Pyruvate dehydrogenase deficiency
Encyclopedia
Pyruvate Dehydrogenase Deficiency (PDH) is a genetic disease that involves human metabolism.
and the citric acid cycle
by transforming pyruvate into Acetyl CoA
The pyruvate dehydrogenase complex facilitates oxidative decarboxylation
, the chemical reaction between glycolysis
and the citric acid cycle
.
Deficiencies of the regulatory complex (pyruvate dehydrogenase phosphatase
) have also been investigated.
; large amounts of lactic acid
in the blood but with a normal pyruvate/lactate
ratio. Symptoms are varied, and include developmental defects (especially of the brain and nervous system), muscular spasticity
and early death.
, which is X-linked, but autosomal recessive variants also exist.
has been described.
Current research is being conducted on the viability of Dichloroacetic acid
to treat the lactic acidosis commonly accompanied by this disorder. Additionally, there is research being conducted on the viability of gene therapy for sufferers of this condition as well as many other mitochondrial defects.
Inheritance and pathophysiology
It most commonly follows an X-linked inheritance pattern, but is approximately equally prevalent in both males and females. This is because heterozygote females commonly manifest severe symptoms, an unusual situation in X-linked conditions. Due to the genes involved being essential to life, some of the genetic causes are extremely rare in the order of 1 in millions. It affects a gene which codes for a critical enzyme complex, the Pyruvate dehydrogenase complex (PDC) which links the metabolic pathways of glycolysisGlycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
and the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
by transforming pyruvate into Acetyl CoA
The pyruvate dehydrogenase complex facilitates oxidative decarboxylation
Oxidative decarboxylation
Pyruvate decarboxylation is the far from equilibrium biochemical reaction that uses pyruvate to form acetyl-CoA, releasing NADH, a reducing equivalent, and carbon dioxide via decarboxylation...
, the chemical reaction between glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
and the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...
.
Deficiencies of the regulatory complex (pyruvate dehydrogenase phosphatase
Pyruvate dehydrogenase phosphatase
pyruvate dehyrogenase phosphatase catalytic subunit 1 , also known as protein phosphatase 2C, is an enzyme that in humans is encoded by the PDP1gene...
) have also been investigated.
Presentation
PDH causes Lactic acidosisLactic acidosis
Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood accompanied by the buildup of lactate especially D-lactate, and is considered a distinct form of metabolic acidosis. The condition typically occurs when cells receive too little oxygen , for example...
; large amounts of lactic acid
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
in the blood but with a normal pyruvate/lactate
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
ratio. Symptoms are varied, and include developmental defects (especially of the brain and nervous system), muscular spasticity
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
and early death.
Genetics
PDH deficiency is most commonly linked to the alpha unit of E1Pyruvate dehydrogenase
Pyruvate dehydrogenase complex is a complex of three enzymes that transform pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the...
, which is X-linked, but autosomal recessive variants also exist.
Treatment
Use of a ketogenic dietKetogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...
has been described.
Current research is being conducted on the viability of Dichloroacetic acid
Dichloroacetic acid
Dichloroacetic acid, often abbreviated DCA, is the chemical compound with formula . It is an acid, an analogue of acetic acid, in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms. The salts and esters of dichloroacetic acid are called dichloroacetates...
to treat the lactic acidosis commonly accompanied by this disorder. Additionally, there is research being conducted on the viability of gene therapy for sufferers of this condition as well as many other mitochondrial defects.