Molecular characteristics

Molecular characteristics
The mitochondrial solute carrier (SLC) family 25 is composed of 53 members that transport a large diversity of metabolites, nucleotides and cofactors across the inner mitochondrial membrane (IMM). These transporters are essential for mitochondria where several metabolic pathways occur including the Krebs cycle and the β-oxidation of fatty acids. More importantly, mitochondria are essential for cellular energy homeostasis synthesizing adenosine triphosphate (ATP) by oxidative phosphorylation.
The SLC25A22 gene is localized at 11p15.5 and encodes the mitochondrial glutamate carrier 1 (GC1) that catalyzes the transport of glutamate associated with a proton (H+) through the inner mitochondrial membrane (IMM). This 323 amino acids protein is highly expressed in brain, liver and pancreas.

Type of mutations
All the pathogenic variants described are bi-allelic variants (homozygous or compound heterozygous). Cell respiration and enzyme activities assays were performed on patient’s cells for some variants and showed that cells failed to oxidize glutamate, despite a functional mitochondrial respiratory chain. Twelve mutations have been described in 12 independent families. No hotspot mutation has been reported.

Suspected pathophysiologic mechanism
In the brain, GC1 is highly expressed in astrocytes, the most numerous cell types in the mammalian central nervous system (CNS). Astrocytes play critical roles in adult CNS homeostasis, provide biochemical and nutritional support to neurons and endothelial cells that form the blood-brain barrier, perform the vast majority of synaptic glutamate uptake, and maintain extracellular potassium levels constant. The specific inhibition of GC1 expression in primary culture of astrocytes results in intracellular accumulation of glutamate. This accumulation could alter glutamate homeostasis and could result in a slowing down of the extracellular glutamate clearance and leading to network hyper-excitability.

Diagnostic testing
The best way to diagnose a SLC25A22-related disorder is to sequence the gene. This gene should be systematically included in all epileptic gene panel that are performed in routine at the hospital.