eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Pyruvate Dehydrogenase Complex Deficiency

Author: Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
Coauthor(s): Paul J Benke, MD, PhD, Director of Clinical Genetics, Joe DiMaggio Children's Hospital
Contributor Information and Disclosures

Updated: Nov 6, 2009

Introduction

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. 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.

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 Media file 1).¹

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.

Clinical

History

The presentation and progression of pyruvate dehydrogenase complex (PDC) deficiency (PDCD) widely varies.

• Nonspecific but common symptoms of metabolic illnesses include the following:
  • Poor feeding
  • Lethargy
  • Rapid breathing (ie, tachypnea)
• Developmental nonspecific signs of metabolic disease include the following:
  • Mental delays
  • Psychomotor delays
  • Growth retardation
• Progressive neurologic symptoms of pyruvate dehydrogenase complex deficiency usually start in infancy but may be evident at birth or in later childhood. The following are signs of poor neurological development or degenerative lesions:
  • Poor acquisition or loss of motor milestones
  • Poor muscle tone
  • New onset seizures
  • Periods of incoordination (ie, ataxia)
  • Abnormal eye movements
  • Poor response to visual stimuli
  • Episodic dystonia: This is associated with a deficiency of the E2 subunit, whereas progressive dystonia appears to be associated with a deficiency in the E1-alpha subunit.
• Early childhood-onset pyruvate dehydrogenase complex deficiency typically presents with intermittent periods of incoordination, especially during mild illnesses.
• The following respiratory symptoms are consistent with neurological disease and severe lactic acidosis:
  • Apnea
  • Dyspnea
  • Respiratory depression
• An acute form resembling Guillain-Barré syndrome with limb weakness has recently been described.

Physical

Low Apgar scores and small for gestational age are nonspecific signs of prenatal onset. With poor feeding and lethargy out of proportion to a mild viral illness, consider metabolic disturbances, especially after bacterial infection has been ruled out.

• Neurologic
  • Hypotonia, ataxia, choreoathetosis, and progressive encephalopathy are found in children with lactic acidosis.
  • Loss of cortical material can result in a positive Babinski reflex, absent deep tendon reflexes, tremors, or spastic diplegia or quadriplegia.
  • Prenatal or postnatal microcephaly may be found.
  • Ophthalmological examination may reveal poor visual tracking, grossly dysconjugate eye movements, poor pupillary responses, and blindness.
  • Seizures vary in type from clonic-tonic to infantile spasms.
  • Episodic or progressive dystonia
• Respiratory: Intermittent hyperpnea at rest, apnea, dyspnea, Cheyne-Stokes respiration, and respiratory failure are nonspecific signs of metabolic and neurologic disease or severe acidosis.
• Dysmorphology
  • A characteristic but uncommon dysmorphology has been described for infantile-onset pyruvate dehydrogenase complex deficiency. Features include narrow forehead, frontal bossing, wide nasal bridge, long philtrum, and anteverted nostrils. Structural brain lesions have also been reported.
  • In addition, a case of X-component deficiency has been described with trigonocephaly, supranasal lipoma, hypertelorism, thin upper lip, bilateral epicanthus, upward slant of the eyes, high palate, and pectus excavatum.

Causes

• The intramitochondrial pyruvate dehydrogenase complex is composed of 3 basic substrate-processing enzymes: a protein X and 2 regulatory enzymes. Thiamine pyrophosphate and lipoic acid are important pyruvate dehydrogenase complex cofactors. Dysfunction in all 3 substrate-processing enzymes, as well as protein X and thiamine dependence of the E1 alpha enzyme, has been described; however, dysfunction of the E1 alpha enzyme subunit is most common.
• The E1 alpha subunit gene is located at Xp22.2-p22.1. More than 90 mutations of the E1 alpha enzyme subunit impair either polypeptide stability or catalytic efficiency.
• The gene for the E1 beta enzyme subunit of the pyruvate dehydrogenase complex has been mapped to 3p13-q23; an isolated deficiency in E1 beta enzyme subunit has recently been documented.
• A thiamine triphosphate synthesis inhibitor may cause pyruvate dehydrogenase complex E1 enzyme thiamine dependence in some patients who present with Leigh syndrome.
• Recently a post-translational modification in which EGFR-PTK-mediated tyrosine-phosphorylation of the E1ss protein led to enhanced ubiquitination followed by proteasome-mediated degradation has been described.²
• A deficiency of lipoic acid, the E2 enzyme cofactor, has been described.
• A deficiency of the E2 enzyme has been described.
• The gene for the X protein of the pyruvate dehydrogenase complex is located at 11p13 and has an autosomal recessive inheritance. Eleven cases of pyruvate dehydrogenase complex X protein deficiency have been documented.
• The E3 enzyme is mapped to 7q31-32 and has an autosomal recessive inheritance. The E3 enzyme is also active in the branched-chain ketoacid dehydrogenase and alpha-ketoglutarate dehydrogenase complexes.

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