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Defective activation of the pyruvate dehydrogenase complex in subacute necrotizing encephalomyelopathy (leigh disease)
Author(s) -
Devivo Darryl C.,
Haymond Morey W.,
Obert Kathleen A.,
Nelson James S.,
Pagliara Anthony S.
Publication year - 1979
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410060605
Subject(s) - pyruvate dehydrogenase complex , oxoglutarate dehydrogenase complex , pyruvate decarboxylation , medicine , pyruvate dehydrogenase kinase , endocrinology , biochemistry , biology , chemistry , pyruvate dehydrogenase phosphatase , enzyme
Autopsy examination confirmed the diagnosis of subacute necrotizing encephalomyelopathy (SNE) in a 7‐monthold male infant who underwent several metabolic studies before death. Intermittent lactic acidemia and fumaric aciduria, an extreme hyperglycemic response to an intravenous bolus of alanine, and an elevated total body flux rate of glucose (58.4 μmoles · kg −1 · min −1 ) suggested a disturbance in the oxidative decarboxylation of pyruvate. Enzymological studies of postmortem samples revealed low nonactivated pyruvate dehydrogenase activity in liver (19.4%) and brain (53.8%). The lowest brain pyruvate dehydrogenase activities were noted in the midbrain and pontine regions. Supramaximal activation of the hepatic pyruvate dehydrogenase complex (135% of control values) occurred in vitro. Spontaneous reactivation following in vitro inactivation of the complex with adenosine triphosphate was significantly less ( p < 0.02) in the patient's samples compared to controls. The biochemical defect was not apparent in fibroblasts. These enzymological observations point to an in vivo defect in the activation mechanism of the pyruvate dehydrogenase complex as the biochemical disturbance in SNE. The findings suggest that dichloroacetate may be beneficial in treating SNE.