Sign Up for a Free Account
  • Updated 08.17.2022
  • Released 03.30.1995
  • Expires For CME 08.17.2025

Alpha-ketoglutarate dehydrogenase deficiency

Introduction

Overview

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.

Key points

• 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.

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 multiunit complex, and each complex has multiple copies of three 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 three alpha-ketoacid dehydrogenases (44). In particular, the alpha-ketoglutarate dehydrogenase enzyme complex consists of multiple copies of the following three 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 (also known as dihydrolipoamide 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 (09; 38).

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; 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.

This is an article preview.
Start a Free Account
to access the full version.

  • Nearly 3,000 illustrations, including video clips of neurologic disorders.

  • Every article is reviewed by our esteemed Editorial Board for accuracy and currency.

  • Full spectrum of neurology in 1,200 comprehensive articles.

  • Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125