1. Clinical, pathological and genetic spectrum in 89 cases of mitochondrial progressive external ophthalmoplegia
- Author
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Juan J. Vílchez, Eduardo Gutiérrez-Rivas, Nuria Muelas, Beatriz San Millán-Tejado, Gerardo Gutiérrez-Gutiérrez, Claudia Rodríguez-López, Luis M. García-Cárdaba, Alberto Blázquez, Joaquín Arenas, Aurelio Hernández-Laín, Miguel A. Martín, Cristina Domínguez-González, and Pablo Serrano-Lorenzo
- Subjects
Male ,0301 basic medicine ,Ophthalmoplegia, Chronic Progressive External ,medicine.medical_specialty ,Mitochondrial DNA ,Pathology ,Mitochondrial Diseases ,Adolescent ,Biopsy ,Cell Cycle Proteins ,Kearns-Sayre Syndrome ,Biology ,DNA, Mitochondrial ,Thymidine Kinase ,Ophthalmoparesis ,Mitochondrial Proteins ,03 medical and health sciences ,0302 clinical medicine ,Ptosis ,Molecular genetics ,Ribonucleotide Reductases ,diagnostics ,Genetics ,medicine ,Humans ,Point Mutation ,Child ,Muscle, Skeletal ,Genetics (clinical) ,Muscle biopsy ,medicine.diagnostic_test ,External ophthalmoplegia ,DNA Helicases ,Infant, Newborn ,Infant ,neuromuscular disease ,DNA Polymerase gamma ,Mitochondria ,Phenotype ,030104 developmental biology ,Palpebral fissure ,muscle disease ,Child, Preschool ,molecular genetics ,Medical genetics ,Female ,medicine.symptom ,clinical genetics ,030217 neurology & neurosurgery - Abstract
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.
- Published
- 2020
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