Leigh syndrome: neuropathology and pathogenesis

J Neuropathol Exp Neurol. 2015 Jun;74(6):482-92. doi: 10.1097/NEN.0000000000000195.

Abstract

Leigh syndrome (LS) is the most common pediatric presentation of a defined mitochondrial disease. This progressive encephalopathy is characterized pathologically by the development of bilateral symmetrical lesions in the brainstem and basal ganglia that show gliosis, vacuolation, capillary proliferation, relative neuronal preservation, and by hyperlacticacidemia in the blood and/or cerebrospinal fluid. Understanding the molecular mechanisms underlying this unique pathology has been challenging, particularly in view of the heterogeneous and not yet fully determined genetic basis of LS. Moreover, animal models that mimic features of LS have only been created relatively recently. Here, we review the pathology of LS and consider what might be the molecular mechanisms underlying its pathogenesis. Data from a wide range of sources, including patient samples, animal models, and studies of hypoxic-ischemic encephalopathy (a condition that shares features with LS), were used to provide insight into the pathogenic mechanisms that may drive lesion development. Based on current data, we suggest that severe ATP depletion, gliosis, hyperlacticacidemia, reactive oxygen species, and potentially excitotoxicity cumulatively contribute to the neuropathogenesis of LS. An intimate understanding of the molecular mechanisms causing LS is required to accelerate the development of LS treatments.

Publication types

  • Review

MeSH terms

  • Adenosine Triphosphate / deficiency
  • Animals
  • Brain / pathology*
  • Electron Transport Complex I
  • Humans
  • Leigh Disease / etiology
  • Leigh Disease / genetics*
  • Leigh Disease / pathology*
  • Mutation / genetics
  • NADH Dehydrogenase / genetics

Substances

  • NDUFS1 protein, human
  • NDUFV1 protein, human
  • Adenosine Triphosphate
  • NADH Dehydrogenase
  • Electron Transport Complex I