GABA is a major inhibitory neurotransmitter in the central nervous system. It modulates the activity of several neurotransmitters including dopamine, serotonin, and norepinephrine. GABA is synthesized in a single step from its precursor glutamate by glutamic acid decarboxylase. GABA is metabolized by successive transamination and oxidation to yield<unk><unk>  and<unk>  acid respectively via the catalyzing effects of GABA transaminase. The<unk><unk>  can be converted into either<unk>  acid by SSADH or to GHB by the enzyme<unk><unk>  reductase. The absence of SSADH leads to a 30-fold increase of GHB and a 2-4 fold increase of GABA in the brains of patients with<unk>  as compared to normal brain concentrations of the compounds. Elevations of GHB have been shown to induce spike and wave activity similar to that seen in generalized absence epilepsy in animal models as well, which has motivated researchers to increase their knowledge on the relationship between GHB and the neurological manifestations seen in<unk> . GABA acts via binding to its receptors which include the ligand gated ion channels, GABAA and GABAC and the G-protein couple receptors GABAB. The GABAB receptor has been found to be the most important of the three receptors for this disorder as it is vital in both GABA and GHB release. This receptor mediates the release through presynaptic effects through a voltage dependent inhibition of high voltage activation of calcium channels. Many experiments have been able to show that it is the increased levels of both GABA and GHB that seem to alter the function of GABAB receptor, which may further play a role in the tonic-clonic seizures that are often seen in patients with the disorder. In terms of intracellular signaling, GHB inhibits mitogen activated protein (MAP) kinase action via the GABAB receptor mechanism. MAP kinase is imperative for numerous physiological changes including regulation of cell division and differentiation, thus, down-regulation of this pathway may occur during the presence of too much GHB as found in<unk> . In 2003, Ren and Mody et al. proved that repeated exposure of GHB to MAP kinase affected myelin expression. This is a critical finding since myelin is the electrical and insulating phospholipid layer that surrounds the axons of many neurons in the brain. Proper myelination is critical for carrying electrical signals, or data, from one nerve cell to the next. When myelin becomes damaged, it can cause numerous neurological problems, many of which are seen in patients with<unk> . Thus, Ren and Mody's work in the relationship between increased levels of GHB and myelin expression may further show the significance of this pathway in terms of the neurological deficits seen in<unk> . Glutamine metabolism may also play a role in the pathophysiology of<unk> . The major ionotropic glutamine receptors include the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainite receptor. High levels of GHB have been shown to depress both the NMDA and AMPA/kainite receptor mediated functions and may also alter glutamatergic excitatory synaptic transmission as well. Decreased glutamine, coupled with elevated GABA, has also suggested disruption of the glutamine–glutamate shuttle which ultimately provides for astrocytic glutamine as a precursor for neuronal glutamate and GABA. This disruption has the potential to impair glutamate homeostasis and may lead to uncoupling of the normal balance between glutamatergic excitatory activity and GABAergic inhibition, and may be responsible for the convulsive seizures that are observed in this disorder. Finally, additional mitochondrial processes may also be affected by<unk> . Succinate<unk>  is considered a reactive carbonyl and may lead to increased oxidative stress. This stress is believed to contribute to the formation of free radicals in the brain tissue of animal models induced with<unk> , which further leads to secondary cell damage and death. Additionally, oxidative stress may be responsible for loss of striatal dopamine which may contribute to pathophysiology of the disease.
Succinic semialdehyde dehydrogenase deficiency
Pyruvate dehydrogenase deficiency
2-Methylbutyryl-CoA dehydrogenase deficiency
3-Methylcrotonyl-CoA carboxylase deficiency
Malonyl-CoA decarboxylase deficiency
Glutaminase deficiency
Pyruvate kinase deficiency
Succinyl-CoA:3-oxoacid CoA transferase deficiency