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  • Updated 05.15.2024
  • Released 03.30.1995
  • Expires For CME 05.15.2027

2-Hydroxyglutaric acidurias



2-hydroxyglutaric acidurias belong to the organic acidurias. They represent inherited disorders, each with characteristic symptomatology, MR pattern, and biochemistry. Three of these disorders have been identified: L-2-hydroxyglutaric aciduria, D-2-hydroxyglutaric aciduria, and combined L-2- and D-2-hydroxyglutaric acidurias. Their genetic basis has been largely clarified in recent years.

Key points

• L-2-hydroxyglutaric and D-2-hydroxyglutaric acids are products of the tricyclic acid (TCA) cycle with different pathways. They are waste products without metabolic function, and accumulation of these products has toxic effects. Removal of these potentially toxic acids is mediated by specific dehydrogenases.

• Three distinct disease entities are known:

- L-2-hydroxyglutaric aciduria (L-2-HGA)
- D-2-hydroxyglutaric aciduria (D-2-HGA) (two subtypes)
- Combined L-2- and D-2-hydroxyglutaric aciduria (D,L-2-HGA)

• All three disorders profoundly and specifically affect development and functioning of the central nervous system.

• Causative gene defects have been found for all three, including subtypes of D-2-hydroxyglutaric aciduria.

• Distinct neuroradiological profiles are associated with L-2- and D-2-hydroxyglutaric aciduria, allowing a presumptive diagnosis prior to metabolic and genetic testing.

• No specific treatments are available. Antenatal diagnosis through gene testing is possible.

Historical note and terminology

L-2-hydroxyglutaric aciduria (L-2-HGA), D-2-hydroxyglutaric aciduria (D-2-HGA), and mixed D-2- and L-2-hydroxygluatic aciduria (D,L-2-HGA) form three distinct entities belonging to the group of genetic organic acidurias. Two of these disorders were discovered in 1980 (16; 26), whereas awareness of their association with defined neurologic conditions began in the 1990s. The first reported case of L-2-hydroxyglutaric aciduria was found in an intellectually disabled male child of consanguineous parents (26). Barth and colleagues profiled the specific clinical and radiological aspects as a slowly progressive subcortical leukoencephalopathy with magnetic resonance signal changes in the basal ganglia and cerebellar dentate nuclei (09). Van der Knaap and associates first profiled clinical and neuroradiological patterns of D-2-hydroxyglutaric aciduria (90; 91). Kranendijk and colleagues discovered that D-2-hydroxyglutaric aciduria was heterogenous, resulting from two mutated genes with different modes of inheritance (39). A third type, causing mixed L-2- and D-2-hydroxyglutaric aciduria, was proposed by Muntau and colleagues (53). Causative gene defects for these three disorders, including two subtypes of D-2-HGA, were discovered in recent years.

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