Glutaric aciduria type I (GA-1) is an autosomal recessive disorder resulting from a deficiency of glutaryl-CoA-dehydrogenase (GCDH). GCDH is found in liver and kidney, but not in the brain. GA-1 patients accumulate glutaric acid (GA) and 3- Hydroxyglutaric acid (3-OHGA) in blood, urine and CSF. These compounds cross the blood-brain barrier and accumulate in the brain leading to neuronal damages. GA-1 is characterized by macrocephaly, progressive dystonia and dyskinesia, usually apparent within the first 3 years of life upon a metabolic crisis induced simply by vaccination or fever.

GA and 3-OHGA are dicarboxylates which are transported in a sodium-dependent manner. At the molecular level, three different sodium-dependent dicarboxylate transporters have been identified (NaDC1, NaDC3, NaCT). But only NaDC3 and NaCT were found in brain samples using RT-PCR (Wada et al. 2006). NaDC3 is localized in astrocytes, whereas NaCT is localized in neurons. In addition, NaDC3 and NaCT are found in cerebral cortex, kidney and liver. It is known that NaDC3, localized in astrocytes, is able to transport glutaric acid and its derivatives. NaCT is localized in neurons where damages take place in the case of GA-1. NaCT mediates the uptake of dicarboxylates because neurons lacking pyruvate dehydrogenase and therefore are unable to produce dicarboxylates. To investigate whether NaCT is able to transport GA and its derivatives, experiments were performed using hNaCT overexpressing Xenopus laevis oocytes and a two-electrode voltage clamp (TEVC) device. As measured in 13 oocytes from 4 donors, citrate (1mM) induces a depolarization of 10.6 mV (1.6 mV) and at -60 mV an inward current of -23.9 nA ( 4.3 nA). Succinate, the prototypical substrate of NaDC3, also mediates inward currents in NaCT-expressing oocytes. The amplitude of these currents, however, is smaller than the amplitude evoked by 1mM citrate. Because of this overlapping in substrate specificities in further experiments 1mM GA, 3-OHGA, D-2-Hydroxyglutaric acid (D-2-OHGA), and L-2-Hydroxyglutaric acid (L-2-OHGA) for transport by NaCT were tested.

The results show no inducible currents by GA, 3-OHGA, D- or L-2-OHGA, indicating that compounds suggested to induce neuronal damage are not transported by NaCT.