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2-Hydroxyglutaric aciduria

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2-Hydroxyglutaric aciduria
Alpha-hydroxyglutaric acid.png
Alpha-Hydroxyglutaric acid

2-hydroxyglutaric aciduria is a rare neurometabolic disorder characterized by the significantly elevated levels of hydroxyglutaric acid in ones urine. It is either autosomal recessive or autosomal dominant.[1]


The signs/symptoms of this condition are consistent with the following:[2]


The different types of 2-hydroxyglutaric aciduria result from mutations in several genes. D-2-HGA type I is caused by mutations in the D2HGDH gene. Type II is caused by mutations in the IDH2 gene. L-2-HGA results from mutations in the L2HGDH gene. Combined D,L-2-HGA is caused by mutations in the SLC25A1 gene.

The D2HGDH and L2HGDH genes provide instructions for making enzymes that are found in mitochondria, which are the energy-producing centers within cells. The enzymes break down compounds called D-2-hydroxyglutarate and L-2-hydroxyglutarate, respectively, as part of a series of reactions that produce energy for cell activities. Mutations in either of these genes lead to a shortage of functional enzyme, which allows D-2-hydroxyglutarate or L-2-hydroxyglutarate to build up in cells. At high levels, these compounds can damage cells and lead to cell death. Brain cells appear to be the most vulnerable to the toxic effects of these compounds, which may explain why the signs and symptoms of D-2-HGA type I and L-2-HGA primarily involve the brain.

The IDH2 gene provides instructions for making an enzyme in mitochondria that normally produces a different compound. When the enzyme is altered by mutations, it takes on a new, abnormal function: production of the potentially toxic compound D-2-hydroxyglutarate. The resulting excess of this compound damages brain cells, leading to the signs and symptoms of D-2-HGA type II. It is unclear why an accumulation of D-2-hydroxyglutarate may be associated with cardiomyopathy in some people with this form of the condition.

The SLC25A1 gene provides instructions for making a protein that transports certain molecules, such as citrate, in and out of mitochondria. Mutations in the SLC25A1 gene reduce the protein's function, which prevents it from carrying out this transport. Through processes that are not fully understood, a loss of this transport allows both D-2-hydroxyglutarate and L-2-hydroxyglutarate to build up, which damages brain cells. Researchers suspect that an imbalance of other molecules, particularly citrate, also contributes to the severe signs and symptoms of combined D,L-2-HGA.


D-2-HGA type I, L-2-HGA, and combined D,L-2-HGA all have an autosomal recessive pattern of inheritance, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. D-2-HGA type II is considered an autosomal dominant disorder because one copy of the altered gene in each cell is sufficient to cause the condition. The disorder typically results from a new mutation in the IDH2 gene and occurs in people with no history of the condition in their family.



2-hydroxyglutaric aciduria is an organic aciduria, and because of the stereoisomeric property of 2-hydroxyglutarate different variants of this disorder are distinguished:

L-2-hydroxyglutaric aciduria

The L-2 form is more common, severe, and mainly affects the central nervous system. The basal ganglia are affected, and cystic cavitations in the white matter of the brain are common, beginning in infancy. This form is chronic, with early symptoms such as hypotonia, tremors, and epilepsy declining into spongiform leukoencephalopathy, muscular choreodystonia, mental retardation, and psychomotor regression.[3]

It is associated with L2HGDH, which encodes L-2-hydroxyglutarate dehydrogenase.[4] L-2-hydroxyglutarate is produced by promiscuous action of malate dehydrogenase on 2-oxoglutarate, and L-2-hydroxyglutarate dehydrogenase is an example of a metabolite repair enzyme that oxidizes L-2-hydroxyglutarate back to 2-oxoglutarate.[5]

D-2-hydroxyglutaric aciduria

The D2 form is rare, with symptoms including macrocephaly, cardiomyopathy, mental retardation, hypotonia, and cortical blindness.[6] It is caused by recessive mutations in D2HGDH[7] (type I) or by dominant gain-of-function mutations in IDH2[8] (type II).

Combined D-2- and L-2-hydroxyglutaric aciduria

The combined form is characterized by severe early-onset epileptic encephalopathy and absence of developmental progress.[9] It is caused by recessive mutations in SLC25A1 encoding the mitochondrial citrate carrier.[10]


The treatment of 2-Hydroxyglutaric aciduria is based on seizure control, the prognosis depends on how severe the condition is.[11]

See also


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