SLC25A1

2-hydroxyglutaric aciduria

At least 12 mutations in the SLC25A1 gene have been found to cause a form of 2-hydroxyglutaric aciduria called combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA). This condition causes severe brain abnormalities that become apparent in early infancy.

Each of the known SLC25A1 gene mutations greatly reduces the function of the SLC25A1 protein. As a result, citrate and malate cannot be transported into and out of mitochondria, which disrupts energy production within cells. Through processes that are not fully understood, the lack of citrate and malate transport allows other compounds to build up abnormally within cells. These compounds include D-2-hydroxyglutarate and L-2-hydroxyglutarate, which at high levels 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,L-2-HGA primarily involve the brain. Researchers suspect that an imbalance of other molecules, particularly citrate, also contributes to the severe signs and symptoms of combined D,L-2-HGA