Pyruvate Dehydrogenase Complex Deficiency 

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. These symptoms may include developmental delay, intermittent ataxia, poor muscle tone, abnormal eye movements, or seizures. Childhood-onset forms of this disorder are often associated with intermittent periods of decompensation but normal neurological development. Therapies are suboptimal for other 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. 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.

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]

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 whose onset of pyruvate dehydrogenase complex deficiency is in childhood.

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.

Frequency

International

Pyruvate dehydrogenase complex deficiency is a rare disorder. Several hundred cases of pyruvate dehydrogenase complex deficiency have been reported. Most mutations are sporadic, and the recurrence rate is very low. The true occurrence of this disorder is unknown because mild mutations of the E1 alpha enzyme subunit gene on the X chromosome may be asymptomatic, especially in females.

Mortality/Morbidity

Individuals with neonatal-onset and infantile-onset types of pyruvate dehydrogenase complex deficiency usually die during the first years of life. 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.

Sex

Gender differences appear for dysfunction of the E1 alpha enzyme subunit, which is coded by the X chromosome. Heterozygous females can manifest severe symptoms, although males are typically affected to a much greater extent.

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 observed more commonly 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.