Loss Of GABA Transporter Function In Doose Syndrome


Loss Of GABA Transporter Function In Doose Syndrome

Normal neuronal activity depends on the fine equilibrium between the actions of excitatory neurotransmitters (eg: glutamate) and inhibitory neurotransmitters (eg: gamma-aminobutyric acid, GABA). Usually, GABA, the major inhibitory neurotransmitter, counterbalances neuronal excitation in the brain, preventing neuronal hyperexcitabilty and seizures. At the same time, in order to ensure that neuronal activity continues at the optimal level, it is critical that GABA present in the space between neurons does not accumulate or linger. In the GABA inhibitory neurons, this process is regulated by a GABA transporter, GAT-1. This transporter mediates the re-uptake of GABA back into inhibitory nerve cells.

Mutations in genes that alter various aspects of GABA signaling have been reported to cause epilepsy. Solute Carrier family 6 (SLC6A1) is the gene that encodes GAT-1 transporter. Interestingly, until now, while mutations in SLCA6 have been linked to schizophrenia, they have never been shown to cause epilepsy in humans.

A recent paper1 published in the American Journal of Human Genetics by Carvill et al., shows for the first time that mutations in SLCA61 gene can be responsible for a specific type of childhood epileptic encephalopathy, namely, epilepsy with myoclonic-atonic seizures (MAE) or Doose syndrome.

To investigate the role of SLC6A1 in the etiology of infantile or childhood epilepsies, the authors performed targeted sequencing of 644 individuals with various epileptic encephalopathies. Interestingly, they found six unique mutations in SLC6A1 among seven individuals, all of whom were suffering with epilepsy with myoclonic-atonic seizures (MAE). MAE is a rare childhood epileptic syndrome characterized by quick jerking movements and abrupt loss of muscle tone, resulting in sudden violent falls and at times, severe injuries. While functional perturbation of  genes such as SCN1A, SCN1B, GABRG2, CDH2 have been implicated in rare cases of MAE, the genetic causality has yet to be clearly established. While each of these genes likely contributes slightly to MAE etiology, they are also associated with a variety of other benign to severe epilepsies.

Based on their analysis, authors of this study suggest that SLCA61 mutations may account for ~4% of individuals with this severe epileptic syndrome and is more likely in individuals with pre-existing developmental delay. While this statistic remains to be validated in large patient populations, this study has identified SLC6A1 as the probable genetic cause for at least a fraction of MAE cases. Therefore, its potential as a therapeutic target for this subset of MAE patients needs to be explored.

1) Carvill et al., Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures. Am J Hum Genet. 2015 Apr 8. S0002-9297(15)00069-5. 

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