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Pyruvate dehydrogenase deficiency: morphological and metabolic effects, creation of animal model to search for curative treatment
, 1, 12, 1, 1
Affiliations- Department of Anatomy and Neurobiology, Medical University of Gdansk, 1 Debinki Street, 80-211 Gdańsk, Poland
- Department of Clinical Anatomy, Pomeranian University in Slupsk, Poland
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Abstract
The main source of energy for brain and other organs is glucose. To obtain energy for all tissue, glucose has to come through glycolysis; then as pyruvate it is converted to acetyl-CoA by pyruvate dehydrogenase complex (PDC) and finally enters citric acid cycle. What happens when one of these stages become disturb? Mutation in genes encoding subunits of PDC leads to pyruvate dehydrogenase deficiency. Abnormalities in PDC activity result in severe metabolic and brain malformations. For better understanding the development and mechanism of pyruvate dehydrogenase deficiency the murine model of this disease has been created. Studies on a murine model showed similar malformation in brain structures as in the patients suffered from pyruvate dehydrogenase deficiency such as reduced neuronal density, heterotopias of grey matter, reduced size of corpus callosum and pyramids. There is still no effective cure for PDC-deficiency. Promising therapy seemed to be ketogenic diet, which substitutes glucose to ketone bodies as a source of energy. Studies have shown that ketogenic diet decreases lactic acidosis and inhibits brain malformations, but not the mortality in early childhood. The newest reports say that phenylbutyrate increases the level of PDC in the brain, because it reduces the level of inactive form of PDH. Experiments on human fibroblast and zebra fish PDC-deficiency model showed that phenylbutyrate is promising cure to PDC-deficiency. This review summarizes the most important findings on the metabolic and morphological effects of PDC-deficiency and research for treatment therapy.
Abstract
The main source of energy for brain and other organs is glucose. To obtain energy for all tissue, glucose has to come through glycolysis; then as pyruvate it is converted to acetyl-CoA by pyruvate dehydrogenase complex (PDC) and finally enters citric acid cycle. What happens when one of these stages become disturb? Mutation in genes encoding subunits of PDC leads to pyruvate dehydrogenase deficiency. Abnormalities in PDC activity result in severe metabolic and brain malformations. For better understanding the development and mechanism of pyruvate dehydrogenase deficiency the murine model of this disease has been created. Studies on a murine model showed similar malformation in brain structures as in the patients suffered from pyruvate dehydrogenase deficiency such as reduced neuronal density, heterotopias of grey matter, reduced size of corpus callosum and pyramids. There is still no effective cure for PDC-deficiency. Promising therapy seemed to be ketogenic diet, which substitutes glucose to ketone bodies as a source of energy. Studies have shown that ketogenic diet decreases lactic acidosis and inhibits brain malformations, but not the mortality in early childhood. The newest reports say that phenylbutyrate increases the level of PDC in the brain, because it reduces the level of inactive form of PDH. Experiments on human fibroblast and zebra fish PDC-deficiency model showed that phenylbutyrate is promising cure to PDC-deficiency. This review summarizes the most important findings on the metabolic and morphological effects of PDC-deficiency and research for treatment therapy.
Keywords
pyruvate dehydrogenase deficiency, metabolic disorders, Leigh syndrome, phenylbutyrate, ketogenic diet
About this articleTitle
Pyruvate dehydrogenase deficiency: morphological and metabolic effects, creation of animal model to search for curative treatment
Journal
Issue
Article type
Review article
Pages
191-197
Published online
2020-02-13
Page views
3249
Article views/downloads
2799
DOI
Pubmed
Bibliographic record
Folia Morphol 2020;79(2):191-197.
Keywords
pyruvate dehydrogenase deficiency
metabolic disorders
Leigh syndrome
phenylbutyrate
ketogenic diet
Authors
A. Ebertowska
B. Ludkiewicz
I. Klejbor
N. Melka
J. Moryś
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