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  • Updated 05.14.2024
  • Released 03.30.1995
  • Expires For CME 05.14.2027

Alpha-ketoglutarate dehydrogenase deficiency

Introduction

Overview

Alpha-ketoglutarate dehydrogenase deficiency is an autosomal recessive disorder caused by partial or total inactivation of the multisubunit mitochondrial enzyme alpha-ketoglutarate dehydrogenase. Alpha-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. 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.

Key points

• Alpha-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

Alpha-ketoglutarate dehydrogenase (also sometimes called oxo-glutarate dehydrogenase or 2-oxoglutarate dehydrogenase, although this designation specifically refers to the E1 subunit of the alpha-ketoglutarate dehydrogenase complex) is a multisubunit 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.

Kreb citric acid cycle

(Courtesy of Wikimedia Commons. Creative Commons Attribution ShareAlike 3.0 license.)

Alpha-ketoglutarate dehydrogenase is one of three alpha-ketoacid dehydrogenases, the others being pyruvate dehydrogenase and branched-chain ketoacid dehydrogenase. Each of these enzymes is a multisubunit complex, and each complex has multiple copies of three functionally and genetically distinct subunits: the E1 (alpha-ketoacid dehydrogenase or oxoglutarate 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 three alpha-ketoacid dehydrogenases (45).

The subunits of alpha-ketoglutarate dehydrogenase are: E1--oxoglutarate dehydrogenase (OGDH); E2--dihydrolipoyl succinyltransferase (DLST); and E3--dihydrolipoyl dehydrogenase (DLD).

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; 39).

The first reported patients with isolated alpha-ketoglutarate dehydrogenase deficiency were two siblings born to consanguineous parents (21). Since that report, an additional four sibships, with a total of seven affected individuals have been reported (04; 15; 01; 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; 37; 48; 30; 06; 03). In the latter cases, deficiency in pyruvate dehydrogenase and branched-chain ketoacid dehydrogenase, in addition to alpha-ketoglutarate dehydrogenase deficiency exists.

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