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

  1. Claudia Rodriguez-Lopez1,
  2. Luis M. Garcia-Cardaba1,
  3. Alberto Blazquez2,3,
  4. Pablo Serrano-Lorenzo4,
  5. Gerardo Gutierrez-Gutierrez5,
  6. Beatriz San Millan-Tejado6,
  7. Nuria Muelas3,7,
  8. Aurelio Hernandez-Lain8,
  9. Juan J. Vilchez3,9,10,
  10. Eduardo Gutierrez-Rivas1,
  11. Joaquin Arenas2,3,
  12. Miguel A. Martin2,3,
  13. Cristina Dominguez-Gonzalez3,4,11
  1. 1
    Neurology, Hospital Universitario 12 de Octubre, Madrid, Comunidad de Madrid, Spain
  2. 2
    Mitochondrial Disorders Laboratory, Clinical Biochemistry Department, Hospital Universitario 12 de Octubre. Instituto de Investigacion Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
  3. 3
    Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain
  4. 4
    Mitochondrial Disorders Research Group, Instituto de Investigacion Sanitaria Hospital 12 de Octubre (imas12), Madrid, Comunidad de Madrid, Spain
  5. 5
    Neurology, Hospital Universitario Infanta Sofia, San Sebastian de los Reyes, Madrid, Spain
  6. 6
    Pathology, Complejo Hospitalario de Vigo Hospital Xeral, Vigo, Galicia, Spain
  7. 7
    Neurology, Hospital Universitari i Politecnic La Fe, Valencia, Valenciana, Spain
  8. 8
    Pathology, Neuropathology Section, Hospital Universitario 12 de Octubre, Madrid, Comunidad de Madrid, Spain
  9. 9
    Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari i Politecnic La Fe, Valencia, Valenciana, Spain
  10. 10
    Neuromuscular and Ataxias Research Group, Instituto de Investigacion Sanitaria La Fe, Valencia, Spain
  11. 11
    Neuromuscular Unit, Hospital Universitario 12 de Octubre, Madrid, Comunidad de Madrid, Spain
  1. Correspondence to
    Dr Miguel A. Martin, Mitochondrial Disorders Laboratory, Hospital Universitario 12 de Octubre, Madrid 28041, Spain; mamcasanueva.imas12{at}h12o.es

Abstract

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
  • diagnostics
  • muscle disease
  • molecular genetics
  • neuromuscular disease

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