Understanding the molecular basis and pathogenesis of hereditary optic neuropathies: towards improved diagnosis and management

Lancet Neurol. 2023 Feb;22(2):172-188. doi: 10.1016/S1474-4422(22)00174-0. Epub 2022 Sep 22.


Hereditary optic neuropathies result from defects in the human genome, both nuclear and mitochondrial. The two main and most recognised phenotypes are dominant optic atrophy and Leber hereditary optic neuropathy. Advances in modern molecular diagnosis have expanded our knowledge of genotypes and phenotypes of inherited disorders that affect the optic nerve, either alone or in combination, with various forms of neurological and systemic degeneration. A unifying feature in the pathophysiology of these disorders appears to involve mitochondrial dysfunction, suggesting that the retinal ganglion cells and their axons are especially susceptible to perturbations in mitochondrial homoeostasis. As we better understand the pathogenesis behind these genetic diseases, aetiologically targeted therapies are emerging and entering into clinical trials, including treatments aimed at halting the cascade of neurodegeneration, replacing or editing the defective genes or their protein products, and potentially regenerating damaged optic nerves, as well as preventing generational disease transmission.

Publication types

  • Review

MeSH terms

  • DNA, Mitochondrial / genetics
  • Humans
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Optic Atrophy, Autosomal Dominant* / diagnosis
  • Optic Atrophy, Autosomal Dominant* / genetics
  • Optic Atrophy, Autosomal Dominant* / therapy
  • Optic Atrophy, Hereditary, Leber* / diagnosis
  • Optic Atrophy, Hereditary, Leber* / genetics
  • Optic Atrophy, Hereditary, Leber* / therapy
  • Optic Nerve
  • Optic Nerve Diseases* / diagnosis
  • Optic Nerve Diseases* / genetics
  • Optic Nerve Diseases* / therapy


  • DNA, Mitochondrial