Leber Hereditary Optic Neuropathy: Exemplar of an mtDNA Disease

Part of the Handbook of Experimental Pharmacology book series (HEP, volume 240)


The report in 1988 that Leber Hereditary Optic Neuropathy (LHON) was the product of mitochondrial DNA (mtDNA) mutations provided the first demonstration of the clinical relevance of inherited mtDNA variation. From LHON studies, the medical importance was demonstrated for the mtDNA showing its coding for the most important energy genes, its maternal inheritance, its high mutation rate, its presence in hundreds to thousands of copies per cell, its quantitatively segregation of biallelic genotypes during both mitosis and meiosis, its preferential effect on the most energetic tissues including the eye and brain, its wide range of functional polymorphisms that predispose to common diseases, and its accumulation of mutations within somatic tissues providing the aging clock. These features of mtDNA genetics, in combination with the genetics of the 1–2000 nuclear DNA (nDNA) coded mitochondrial genes, is not only explaining the genetics of LHON but also providing a model for understanding the complexity of many common diseases. With the maturation of LHON biology and genetics, novel animal models for complex disease have been developed and new therapeutic targets and strategies envisioned, both pharmacological and genetic. Multiple somatic gene therapy approaches are being developed for LHON which are applicable to other mtDNA diseases. Moreover, the unique cytoplasmic genetics of the mtDNA has permitted the first successful human germline gene therapy via spindle nDNA transfer from mtDNA mutant oocytes to enucleated normal mtDNA oocytes. Such LHON lessons are actively being applied to common ophthalmological diseases like glaucoma and neurological diseases like Parkinsonism.


Animal models Estrogen receptor beta Gene therapy Haplogroup Leber’s hereditary optic neuropathy LHON Mitochondrial disease Mitochondrial DNA Mitochondrial physiology mtDNA copy number Oxidative stress Retinal ganglion cells Transmitochondrial cybrids 



This work was supported by NIH grant 5R01-NS021328-30 awarded to DCW.


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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  2. 2.Department of Pathology and Laboratory MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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