Pyruvate dehydrogenase (PDH) is a multienzyme complex that catalyses the oxidative decarboxylation of pyruvate to yield acetyl CoA. This is an irreversible reaction that links the pathway of glycolysis in the cytoplasm and the citric acid cycle in the mitochondrion. The enzyme is particularly important in the brain in which, under normal conditions, essentially all of the energy is derived from aerobic glucose oxidation. The complex comprises three catalytic components, PDH (E1), dihydrolipoamide acetyltransferase (E2) and dihydrolipoamide dehydrogenase (E3), and two regulatory components, E1 kinase and phospho-E1-phosphatase, together with a sixth component, E3-binding protein, which is believed to play a role in the attachment of E3 to the E2 core. The E1 enzyme is a heterotetramer of two E1 alpha subunits and two E1 beta subunits with thiamine pyrophosphate as a cofactor. The cofactor binding and catalytic sites are formed at the interface of the alpha and beta subunits.
PDH deficiency is a well defined biochemical defect that is clinically highly heterogeneous. It is one of the major causes of severe primary lactic acidosis in the newborn period and infancy but can also present as a more chronic neurodegenerative disease with extensive cerebral atrophy and structural anomalies in the brain, as Leigh syndrome or as episodic ataxia.
In Brown et al. (2004) two unrelated patients with PDH deficiency attributable to missense mutations in PDHB (= PDHBD, PDHE1-B, PHE1B) are described. Both patients presented with lactic acidosis and neurological dysfunction and had little residual PDH activity in cultured fibroblasts (PMID:15138885).
Brown et al. (2004) reported 2 unrelated patients with pyruvate dehydrogenase deficiency. The first patient, the son of first-cousin parents, was investigated at age 3 months because of lactic acidosis and hypotonia. Two previous sibs had died early, ... Brown et al. (2004) reported 2 unrelated patients with pyruvate dehydrogenase deficiency. The first patient, the son of first-cousin parents, was investigated at age 3 months because of lactic acidosis and hypotonia. Two previous sibs had died early, one with lactic acidosis. The patient developed metabolic acidosis on day 1. He required ventilation from day 3 to day 22. MRI demonstrated agenesis of the corpus callosum. At age 3 months, he showed global hypotonia and reduced reflexes. He developed severe lactic acidosis following general anesthesia for muscle biopsy and lumbar puncture. He suffered respiratory arrest but was successfully treated with ventilation and bicarbonate. The second patient, also the son of consanguineous parents, was hypotonic at birth with poor respiratory effort. He was investigated at 9 weeks of age because of continuing hypotonia, lack of visual attention, and respiratory stridor. MRI of the brain was normal. He made little developmental progress and died at 12 months of age.
In 2 unrelated patients with pyruvate dehydrogenase deficiency, Brown et al. (2004) identified homozygous mutations in the PDHB gene (179060.0001-179060.0002).