Alpha-ketoglutarate dehydrogenase deficiency is an autosomal recessive disorder caused by partial or total inactivation of the mitochondrial enzyme alpha-ketoglutarate dehydrogenase. Αlpha-ketoglutarate dehydrogenase is a mitochondrial Krebs cycle enzyme that catalyzes the oxidative decarboxylation of alpha-ketoglutarate to succinyl CoA, which generates NADH that directly provides electrons for the mitochondrial respiratory chain complex. Most affected infants appear normal at birth but develop hypotonia with mild motor delay in the first year of life and later become progressively hypertonic. Infants with deficient activity of dihydrolipoyl dehydrogenase develop persistent lactic acidosis followed by ketoacidotic crises with increased lactic acidemia, lethargy, vomiting, and respiratory distress. Outcomes include overall developmental delay with failure to thrive and microcephaly.
• Αlpha-ketoglutarate dehydrogenase is a mitochondrial Krebs cycle enzyme that catalyzes the oxidative decarboxylation of alpha-ketoglutarate to succinyl CoA and in so doing generates NADH, which directly provides electrons for the mitochondrial respiratory chain complex.
Historical note and terminology
Αlpha-ketoglutarate dehydrogenase (also called oxo-glutarate dehydrogenase or 2-oxoglutarate dehydrogenase) is a mitochondrial Krebs cycle enzyme that catalyzes the oxidative decarboxylation of alpha-ketoglutarate to succinyl CoA, and in so doing generates NADH, which directly provides electrons for the mitochondrial respiratory chain complex.
Alpha-ketoglutarate dehydrogenase is 1 of 3 alpha-ketoacid dehydrogenases, the others being pyruvate dehydrogenase and branched-chain ketoacid dehydrogenase. Each of these enzymes is a multiunit complex, and each complex has multiple copies of 3 functionally and genetically distinct subunits: the E1 (alpha-ketoacid dehydrogenase) and the E2 subunits (dihydrolipoyl transacetylase) are unique to each enzyme, whereas the E3 subunit (the flavoprotein dihydrolipoyl dehydrogenase or lipoamide dehydrogenase) is identical in all 3 alpha-ketoacid dehydrogenases (44). In particular, the alpha-ketoglutarate dehydrogenase enzyme complex consists of multiple copies of the following 3 subunits: alpha-ketoglutarate dehydrogenase (KGDH or E1k, EC 184.108.40.206), dihydrolipoyl succinyltransferase (DLST or E2k, EC 220.127.116.11), and dihydrolipoyl dehydrogenase (also known as dihydrolipoamide dehydrogenase; DLD or E3, EC 18.104.22.168).
Alpha-ketoglutarate dehydrogenase, fumarase, and succinate dehydrogenase are the only enzymes of the human Krebs cycle in which a single enzyme deficiency state has been defined (09; 38).
The first reported patients with isolated alpha-ketoglutarate dehydrogenase deficiency were 2 siblings born to consanguineous parents (21). Since that report, an additional 4 sibships, with a total of 7 affected individuals have been reported (04; 15; Al Aqueel et al 1994; 10). More commonly, alpha-ketoglutarate dehydrogenase deficiency has been described as a variant form of maple syrup urine disease as a result of deficiency of the E3 component, dihydrolipoyl dehydrogenase (16; 36; 47; 29; 06; 03). In the latter cases, deficiency in pyruvate dehydrogenase and branched-chain ketoacid dehydrogenase, in addition to alpha-ketoglutarate dehydrogenase deficiency exists.