Pyruvate Dehydrogenase Complex Deficiency

Updated: Feb 18, 2016
  • Author: Richard E Frye, MD, PhD; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
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Overview

Background

Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism. The citric acid cycle is a major biochemical process that derives energy from carbohydrates. Malfunction of this cycle deprives the body of energy. An abnormal lactate buildup results in nonspecific symptoms (eg, severe lethargy, poor feeding, tachypnea), especially during times of illness, stress, or high carbohydrate intake.

Progressive neurological symptoms usually start in infancy but may be evident at birth or in later childhood and very rarely in adults. These symptoms may include developmental delay, intermittent ataxia, poor muscle tone, abnormal eye movements, or seizures. Childhood- and adult-onset forms of this disorder are often associated with intermittent periods of decompensation but normal or mildly delayed neurological development. Therapies are suboptimal for most forms of pyruvate dehydrogenase complex deficiency; resolution of the lactic acidosis may occur, but cessation of the underlying progressive neurological damage is rare.

The key feature of this condition is gray matter degeneration with foci of necrosis and capillary proliferation in the brainstem in many but not all patients. The group of disorders that result in this pathology are termed Leigh syndrome. Defects in one of many of the mitochondrial enzymes involved in energy metabolism may demonstrate similar brain pathology.

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Pathophysiology

Pyruvate dehydrogenase complex (PDC) converts pyruvate to acetyl-coenzyme A (CoA), which is one of the two essential substrates needed to produce citrate (see the image below). [1]

This diagram shows a simplified version of the cit This diagram shows a simplified version of the citric acid cycle and shows the enzyme deficit. The dashed line indicates the blocked pathway and the size of the arrows indicates the relative flow of products. Because pyruvate does not proceed to acetyl-coenzyme A (CoA), it is shunted to other pathways that produce lactic acid and alanine.

A deficiency in this enzymatic complex limits the production of citrate. Because citrate is the first substrate in the citric acid cycle, the cycle cannot proceed. Alternate metabolic pathways are stimulated in an attempt to produce acetyl-CoA; however, an energy deficit remains, especially in the CNS. The magnitude of the energy deficit depends on the residual activity of the enzyme.

Severe enzyme deficiencies may lead to congenital brain malformation because of a lack of energy during neural development. Morphological abnormalities occur before 10 weeks' gestation. Maldevelopment of the corpus callosum is commonly observed in those with prenatal-onset types of pyruvate dehydrogenase complex deficiency.

Progressive neurological deterioration varies in neonates with an apparently healthy brain. Hypomyelination, cystic lesions, and gliosis of the cortex or cerebellum, with gray matter degeneration or necrotizing encephalopathy, may occur in some individuals with pyruvate dehydrogenase complex deficiency, whereas a gliosis of the brainstem and basal ganglia with capillary proliferation occurs in those with Leigh syndrome. Underlying neuropathology is not usually observed in individuals with a later onset of pyruvate dehydrogenase complex deficiency.

The most common form of pyruvate dehydrogenase complex deficiency is caused by mutations in the X-linked E1 alpha gene; all other causes are due to alterations in recessive genes.

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Epidemiology

Frequency

The incidence of pyruvate dehydrogenase deficiency is not known, but it is likely to be less than 1;50,000. It may be more common than appreciated, because this condition is potentially responsible for unexplained seizures, acidosis, and developmental delays in cases in which enzyme testing is not done, as well as unexplained Leigh syndrome with demonstrable central nervous system (CNS) pathology. For X-linked cases, there is likely a 2 in 3 risk that the mother is an unexpressing carrier. For recessive cases, which are less common, there is a 1 in 4 recurrence risk. In-frame mutations of the X-linked E1 alpha gene have been shown for very mild cases. [2]

Mortality/Morbidity

Individuals with neonatal-onset and infantile-onset types of pyruvate dehydrogenase complex deficiency usually die during the first years of life. [3] Later childhood onset of the disease is usually, but not always, associated with survival into adulthood.

All children are born with some residual enzyme activity, because a complete deficiency of pyruvate dehydrogenase complex is incompatible with life. Infants with 15% or less pyruvate dehydrogenase complex activity normally do not survive the newborn period.

Pyruvate dehydrogenase complex activity greater than 25% is associated with less severe disease and is usually characterized by ataxia and mild psychomotor delay. Some therapies may extend the lives of individuals who are severely affected with pyruvate dehydrogenase complex deficiency; however, the progressive nature of the neurological deterioration results in significant morbidity.

Affected males outnumber affected females, because the most common form of the pyruvate dehydrogenase deficiency is X-linked, Some female carriers may have mild symptoms. There is a wide range of presentation in the recessive forms of the disease, but most are milder than the X-linked form of the disease.

Race

Pyruvate dehydrogenase deficiency does not appear to have a predilection for race/ethnicity.

Sex

Males are more commonly affected than females, because the most common form of the pyruvate dehydrogenase deficiency, that of the E1 alpha enzyme subunit, is X-linked, Some female carriers have mild to moderate symptoms because of variable X-chromosome inactivation. There is a wide range of presentation in the recessive forms of the disease, but many are equally as severe as the X-linked form of the disease.

West syndrome is more common in females with pyruvate dehydrogenase complex deficiency. Severe lactic acidosis with early demise and Leigh syndrome are more commonly observed in males with pyruvate dehydrogenase complex deficiency. Progressive neurological degeneration is also observed in females with pyruvate dehydrogenase complex deficiency.

Age

Age of presentation varies from prenatal to early childhood and depends on the residual activity of the pyruvate dehydrogenase complex. Individuals with severe disease have prenatal onset with structural brain abnormalities. Moderate disease presents in infants as psychomotor delay. Individuals with less severe disease usually present in early childhood with intermittent lethargy or ataxia.

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