Alpha-ketoglutarate dehydrogenase deficiency

Douglas J Lanska MD FAAN MS MSPH (Dr. Lanska of the University of Wisconsin School of Medicine and Public Health has no relevant financial relationships to disclose.)
Originally released March 30, 1995; last updated January 28, 2017; expires January 28, 2020

This article includes discussion of alpha-ketoglutarate dehydrogenase deficiency and oxo-glutarate dehydrogenase. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Historical note and terminology

Αlpha-ketoglutarate dehydrogenase (also called oxo-glutarate dehydrogenase) is a mitochondrial Krebs cycle enzyme that in conjunction with various cofactors 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.

Image: Kreb citric acid cycle

Alpha-ketoglutarate dehydrogenase is an enzyme of the Krebs cycle that catalyzes the oxidation of alpha-ketoglutarate to succinyl CoA. 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 (Smith and Robinson 2011). In particular, the alpha-ketoglutarate dehydrogenase enzyme complex consists of multiple copies of the following 3 subunits: alpha-ketoglutarate dehydrogenase (KGDH or E1k, EC 1.2.4.2), dihydrolipoyl succinyltransferase (DLST or E2k, EC 2.3.1.61), and dihydrolipoyl dehydrogenase (DLD or E3, EC 1.8.1.4).

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 (De Vivo 1994; Rustin et al 1997).

The first reported patients with isolated alpha-ketoglutarate dehydrogenase deficiency were 2 siblings born to consanguineous parents (Kohlschutter et al 1982). Since that report, an additional 4 sibships, with a total of 7 affected individuals have been reported (Bonnefont et al 1992; Guffon et al 1993; Al Aqueel et al 1994; Dunckelmann et al 2000). 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 (Haworth et al 1976; Robinson et al 1977; Taylor et al 1978; Munnich et al 1982; Cerna et al 2001). 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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