Defective activation of the pyruvate dehydrogenase complex in subacute necrotizing encephalomyelopathy (Leigh disease).

Abstract:

:Autopsy examination confirmed the diagnosis of subacute necrotizing encephalomyelopathy (SNE) in a 7-month-old 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 mumoles . 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 less than 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.

journal_name

Ann Neurol

journal_title

Annals of neurology

authors

DeVivo DC,Haymond MW,Obert KA,Nelson JS,Pagliara AS

doi

10.1002/ana.410060605

keywords:

subject

Has Abstract

pub_date

1979-12-01 00:00:00

pages

483-94

issue

6

eissn

0364-5134

issn

1531-8249

journal_volume

6

pub_type

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