1007\/s11064-007-9403-0","article-title":"The Effects and Mechanisms of Mitochondrial Nutrient \u03b1-Lipoic Acid on Improving Age-Associated Mitochondrial and Cognitive Dysfunction: An Overview","volume":"33","author":"Liu","year":"2008","journal-title":"Neurochem. Res."},{"key":"ref_152","first-page":"454253","article-title":"The Effect of Lipoic Acid Therapy on Cognitive Functioning in Patients with Alzheimer\u2019s Disease","volume":"2013","author":"Fava","year":"2013","journal-title":"J. Neurodegener. Dis."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.biocel.2017.04.002","article-title":"Neurochemical effects of the R form of \u03b1-lipoic acid and its neuroprotective mechanism in cellular models of Parkinson\u2019s disease","volume":"87","author":"Zhao","year":"2017","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1002\/ana.20746","article-title":"Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion","volume":"59","author":"Pineda","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1186\/s13023-014-0217-2","article-title":"Follow-up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome","volume":"9","author":"Montero","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1055\/s-2007-991150","article-title":"Mitochondrial complex I encephalomyopathy and cerebral 5-methyltetrahydrofolate deficiency","volume":"38","author":"Ramaekers","year":"2007","journal-title":"Neuropediatrics"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1096\/fj.03-0240fje","article-title":"Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants","volume":"17","author":"Jauslin","year":"2003","journal-title":"FASEB J."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"100037","DOI":"10.1016\/j.arres.2022.100037","article-title":"Pharmacological significance of MitoQ in ameliorating mitochondria-related diseases","volume":"5","author":"Sulaimon","year":"2022","journal-title":"Adv. Redox Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"eadd5163","DOI":"10.1126\/sciadv.add5163","article-title":"Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study","volume":"9","author":"Lapatto","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_160","doi-asserted-by":"crossref","unstructured":"Airhart, S.E., Shireman, L.M., Risler, L.J., Anderson, G.D., Gowda, G.A.N., Raftery, D., Tian, R., Shen, D.D., and O\u2019Brien, K.D. (2017). An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186459"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.ymgme.2016.01.010","article-title":"Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation","volume":"117","author":"Emrick","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.jacbts.2018.12.005","article-title":"Elamipretide Improves Mitochondrial Function in the Failing Human Heart","volume":"4","author":"Chatfield","year":"2019","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1007\/s10741-021-10177-8","article-title":"Elamipretide for Barth syndrome cardiomyopathy: Gradual rebuilding of a failed power grid","volume":"27","author":"Sabbah","year":"2022","journal-title":"Heart Fail. Rev."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1186\/s13023-022-02469-5","article-title":"Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome","volume":"17","author":"Hornby","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"11733","DOI":"10.1038\/s41598-017-09417-5","article-title":"Therapeutic effects of the mitochondrial ROS-redox modulator KH176 in a mammalian model of Leigh Disease","volume":"7","author":"Das","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"552","DOI":"10.3389\/fneur.2018.00552","article-title":"KL1333, a Novel NAD(+) Modulator, Improves Energy Metabolism and Mitochondrial Dysfunction in MELAS Fibroblasts","volume":"9","author":"Seo","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_167","doi-asserted-by":"crossref","unstructured":"Li, Y., Liu, H., Zeng, W., and Wei, J. (2017). Edaravone protects against hyperosmolarity-induced oxidative stress and apoptosis in primary human corneal epithelial cells. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174437"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1182\/blood-2018-99-113773","article-title":"First-in-Human Mitochondrial Augmentation of Hematopoietic Stem Cells in Pearson Syndrome","volume":"132","author":"Jacoby","year":"2018","journal-title":"Blood"},{"key":"ref_169","doi-asserted-by":"crossref","unstructured":"Zelissen, R., Ahmadian, S., Montilla-Rojo, J., Timmer, E., Ummelen, M., Hopman, A., Smeets, H., and van Tienen, F. (2023). Fusion of Wild-Type Mesoangioblasts with Myotubes of mtDNA Mutation Carriers Leads to a Proportional Reduction in mtDNA Mutation Load. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032679"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1186\/s13287-019-1510-8","article-title":"Healthy, mtDNA-mutation free mesoangioblasts from mtDNA patients qualify for autologous therapy","volume":"10","author":"Zelissen","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"e28926","DOI":"10.1002\/pbc.28926","article-title":"Hematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalopathy: A single-center experience underscoring the multiple factors involved in the prognosis","volume":"68","author":"Zaidman","year":"2021","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/brain\/awv226","article-title":"Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy","volume":"138","author":"Halter","year":"2015","journal-title":"Brain"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/14\/2\/135\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:50:31Z","timestamp":1760104231000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/14\/2\/135"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,27]]},"references-count":172,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["brainsci14020135"],"URL":"https:\/\/doi.org\/10.3390\/brainsci14020135","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,27]]}}}