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Review
. 2012 Jul;35(4):571-87.
doi: 10.1007/s10545-012-9462-5. Epub 2012 Mar 6.

Progress in understanding 2-hydroxyglutaric acidurias

Martijn Kranendijk  1 , Eduard A Struys, Gajja S Salomons, Marjo S Van der Knaap, Cornelis Jakobs
Affiliations
Review

Progress in understanding 2-hydroxyglutaric acidurias

Martijn Kranendijk et al. J Inherit Metab Dis. 2012 Jul.

Abstract

The organic acidurias D: -2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA) cause neurological impairment at young age. Accumulation of D-2-hydroxyglutarate (D-2-HG) and/or L-2-hydroxyglutarate (L-2-HG) in body fluids are the biochemical hallmarks of these disorders. The current review describes the knowledge gathered on 2-hydroxyglutaric acidurias (2-HGA), since the description of the first patients in 1980. We report on the clinical, genetic, enzymatic and metabolic characterization of D-2-HGA type I, D-2-HGA type II, L-2-HGA and D,L-2-HGA, whereas for D-2-HGA type I and type II novel clinical information is presented which was derived from questionnaires.

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Figures

Fig. 1
Fig. 1
2-hydroxyglutaric acid with a chiral center at the 2nd carbon (*)
Fig. 2
Fig. 2
Enantiomers d- and l-2-hydroxyglutaric acid (D-2-HG and L-2-HG, systemic IUPAC names included)
Fig. 3
Fig. 3
Enzymes L-malDH and HOT are responsible for production of D-2-HG and L-2-HG from 2-KG
Fig. 4
Fig. 4
Mutations reported in D2HGDH (Misra et al ; Struys et al , ; Haliloglu et al ; Kranendijk et al ; Pervaiz et al 2011)
Fig. 5
Fig. 5
D-2-HG is formed from 2-KG via HOT. D-2-HGDH catalyzes the conversion of D-2-HG to 2-KG. D-2-HG accumulates in D-2-HGA type I patients when D-2-HGDH is impaired
Fig. 6
Fig. 6
Novel IDH2-mutant gain-of-function produces D-2-HG from 2-KG in addition to production of D-2-HG via HOT. It is hypothesized that D-2-HGDH cannot fully metabolize all of the generated D-2-HG, resulting in D-2-HG accumulation in D-2-HGA type II
Fig. 7
Fig. 7
L-2-HG is formed via the non-specific interaction of L-malDH with 2-KG using NADH. The “enzyme of metabolite repair” L-2-HGDH catalyzes the interconversion of L-2-HG to 2-KG using FAD as cofactor. L-2-HG accumulates in L-2-HGA patients when L-2-HGDH is impaired
Fig. 8
Fig. 8
Diagnostic flow chart for 2-hydroxyglutaric acidurias
See this image and copyright information in PMC

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MeSH terms

Supplementary concepts