Clinical, pathological and genetic spectrum in 89 cases of mitochondrial progressive external ophthalmoplegia

• Published in: Journal of medical genetics Vol. 57; no. 9; pp. 643 - 646
• Main Authors: Rodríguez-López, Claudia, García-Cárdaba, Luis M., Blázquez, Alberto, Serrano-Lorenzo, Pablo, Gutiérrez-Gutiérrez, Gerardo, San Millán-Tejado, Beatriz, Muelas, Nuria, Hernández-Laín, Aurelio, Vílchez, Juan J., Gutiérrez-Rivas, Eduardo, Arenas, Joaquín, Martín, Miguel A., Domínguez-González, Cristina
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.09.2020
• Subjects: Age; Biopsy; Defects; Deoxyribonucleic acid; Diplopia; DNA; Dysarthria; Dysphagia; Family medical history; Genes; Genetic disorders; Genetic screening; Genotype & phenotype; Genotypes; Kinases; Laboratories; Mitochondrial DNA; Musculoskeletal system; Mutation; Ophthalmoplegia; Patients; Phenotypes; molecular genetics; neuromuscular disease; diagnostics; muscle disease; clinical genetics
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmedgenet-2019-106649

BackgroundMitochondrial progressive external ophthalmoplegia (PEO) encompasses a broad spectrum of clinical and genetic disorders. We describe the phenotypic subtypes of PEO and its correlation with molecular defects and propose a diagnostic algorithm.MethodsRetrospective analysis of the clinical, pathological and genetic features of 89 cases.ResultsThree main phenotypes were found: ‘pure PEO’ (42%), consisting of isolated palpebral ptosis with ophthalmoparesis; Kearns-Sayre syndrome (10%); and ‘PEO plus’, which associates extraocular symptoms, distinguishing the following subtypes: : myopathic (33%), bulbar (12%) and others (3%). Muscle biopsy was the most accurate test, showing mitochondrial changes in 95%. Genetic diagnosis was achieved in 96% of the patients. Single large-scale mitochondrial DNA (mtDNA) deletion was the most frequent finding (63%), followed by multiple mtDNA deletions (26%) due to mutations in TWNK (n=8), POLG (n=7), TK2 (n=6) or RRM2B (n=2) genes, and point mtDNA mutations (7%). Three new likely pathogenic mutations were identified in the TWNK and MT-TN genes.ConclusionsPhenotype–genotype correlations cannot be brought in mitochondrial PEO. Muscle biopsy should be the first step in the diagnostic flow of PEO when mitochondrial aetiology is suspected since it also enables the study of mtDNA rearrangements. If no mtDNA deletions are identified, whole mtDNA sequencing should be performed.