2-Hydroxyglutaric acidurias

Peter G Barth MD PhD (Dr. Barth of the University of Amsterdam has no relevant financial relationships to disclose.)
Gary D Clark MD, editor. (Dr. Clark has no relevant financial relationships to disclose.)
Originally released March 30, 1995; last updated October 6, 2016; expires October 6, 2019
Notice: This article has expired and is therefore not available for CME credit.

This article includes discussion of 2-hydroxyglutaric acidurias, D-2-hydroxyglutaric aciduria, L-2-hydroxyglutaric aciduria, D,L-2-hydroxyglutaric aciduria. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


2-hydroxyglutaric acidurias belong to organic acidurias. They represent inherited disorders, each with a 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. An overview of these disorders is provided by the author, who is the first author who presented a clinical and radiological profile of L-2-hydroxyglutaric aciduria based on serial clinical and MR studies.

Key points


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


• All 3 disorders profoundly and specifically affect development and functioning of the central nervous system.


• Causative gene defects have been found for all 3, 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 has become 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 3 distinct entities belonging to the group of genetic organic acidurias. The discovery of the first 2 of these acidurias dates back to 1980 (Chalmers et al 1980; Duran et al 1980), whereas awareness of their association with defined neurologic conditions dates from the 1990s. The first reported case of L-2-hydroxyglutaric aciduria was found in an intellectually disabled male child of consanguineous parents (Duran et al 1980). Barth and colleagues profiled the specific clinical and radiological aspects as a slowly progressive subcortical leukoencephalopathy with signal changes in the basal ganglia and cerebellar dentate nuclei (Barth et al 1992). Van der Knaap and associates first profiled clinical and neuroradiological patterns of D-2-hydroxyglutaric aciduria (Van der Knaap 1999a; Van der Knaap 1999b). Kranendijk and colleagues discovered that D-2-hydroxyglutaric aciduria was heterogenous, resulting from 2 mutated genes with different modes of inheritance (Kranendijk et al 2010). A third type, causing mixed L-2- and D-2-hydroxyglutaric aciduria, was proposed by Muntau and colleagues (Muntau et al 2000). Causative gene defects for these 3 disorders, including 2 subtypes of D-2-HGA, were discovered in recent years.

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