Classification
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.[5]
It is associated with L2HGDH, which encodes L-2-hydroxyglutarate dehydrogenase.[6] 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.[7]
Combined D-2- and L-2-hydroxyglutaric aciduria
The combined form is characterized by severe early-onset epileptic encephalopathy and absence of developmental progress.[11] It is caused by recessive mutations in SLC25A1 encoding the mitochondrial citrate carrier.[12]
