Lactic acidosis and developmental delay due to deficiency of E3 binding protein (protein X) of the pyruvate dehydrogenase complex

Pyruvate dehydrogenase complex deficiency is an inherited inborn error of metabolism causing lactic acidosis and several neurological symptoms. Its incidence and prevalence are not known. Here we report about a child with global developmental delay, central hypotonia and dyskinesia. Sanger sequencing was done and found to have homozygous nonsense mutation in exon 4 of PDHX gene causing lactic acidosis. In the next pregnancy selective Sanger variant analysis was carried out and the fetus was also found to be affected with the same genetic defect. Hence medical termination of Pregnancy was carried out. We conclude that early selective genetic testing will prevent further affected births.

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Pyruvate Dehydrogenase Complex Deficiency

10.1093/med/9780199972135.003.0006 ◽

2016 ◽

Author(s):

Mirian C. H. Janssen ◽

Shamima Rahman

Keyword(s):

Lactic Acidosis ◽

Pyruvate Dehydrogenase ◽

Neonatal Death ◽

Pyruvate Dehydrogenase Complex ◽

Leigh Syndrome ◽

Successful Therapy ◽

Complex Deficiency ◽

Benign Course ◽

Pyruvate Dehydrogenase Complex Deficiency ◽

Dehydrogenase Complex

Pyruvate dehydrogenase complex (PDHc) deficiency usually first manifests at a young age and is rarely diagnosed in adulthood. The clinical picture varies from neonatal death with overwhelming lactic acidosis to a relatively benign course early in life. The three main presentations are congenital lactic acidosis, Leigh syndrome, and episodic ataxia. Treatment consists of a ketogenic diet and cofactor supplementation with thiamine. Successful therapy is rare.

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Role of dihydrolipoyl dehydrogenase (E3) and a novel E3-binding protein in the NADH sensitivity of the pyruvate dehydrogenase complex from anaerobic mitochondria of the parasitic nematode, Ascaris suum

Molecular and Biochemical Parasitology ◽

10.1016/s0166-6851(02)00221-9 ◽

2002 ◽

Vol 125 (1-2) ◽

pp. 135-146 ◽

Cited By ~ 2

Author(s):

Sally Harmych ◽

Robin Arnette ◽

Richard Komuniecki

Keyword(s):

Pyruvate Dehydrogenase ◽

Parasitic Nematode ◽

Binding Protein ◽

Ascaris Suum ◽

Pyruvate Dehydrogenase Complex ◽

Dihydrolipoyl Dehydrogenase ◽

Dehydrogenase Complex

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Utility of specific amino acid ratios in screening for pyruvate dehydrogenase complex deficiencies and other mitochondrial disorders associated with congenital lactic acidosis and newborn screening prospects

JIMD Reports ◽

10.1002/jmd2.12153 ◽

2020 ◽

Vol 56 (1) ◽

pp. 70-81

Author(s):

Jirair K. Bedoyan ◽

Rosemary Hage ◽

Ha Kyung Shin ◽

Sharon Linard ◽

Edwin Ferren ◽

...

Keyword(s):

Amino Acid ◽

Lactic Acidosis ◽

Newborn Screening ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Complex ◽

Mitochondrial Disorders ◽

Specific Amino Acid ◽

Dehydrogenase Complex

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First prenatal diagnosis of defects in theHsPDX1 gene encoding protein X, an additional lipoyl-containing subunit of the human pyruvate dehydrogenase complex

Prenatal Diagnosis ◽

10.1002/(sici)1097-0223(199912)19:12<1160::aid-pd712>3.0.co;2-2 ◽

1999 ◽

Vol 19 (12) ◽

pp. 1160-1164 ◽

Cited By ~ 7

Author(s):

C. Rouillac ◽

B. Aral ◽

F. Fouque ◽

D. Marchant ◽

J-M. Saudubray ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Complex ◽

Gene Encoding ◽

Protein X ◽

Encoding Protein ◽

Dehydrogenase Complex

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Carbohydrate-response Element-binding Protein Deletion Alters Substrate Utilization Producing an Energy-deficient Liver

Journal of Biological Chemistry ◽

10.1074/jbc.m706540200 ◽

2007 ◽

Vol 283 (3) ◽

pp. 1670-1678 ◽

Cited By ~ 43

Author(s):

Shawn C. Burgess ◽

Katsumi Iizuka ◽

Nam Ho Jeoung ◽

Robert A. Harris ◽

Yoshihiro Kashiwaya ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Pyruvate Dehydrogenase ◽

Binding Protein ◽

Pyruvate Dehydrogenase Complex ◽

Substrate Utilization ◽

Acid Oxidation ◽

Nadh Ratio ◽

Element Binding Protein ◽

Dehydrogenase Complex

Livers from mice lacking the carbohydrate-responsive element-binding protein (ChREBP) were compared with wild type (WT) mice to determine the effect of this transcription factor on hepatic energy metabolism. The pyruvate dehydrogenase complex was considerably more active in ChREBP-/- mice because of diminished pyruvate dehydrogenase kinase activity. Greater pyruvate dehydrogenase complex activity caused a stimulation of lactate and pyruvate oxidation, and it significantly impaired fatty acid oxidation in perfused livers from ChREBP-/- mice. This shift in mitochondrial substrate utilization led to a 3-fold reduction of the free cytosolic [NAD+]/[NADH] ratio, a 1.7-fold increase in the free mitochondrial [NAD+]/[NADH] ratio, and a 2-fold decrease in the free cytosolic [ATP]/[ADP][Pi] ratio in the ChREBP-/- liver compared with control. Hepatic pyruvate carboxylase flux was impaired with ChREBP deletion secondary to decreased fatty acid oxidation, increased pyruvate oxidation, and limited pyruvate availability because of reduced activity of liver pyruvate kinase and malic enzyme, which replenish pyruvate via glycolysis and pyruvate cycling. Overall, the shift from fat utilization to pyruvate and lactate utilization resulted in a decrease in the energy of ATP hydrolysis and a hypo-energetic state in the livers of ChREBP-/- mice.

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