Pathogenic role of mtDNA duplications in mitochondrial diseases associated with mtDNA deletions

Francesca Odoardi, Michele Rana, Aldobrando Broccolini, Massimiliano Mirabella, Anna Modoni, Adele D'Amico, Manuela Papacci, Pietro Tonali, Serenella Servidei, Gabriella Silvestri

Research output: Contribution to journalArticlepeer-review


We estimated the frequency of multiple mtDNA rearrangements by Southern blot in 32 patients affected by mitochondrial disorders associated with single deletions in order to assess genotype-phenotype correlations and elucidate the pathogenic significance of mtDNA duplications. Muscle in situ hybridization studies were performed in patients showing mtDNA duplications at Southern blot. We found multiple rearrangements in 12/32 (37.5%) patients; in particular, mtDNA duplications were detected in 4/4 Kearns-Sayre syndrome (KSS), in 1 Pearson's syndrome, in 1/3 encephalomyopathies with progressive external ophthalmoplegia (PEO), and in 2/23 PEO. In situ studies documented an exclusive accumulation of deleted mtDNAs in cytochrome c oxidase negative fibers of patients with mtDNA duplications. The presence of mtDNA duplications significantly correlated with onset of symptoms before age 15 and occurrence of clinical multi-system involvement. Analysis of biochemical data documented a predominant reduction of complex III in patients without duplications compared to patients with mtDNA duplications. Our data indicate that multiple mtDNA rearrangements are detectable in a considerable proportion of patients with single deletions and that mtDNA duplications do not cause any oxidative impairment. They more likely play a pathogenic role in the determination of clinical expression of mitochondrial diseases associated with single mtDNA deletions, possibly generating deleted mtDNAs in embryonic tissues by homologous recombination.

Original languageEnglish
Pages (from-to)247-254
Number of pages8
JournalAmerican Journal of Medical Genetics
Volume118 A
Issue number3
Publication statusPublished - Apr 30 2003


  • Mitochondrial encephalomyopathies
  • MtDNA deletions
  • MtDNA duplications
  • Multiple mtDNA rearrangements

ASJC Scopus subject areas

  • Genetics(clinical)


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