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D-2-hydroxyglutaric aciduria type I: clinically important pathways

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The enzyme hydroxyacid-oxoacid transhydrogenase (HOT) (B) oxidizes gamma-hydroxybutyric acid, a potentially toxic metabolite, to succinic semialdehyde, simultaneously reducing 2-ketoglutaric acid to D-2-OH glutaric acid. Accumulation of D-2-OH-glutaric acid due to this interconversion is normally balanced by D-2-hydroxyglutarate dehydrogenase (A). A block in A by D-2-hydroxyglutarate dehydrogenase deficiency shifts the equilibrium in B causing an accumulation of D-2-OH-glutaric acid as well as succinic semialdehyde. The latter in turn causes an increase in GABA. In D-2-hydroxyglutaric aciduria type II, there is no block at A, but accumulation of D-2-OH-glutaric acid arises from excess production due to a molecular change in mitochondrial isocitric dehydrogenase. (Adapted from: Struys EA, Verhoeven NM, Ten Brink HJ, et al. Kinetic characterization of human hydroxyacid-oxoacid transhydrogenase: relevance to D-2-hydroxyglutaric and gamma-hydroxybutyric acidurias. J Inherit Metab Dis 2005c;28(6):921-30.)