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At a glance

It is a rare neurometabolic disease caused by an increased level of hydroxyglutaric acid in the urine. It is one of the isomeric forms of the 2-hydroxyglutaric aciduria. Clinically, the D-2-hydroxyglutaric aciduria has two phenotypes, mild and severe. Affected individuals present depending on the phenotype variable clinical manifestation. The severe types include psychomotor retardation, generalized hypotonia, macrocephaly, cardiomyopathy, and cortical blindness. Other features include abnormalities of the cerebrum and seizures. The mild phenotype has variable symptomatology.


D-2-hydroxyglutaric aciduria was first described by Chalmers in 1980. The two phenotypes were subsequently identified by van der Knaap in 1999.


The D-2-hydroxyglutaric aciduria is an organic aciduria that is manifested according to its stereoisomeric property into three variants that consist of:

  • D-2-Hydroxyglutaric Aciduria: Neurometabolic disorder with two phenotypes (mild and severe). The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and, usually associated with severe cardiomyopathy. Individual affected with the severe phenotype have a short life expectancy. The mild phenotype has a more variable clinical presentation.

  • L-2-Hydroxyglutaric Aciduria: The L-2 form is more common, severe, and mainly affects the central nervous system. Clinically, it is characterized by an onset during infancy, severe muscle hypotonia, tremors, and seizures. The disease evolves into spongiform leukoencephalopathy, muscular choreodystonia, and mental retardation following a period of psychomotor deterioration.

  • Combined D-2- and L-2-Hydroxyglutaric Aciduria: Characterized by severe early-onset epileptic encephalopathy and absence of neurological developmental progress. It is caused by recessive mutations in the SLC25A1 gene, responsible in encoding the mitochondrial citrate carrier.


Incidence is unknown, but approximately 30 cases have been reported.

Genetic inheritance

It is believed inherited as autosomal recessive, presenting variable clinical expression. It is caused by recessive mutations in D-2-HGDH (Type I). Type II results from a dominant gain-of-function mutation in the IDH2 gene.


Accumulation of D-2-hydroxyglutarate (D-2-HG) and/or L-2-hydroxyglutarate (L-2-HG) in body fluids can be considered the biochemical hallmarks of these neurometabolic disorders.

Clinical aspects

The enzymatic defect causing this progressive neurometabolic disorder has not been found. D-2-Hydroxyglutaric acid is a stereoisomer of L-2-hydroxyglutaric acid and an intermediate in glutamate, 5-aminolevulinic acid, and gamma-aminobutyric acid (GABA) metabolism. Elevated levels of GABA were found in the cerebrospinal fluid of some patients with D-2-hydroxyglutaric aciduria. A mild and a severe phenotype have been reported, with a more variable clinical picture and less consistency seen on MRI findings of the mild phenotype. Regardless of the phenotype, progressive psychomotor degeneration with macrocephaly, epilepsy (hypsarrhythmia), hypotonia, cerebral and/or cerebellar atrophy with cerebellar ataxia, and mental and motor developmental delay can ...

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