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At a glance

Pyruvate Dehydrogenase Complex Deficiency (PDHCD) is a mitochondrial disease that leads to lactic acidosis without hypoglycemia. One of the most common causes of primary lactic acidosis in children.

Synonym

Pyruvate Dehydrogenase Deficiency.

Incidence

The exact incidence is unknown, but several hundred cases have been described.

Genetic inheritance

The most common (70%) of the PDHCD affects the E1α subunit, which is inherited as an X-linked dominant disease. X-linked PDH deficiency is one of the few X-linked diseases in which a high proportion of heterozygous females have severe symptoms.

Pathophysiology

Pyruvate dehydrogenase (PDH) is an enzyme complex consisting of three catalytic subunits, pyruvate dehydrogenase (E1, a heterotetramer, α2β2), dihydrolipoamide acyltransferase (E2, a monomer), and dihydrolipoamide dehydrogenase (E3, a dimer), and two cofactors, thiamine pyrophosphate and lipoic acid. In addition, there are other subunits, E3 binding protein (E3-BP) and two complex-regulating enzymes: pyruvate dehydrogenase kinase, which inactivates the complex, and pyruvate dehydrogenase phosphatase, which reactivates the complex. The enzyme complex converts pyruvate—after it enters the mitochondria—into acetyl-CoA, one of two essential substrates (oxaloacetate being the other) in the production of citrate. PDHCD, therefore, leads to a limited production of citrate and because citrate is the first substrate in the tricarboxylic acid (citric acid or Krebs) cycle, the cycle is blocked and other metabolic pathways need to be stimulated to produce acetyl-CoA. The decreased level of energy substrates (ATP) primarily affects the central nervous system (CNS), because brain acetyl-CoA is synthesized almost exclusively from pyruvate. The most common deficiency involves the E1 subunit, a heterotetramer consisting of two alpha and two beta subunits with the defect located on the alpha subunit (E1α), which contains several serine phosphorylation sites and seems to be involved in the regulation of the whole complex. Mutations in E2, E3, and E3-BP are less often the cause for PDHCD. The enzyme defect causes more pyruvate to be metabolized to lactate and leads to lactic acidosis.

Diagnosis

The most important laboratory test for the diagnosis of a possible PDHCD is the measurement of plasma and cerebrospinal fluid (CSF) lactate and pyruvate. The combination of an otherwise unexplained lactic acidosis with early-onset neurological disease and structural brain anomalies should always include PDHCD in the differential diagnosis. In addition to pyruvate carboxylase deficiency, defects in the mitochondrial chain of electron transport or in gluconeogenesis should be considered. However, lactic acidosis in the absence of hypoglycemia does not match with a defect in gluconeogenesis, whereas a defect in the mitochondrial respiratory chain would also affect other organ systems, such as muscle, heart, liver, and kidneys. In contrast to a respiratory chain defect, the blood lactate/pyruvate ratio in PDHCD is normal and both lactate and pyruvate decrease after fasting. Specific enzyme assays are available ...

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