Background Mitochondrial 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.
Methods Retrospective analysis of the clinical, pathological and genetic features of 89 cases.
Results Three 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.
Conclusions Phenotype–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.
- clinical genetics
- muscle disease
- molecular genetics
- neuromuscular disease
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CR-L and LMG-C contributed equally.
Contributors CR-L and LMG-C carried out the systematic review analysis, collected the data, performed the statistical analysis and drafted the manuscript. AB and PS-L contributed to the diagnosis with laboratory investigations. GG-G, BSMT and NM performed the clinical diagnosis and communication with patients, and provided clinical data to classify the patients. GG-G and CD-G contributed to the diagnosis of patients in Madrid region. BSMT contributed to the diagnosis of patients in Galicia region. NM and JJV contributed to the diagnosis of patients in Valencia region. AH-L performed, analysed and interpreted the muscle tissue pathological data and critically revised the manuscript. JJV provided clinical data and relevant content according to his expertise to analyse the whole clinical data, and critically revised the manuscript. EG-R and JA contributed relevant content according to their expertise to analyse and interpret the whole clinical data, and critically revised the manuscript for important intellectual content. MAM contributed to the diagnosis with laboratory investigations, analysed and interpreted the data, and drafted and critically revised the manuscript. CD-G conceived the work, provided clinical data and drafted the manuscript. All authors revised and approved the final version of the manuscript to be published.
Funding This work was supported by the Spanish Instituto de Salud Carlos III (ISCIII) and the European Regional Development Fund (ERDF; FEDER) (grants PI18/01374 and PI15/00431 to MAM).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The study was approved by the local ethics committee (IRB) in accordance with the Declaration of Helsinki.
Provenance and peer review Not commissioned; externally peer reviewed.