Alpha-ketoglutarate dehydrogenase deficiency

Douglas J Lanska MD FAAN MS MSPH (

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health, the Medical College of Wisconsin, and IM Sechenov First Moscow State Medical University has no relevant financial relationships to disclose.

Originally released March 30, 1995; last updated November 19, 2019; expires November 19, 2022

This article includes discussion of alpha-ketoglutarate dehydrogenase deficiency, oxo-glutarate dehydrogenase deficiency, alpha-kgd deficiency, 2-ketoglutarate dehydrogenase deficiency, and oxoglutaric aciduria. 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.

Diagram of the kreb citric acid cycle 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, dihydrolipoyl succinyltransferase (DLST or E2k, EC, and dihydrolipoyl dehydrogenase (also known as dihydrolipoamide dehydrogenase; DLD or E3, EC

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; Ambrus and Adam-Vizi 2018). 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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