title: Hypocapnic hypothesis of Leigh disease.
abstract: Leigh syndrome (LS) is a neurogenetic disorder of children caused by mutations in at least 75 genes which impair mitochondrial bioenergetics. The changes have typical localization in basal ganglia and brainstem, and typical histological picture of spongiform appearance, vascular proliferation and gliosis. ATP deprivation, free radicals and lactate accumulation are suspected to be the causes. Hypocapnic hypothesis proposed in the paper questions the energy deprivation as the mechanism of LS. We assume that the primary harmful factor is hypocapnia (decrease in pCO2) and respiratory alkalosis (increase in pH) due to hyperventilation, permanent or in response to stress. Inside mitochondria, the pH signal of high pH/low bicarbonate ion (HCO-3) is transmitted by soluble adenyl cyclase (sAC) through cAMP dependent manner. The process can initiate brain lesions (necrosis, apoptosis, hypervascularity) in OXPHOS deficient cells residing at the LS area of the brain. The major message of the article is that it is not the ATP depletion but intracellular alkalization (and/or hyperoxia?) which seem to be the cause of LS. The paper includes suggestions concerning the methodology for further research on the LS mechanism and for therapeutic strategy.
authors.affiliation: The Children's Memorial Health Institute, Department of Pediatrics, Nutrition and Metabolic Diseases, Aleja Dzieci Polskich 20, 04-730 Warsaw, Poland. Electronic address: e.pronicka@ipczd.pl.
authors.forename: Ewa
authors.initials: E
authors.lastname: Pronicka
mesh_terms: D000138:Acidosis; D000255:Adenosine Triphosphate / Q000737:chemistry; D000472:Alkalosis, Respiratory / Q000473:pathology; D000818:Animals; D001479:Basal Ganglia / Q000503:physiopathology; D001639:Bicarbonates / Q000737:chemistry; D001784:Blood Gas Analysis; D001930:Brain Injuries / Q000473:pathology; D001933:Brain Stem / Q000503:physiopathology; D002245:Carbon Dioxide / Q000737:chemistry; D002648:Child; D000242:Cyclic AMP / Q000378:metabolism; D005609:Free Radicals / Q000737:chemistry; D005911:Gliosis / Q000503:physiopathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006985:Hyperventilation; D016857:Hypocapnia / Q000235:genetics / Q000503:physiopathology*; D000860:Hypoxia / Q000473:pathology; D007773:Lactates / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D007888:Leigh Disease / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D009154:Mutation; D011312:Pressure
chemical_list: D001639:Bicarbonates; D005609:Free Radicals; D007773:Lactates; D002245:Carbon Dioxide; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D000242:Cyclic AMP
keywords: Carbon dioxide pressure; Hypocapnia; Hypothesis; Lactate; Leigh disease; Respiratory alkalosis; Soluble adenyl cyclase