Aspartate-Glutamate Carrier 1 (SLC25A12) Deficiency: Malate-Aspartate Shuttle Failure, Neurodevelopmental Epileptic...

Aspartate-glutamate carrier 1 (AGC1) deficiency is a rare neurometabolic disorder caused by biallelic pathogenic variants in SLC25A12. Clinically, it is characterized by early-onset developmental and epileptic encephalopathy, often associated with hypomyelination and reduced brain N-acetylaspartate. AGC1 loss reduces malate-aspartate shuttle flux, limiting cytosolic NAD⁺ regeneration and impairing neuronal redox coupling, ATP supply, and aspartate-dependent biosynthesis during brain development. We integrate human genetics with mechanistic evidence from mammalian, Drosophila melanogaster, and Saccharomyces cerevisiae models to describe conserved transport principles and species-specific regulation underlying selective central nervous system vulnerability. We review the management of AGC1 deficiency, focusing on ketogenic therapy. Published reports show reproducible seizure reduction and, in some patients, improved myelination and N-acetylaspartate. However, these responses are heterogeneous and appear to depend on the timing, duration, and stability of ketosis. Preclinical evidence suggests that β-hydroxybutyrate may contribute to metabolic support in AGC1 deficiency. Prospective studies should test disease modification using standardized endpoints plus MRI/¹H-MRS and ketosis measures.