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.
The signs/symptoms of this condition are consistent with the following:
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2-hydroxyglutaric aciduria is an organic aciduria, and because of the stereoisomeric property of 2-hydroxyglutarate different variants of this disorder are distinguished:
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.
It is associated with L2HGDH, which encodes L-2-hydroxyglutarate dehydrogenase. 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.
The D2 form is rare, with symptoms including macrocephaly, cardiomyopathy, mental retardation, hypotonia, and cortical blindness. It is caused by recessive mutations in D2HGDH (type I) or by dominant gain-of-function mutations in IDH2 (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. It is caused by recessive mutations in SLC25A1 encoding the mitochondrial citrate carrier.
The treatment of 2-Hydroxyglutaric aciduria is based on seizure control, the prognosis depends on how severe the condition is.
- 2-hydroxyglutarate synthase
- 2-hydroxyglutarate dehydrogenase
- Hydroxyacid-oxoacid transhydrogenase
- Alpha-Hydroxyglutaric acid
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