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Original Article
Phenotype-genotype correlations in Leigh syndrome: new insights from a multicentre study of 96 patients
  1. Kalliopi Sofou1,
  2. Irenaeus F M de Coo2,
  3. Elsebet Ostergaard3,
  4. Pirjo Isohanni4,5,
  5. Karin Naess6,
  6. Linda De Meirleir7,
  7. Charalampos Tzoulis8,9,
  8. Johanna Uusimaa10,11,
  9. Tuula Lönnqvist4,
  10. Laurence Albert Bindoff8,9,
  11. Már Tulinius1,
  12. Niklas Darin1
  1. 1 Department of Pediatrics, The Queen Silvia Children’s Hospital, University of Gothenburg, Gothenburg, Sweden
  2. 2 Department of Neurology, The Erasmus University Medical Center, Rotterdam, Netherlands
  3. 3 Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
  4. 4 Department of Paediatric Neurology, Children’s Hospital, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
  5. 5 Research Programs Unit, Molecular Neurology, Biomedicum, University of Helsinki, Helsinki, Finland
  6. 6 Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden
  7. 7 Department of Paediatric Neurology, University Hospital Vrije Universiteit Brussel (VUB), Brussels, Belgium
  8. 8 Department of Neurology, Haukeland University Hospital, Bergen, Norway
  9. 9 Department of Clinical Medicine, University of Bergen, Bergen, Norway
  10. 10 Department of Paediatrics, Institute of Clinical Medicine, University of Oulu, Oulu, Finland
  11. 11 Medical Research Center, Oulu University Hospital, Oulu, Finland
  1. Correspondence to Dr Kalliopi Sofou, Department of Pediatrics, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden; kalliopi.sofou{at}


Background Leigh syndrome is a phenotypically and genetically heterogeneous mitochondrial disorder. While some genetic defects are associated with well-described phenotypes, phenotype-genotype correlations in Leigh syndrome are not fully explored.

Objective We aimed to identify phenotype-genotype correlations in Leigh syndrome in a large cohort of systematically evaluated patients.

Methods We studied 96 patients with genetically confirmed Leigh syndrome diagnosed and followed in eight European centres specialising in mitochondrial diseases.

Results We found that ataxia, ophthalmoplegia and cardiomyopathy were more prevalent among patients with mitochondrial DNA defects. Patients with mutations in MT-ND and NDUF genes with complex I deficiency shared common phenotypic features, such as early development of central nervous system disease, followed by high occurrence of cardiac and ocular manifestations. The cerebral cortex was affected in patients with NDUF mutations significantly more often than the rest of the cohort. Patients with the m.8993T>G mutation in MT-ATP6 gene had more severe clinical and radiological manifestations and poorer disease outcome compared with patients with the m.8993T>C mutation.

Conclusion Our study provides new insights into phenotype-genotype correlations in Leigh syndrome and particularly in patients with complex I deficiency and with defects in the mitochondrial ATP synthase.

  • Leigh syndrome
  • mitochondrial DNA
  • complex I
  • genetic
  • MRI

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  • Contributors All authors have contributed to the planning, conduct and reporting of the work described in this paper. Moreover, KS coordinated the conduct of this work and ND is responsible for the overall content as guarantor.

  • Competing interests None declared.

  • Ethics approval Ethical Committee at the University of Gothenburg and local ethical committees at the respective centres as per the standing regulatory requirements.

  • Provenance and peer review Not commissioned; externally peer reviewed.