title: Leigh syndrome: neuropathology and pathogenesis.
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.
authors.affiliation: From the Murdoch Children's Research Institute, The Royal Children's Hospital (NJL, MJB); and Department of Paediatrics (NJL, MJB) and Center for Neural Engineering, Department of Electrical and Electronic Engineering (MJB), The University of Melbourne, Melbourne, Victoria, Australia; Research Programs Unit, Molecular Neurology Biomedicum-Helsinki (PI), University of Helsinki; and Department of Child Neurology (PI), Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland; and Department of Pathology, HUSLAB (AP), Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Lake
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bird
authors.forename: Pirjo
authors.initials: P
authors.lastname: Isohanni
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
mesh_terms: D000255:Adenosine Triphosphate / Q000172:deficiency; D000818:Animals; D001921:Brain / Q000473:pathology*; D042967:Electron Transport Complex I; D006801:Humans; D007888:Leigh Disease / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009245:NADH Dehydrogenase / Q000235:genetics
chemical_list: C487793:NDUFS1 protein, human; C112232:NDUFV1 protein, human; D000255:Adenosine Triphosphate; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I